23 January 2018: Review Paper
Pharmacokinetic Drug–Drug Interactions Between Immunosuppressant and Anti-Infective Agents: Antimetabolites and Corticosteroids
Edward T. Van Matre ADEF 1, Gowri Satyanarayana E 2, Robert L. Page 2nd AEF 1, Marilyn E. Levi EF 3, JoAnn Lindenfeld AEF 4, Scott W. Mueller AEF 1
DOI: 10.12659/AOT.906164
Ann Transplant 2018; 23:66-74
23 January 2018: Review Paper
Pharmacokinetic Drug–Drug Interactions Between Immunosuppressant and Anti-Infective Agents: Antimetabolites and Corticosteroids
Edward T. Van Matre ADEF 1, Gowri Satyanarayana E 2, Robert L. Page 2nd AEF 1, Marilyn E. Levi EF 3, JoAnn Lindenfeld AEF 4, Scott W. Mueller AEF 1
DOI: 10.12659/AOT.906164
Ann Transplant 2018; 23:66-74
Abstract
ABSTRACT: Infections account for 15–20% of deaths in transplant recipients, requiring rapid and appropriate therapeutic interventions. Many anti-infective agents interact with immunosuppressive regimens used in transplantation, placing patients at increased risk for adverse drug reactions and prolonged hospitalizations. There is established data regarding the level of evidence and magnitude of interactions between calcineurin inhibitors and mammalian target of rapamycin inhibitors with anti-infective agents. Less is known about the interactions with anti-proliferative agents and corticosteroids, with gaps in knowledge on the appropriate management of these interactions. The objective of this review was to highlight the pharmacokinetic drug–drug interactions between antimetabolites and corticosteroids with commonly used anti-infective agents.
Keywords: Anti-Infective Agents, Antimetabolites, Drug Interactions, corticosteroids
Background
Infections remain a significant complication after solid organ transplantation (SOT). Use of various induction regimens, administration of novel immunosuppressive agents, and incorporation of newer prophylactic strategies continue to change the spectrum and severity of infections in SOT recipients [1]. Corticosteroids and anti-proliferative agents, azathioprine (AZA), and mycophenolic acid (MPA) are cornerstone therapies for rejection prevention in patients undergoing SOT [2]. Corticosteroids are utilized for immunosuppression induction to prevent acute rejection, and for chronic anti-rejection maintenance therapy. Anti-proliferative agents are primarily utilized for anti-rejection maintenance prophylaxis [2]. The use of these treatments in conjunction with specific antimicrobial agents introduces the potential for drug–drug interactions. This review highlights clinically important pharmacokinetic interactions between these classes of immunosuppressants and select antimicrobials, focusing on mechanisms, magnitude of effects, and management strategies.
Interactions with Antimetabolites
In general, long-term data demonstrating a decrease in the risk of rejection and improved survival with mycophenolate mofetil (MMF) compared with AZA has prompted many transplant centers to replace routine use of AZA with MMF [3–6]. Azathioprine is a prodrug converted rapidly by plasma esterases or non-enzymatically via glutathione to 6-mercaptopurine, which is further converted to thioinosine-monophosphate, its active metabolite. Only about 10% of AZA is eliminated as unchanged drug in the urine. The majority of AZA’s metabolism is based on plasma esterases or non-enzymatic processes [2].
Antivirals
RIBAVIRIN:
Ribavirin is a nucleoside analogue, which inhibits viral replication of a wide spectrum of RNA and DNA viruses. In solid organ transplant patients, ribavirin is utilized for the treatment of patients infected with hepatitis C (HCV), respiratory syncytial virus, and other viral infections [7–9]. Ribavirin has a well-established inhibitory effect on inosine monophosphate dehydrogenase (IMPDH). This enzyme is key to the metabolism of AZA. Inhibition of IMPDH leads to an increase in 6-methyl-thioinosine monophosphate, which has been associated with myelotoxicity [10].
Several case reports have described patients with normal thiopurine methyltransferase genotype, and who received chronic AZA treatment and developed severe pancytopenia resulting in the discontinuation of ribavirin and AZA [11,12]. A case series of eight patients on AZA treated for HCV with ribavirin showed significant pancytopenia with a mean cell count nadir of 4.6±1.6 weeks following initiation of ribavirin. Three of the patients underwent bone marrow aspiration and were found to be profoundly hypocellular. Following the withdrawal of ribavirin and AZA, full blood count recovery was seen at 5±1 week and hematologic toxicity was not seen following reintroduction of ribavirin or AZA alone in any patient. Within the case series, two patients’ plasma concentrations of methylated derivatives and 6-thioguanine nucleotide were evaluated. From baseline to cell count nadir there was an average threefold increase in methylated derivatives plasma concentration and 44% reduction in plasma 6-thioguanine nucleotide concentrations [13]. The concomitant use of AZA and ribavirin should be avoided given the significant risks for pancytopenia.
Mycophenolate mofetil is a 2-morpholinoethyl ester prodrug, with a complex metabolism pathway (Figure 1). After absorption from the stomach, MMF is rapidly hydrolyzed by esterases to its active metabolite MPA. This represents the first MPA peak plasma concentration. Once in the liver, MPA is metabolized primarily by uridine diphosphate-glucuronosyltransferases (UGTs), specifically UGT1A9, to form MPA’s phenolic glucuronide metabolite, MPAG, which is devoid of pharmacologic activity. MPAG is excreted via renal mechanisms as well as into the bile and ultimately into the distal small bowel and colon [14]. Colonic and intestinal gram-negative aerobic and anaerobic flora produce β-glucuronidase, which cleaves MPAG’s glucuronide conjugate converting it back to MPA. Once de-conjugated, MPA may be reabsorbed back into the circulation [15]. The biliary excretion of MPAG and the subsequent MPA enterohepatic recirculation involve several transport mechanisms including P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP), and multi-drug resistant protein 2 (MRP2) [16]. This recirculation results in MPA’s second peak plasma concentration and may account for as much as 40% of the MPA exposure measured by the area under the curve (AUC) [14].
While a limited number of pharmacokinetic drug–drug interactions have been reported with MMF, potential mechanisms involve alterations in absorption or enterohepatic recycling, competition of renal tubular excretion of MPAG, and changes in UGT activity [17]. Although antiretroviral and HCV therapies can influence these pathways, no pharmacokinetic drug interactions have been reported to date. A pharmacokinetic analysis of MMF before, during, and after treatment with ombitasvir, paritaprevir/ritonavir and dasabuvir found no significant changes in MPA concentrations [18]. Regardless, caution and clinical monitoring is prudent when co-administering MMF with antivirals that may influence MPA elimination pathway.
Antibiotics and Alteration of Intestinal Flora
Oral antibiotics, including fluoroquinolones, metronidazole, and amoxicillin-clavulanate, can inhibit or eliminate normal intestinal bacterial flora, which express enzymes responsible for MPAG de-glucuronidation, leading to alterations in MPA levels (Table 1). Two case reports showed a 39% and 63% drop in MPA AUC with amoxicillin-clavulanate and a doubling of the MPA exposure five days following the discontinuation of amoxicillin-clavulanate [19]. While use of oral fluoroquinolones have resulted in decreased MPA levels secondary to destruction of normal intestinal flora, further interruption of the pathway converting MPAG to MPA has been shown,
Anti-Tubercular Agents
Rifampin is a potent inducer of cytochrome P450 (CYP) 3A4, P-gp, monoamine oxidase B, and glutathione S-transfereases. Rifampin increases UGT expression, particularly intestinal UGT1A7 and UGT1A8, as well as hepatic and intestinal UGT1A9, which accounts for 55% of MPAG production [23–25]. Rifampin induces MRP2 and P-gp, which are responsible for MPAG’s biliary and renal excretion, as well as MPA’s enterohepatic recirculation [24,25].
One case report showed a three-fold increase in MMF dosing was needed to maintain a MPA concentration of 2.5 mcg/mL following rifampin administration [26]. The corresponding dose-corrected 12 hour MPA AUC increased 221% while MPA total body clearance decreased by 68.9% after rifampin discontinuation [26]. These findings may have been due to intestinal, hepatic, and renal UGT1A9 augmentation, increased renal MRP2, and possible interruption of intestinal flora. Rifampin may increase MPAG levels in the circulation and gut lumen, subsequently increasing renal elimination, and ultimately reducing MPA reabsorption from the distal gut [26,27].
Antifungals
ISAVUCONAZOLE:
Isavuconazole is second-generation triazole indicated for the treatment of invasive aspergillosis and mucormycosis infections. A prospective pharmacokinetic interaction study of 22 patients evaluated interactions between isavuconazole and MMF [28]. Isavuconazole increased MPA mean AUC0–∞ by 35% and decreased Cmax by 11%. Conversely, MPAG mean AUC0–∞ decreased by 24% and Cmax decreased by 32%. Isavuconazole pharmacokinetics were largely unchanged with the addition of MMF.
Isavuconazole’s secondary metabolism is mediated in part by the UGT pathway and is also a mild inhibitor of this pathway. The increased MMF exposure in conjunction with isavuconazole administration is likely the result of the inhibition of the UGT pathway. Effects of other antifungal agents on MMF concentrations are not reported but are unlikely due to the lack of interaction with the UGT pathway [29]. A dose reduction of MMF by 25% and/or close monitoring for signs and symptoms of toxicity are reasonable approaches when administering isavuconazole.
Corticosteroids
Corticosteroids may undergo 6β-hydroxylation via the CYP3A4 metabolic pathway, and are inducers of MRP2, as well as substrates, inhibitors, and inducers of OATP and P-gp [16]. Detection of pharmacokinetic interactions with corticosteroids is difficult as serum concentrations are not routinely measured and patients are often receiving concomitant inhibitors and/or inducers of drug transporters and CYP enzymes. Therefore, potential interactions are derived from pharmacokinetic studies conducted in non-SOT patients or healthy volunteers.
Prednisone and methylprednisolone are the two most commonly used synthetic corticosteroids in SOT recipients [2]. While structurally similar, differences exist. Prednisone is an inactive prodrug, converted through first pass metabolism to the active drug, prednisolone. While methylprednisolone is active, it differs from prednisolone by the presence of a methyl group at the 6α position and a hydrogen-bond donor at position C-11. These minor structural modifications enhances its P-gp affinity and cellular efflux, increasing its susceptibility to pharmacokinetic drug–drug interactions [23,30].
Anti-Fungal Agents
FLUCONAZOLE:
Although pharmacokinetic confirmation is lacking, an Addisonian crisis has been reported after discontinuation of prophylactic fluconazole in a liver transplant patient taking prednisone [31]. One large tertiary care hospital investigated the clinical impact of combination of fluconazole with prednisone. The study found 70.3% (n=2,941) of patients prescribed an azole experienced a potential drug interaction. The most common potential interaction was of fluconazole with prednisone (n=745) [32]. No steroid related adverse events were noted by chart review, with 47 patients administered fluconazole with prednisone, suggesting little clinical significance of this interaction at commonly prescribed doses; however, monitoring for signs and symptoms of an interaction when initiating or discontinuing fluconazole in the setting of a steroid is warranted.
KETOCONAZOLE:
One study reported that six healthy participants who were given ketoconazole 200 mg/day for six days had decreased intravenous (IV) methylprednisolone clearance by 60% and increased the AUC by 135%, leading to a reduced 24-hour cortisol AUC [33]. In a follow-up study, eight healthy participants were given IV methylprednisolone (15 or 30 mg) alone, then they were given ketoconazole 200 mg daily for seven days, and showed oral methylprednisolone clearance decreased by 46% with the administration of ketoconazole, leading to recommendations for a 50% reduction in methylprednisolone dose when used in conjunction with ketoconazole [34].
In a similar study involving four healthy participants, ketoconazole 200 mg/day for six days did not significantly alter prednisolone pharmacokinetics after administration of oral prednisone at 20 mg. No significant changes were noted in renal excretion of prednisone or prednisolone. In addition, 24 hour cortisol AUC ratios (with prednisone: baseline) were not significantly altered with ketoconazole administration [35]. This was confirmed in a subsequent study evaluating six healthy volunteers receiving IV prednisolone (14.8 mg) after six days of ketoconazole 200 mg daily [36].
In contrast, Zurcher et al. evaluated 10 healthy participants receiving ketoconazole at 200 mg/day for seven days with oral prednisone (0.8 mg/kg) and IV prednisolone (0.8 mg/kg) on separate occasions, and showed a two-fold decrease in urinary excretion of 6-beta-OH-prednisolone in all participants suggesting ketoconazole inhibits 6-beta-hydroxylase, a major metabolism pathway of prednisolone. In addition, the ratio of 6-beta-OH-cortisol/17-OH-corticosteroids declined by more than 50%. However, AUC ratios of prednisolone/prednisone after oral prednisone and IV prednisolone were found to be independent of ketoconazole suggesting the conversion of prednisone to prednisolone is not affected by ketoconazole. Therefore, it was concluded that ketoconazole increases exposure to prednisolone [37]. There is insufficient evidence for empiric dose reduction with concomitant use of ketoconazole and prednisone or prednisolone. Clinicians should monitor for steroid-related adverse effects.
ITRACONAZOLE:
Being a potent CYP3A4 inhibitor, itraconazole has been shown to inhibit metabolism of both oral and IV methylprednisolone. In a double-blind, placebo-controlled crossover study, 10 healthy individuals received itraconazole at 200 mg (or placebo) orally for four days, then 16 mg of oral methylprednisolone. Oral methylprednisolone AUC increased 3.9-fold, Cmax 1.9-fold, and half-life 2.4-fold following itraconazole when compared to placebo. This led to mean cortisol plasma levels of only 13% when compared to methylprednisolone alone [38]. In a similar study design, itraconazole increased IV methylprednisolone total AUC 2.6-fold, 12–24 hour AUC 12.2-fold, half-life from 2.1 to 4.8 hours and decreased clearance by 60%. This led to morning cortisol level reduction by 91% when compared to methylprednisolone alone [39]. This interaction was again confirmed in a study of 14 healthy males receiving oral methylprednisolone at 48 mg, then prednisone at 60 mg after a washout period with and without four days of itraconazole (400 mg on day one, then 200 mg daily for three days). The study showed itraconazole increased methylprednisolone 24 hour AUC, Cmax, and half-life by 2.5, 1.6, and 1.7-fold, respectively [40]. Furthering this point, the effect of itraconazole at 200 mg twice daily on methylprednisolone (12 mg orally) pharmacokinetics resulted in case reports of patient harm [41]. A dose reduction of 50% in methylprednisolone should be considered when starting itraconazole.
In a similar study design, only small changes in measured prednisolone AUC, Cmax, or half-life were observed following prednisone administration with or without itraconazole [40]. Contradictory to these findings, Varis et al. evaluated itraconazole at 200 mg daily for four days on 20 mg of oral prednisolone pharmacokinetics in 10 healthy participants in a double-blind placebo-controlled crossover study. Itraconazole statistically significantly increased prednisolone total AUC by 24% and half-life by 29% compared to placebo. This related to a statistically significant decrease in mean morning cortisol concentrations by 27% compared to placebo. The study authors concluded that though statistically different, these relatively small changes in prednisolone pharmacokinetics may not be clinically relevant [42]. Taken together, the effect of itraconazole on prednisolone pharmacokinetics may be less pronounced than the effect of methylprednisolone.
In a double-blind crossover study of eight health patients, itraconazole 200 mg daily for four days increased oral dexamethasone AUC, Cmax, and half-life by 3.7 fold, 1.7 fold, and 2.8 fold, respectively. Intravenous dexamethasone AUC and half-life increased by 3.3 fold and 3.2 fold, respectively; whereas, systemic clearance decreased by 68% when given with itraconazole. Morning cortisol concentrations where significantly lower at 47 hours and 71 hours after both oral and IV dexamethasone administration with itraconazole compared to the same dose of dexamethasone and four days of placebo [43]. The combination of dexamethasone and itraconazole may result in prolonged steroid-related adrenal suppression.
Administration of voriconazole and posaconazole may result in similar drug interactions since inhibition of similar CYP enzymes are expected. Monitoring for steroid related side-effects is warranted when using these combinations.
ISAVUCONAZOLE:
A prospective pharmacokinetic interaction study of 20 patients evaluated interactions between isavuconazole at 200 mg three times daily for two days followed by 200 mg daily, and prednisone at 20 mg once on day 9, found no clinically significant changes in prednisolone mean AUC0–∞ or Cmax [28]. The Cmax of isavuconazole was increased by approximately 26% and the AUCτ was unchanged. No dose adjustments for prednisone or isavuconazole are anticipated with concomitant use based on this study.
ANTI-TUBERCULAR AGENTS:
Rifampin increases the metabolism of cortisol, thereby [44] lowering prednisolone AUC by 66% and increasing clearance by 45% [45]. In another study, rifampin significantly decreased the plasma half-life and bioavailability of prednisolone in patients with asthma. Even with dose increases of 93% of prednisolone, asthma control remained inferior. One patient was withdrawn from the study due to poor asthma control after a five-fold increase in prednisolone dose [46].
Other case reports of harm occurring due to loss of steroid efficacy with rifampin range in diseases such as nephrotic syndrome, giant cell arteritis, immunosuppression for renal transplant, and asthma [47–50]. A pharmacokinetic study of two patients with giant cell arteritis treated with prednisone and rifampin found that prednisolone clearance increased by greater than 200% and half-life decreased by 40% to 60% compared to prednisolone administration without rifampin. Authors suggest a doubling of prednisone dose when used with rifampin [48]. Though not as well characterized, a similar interaction between rifampin and methylprednisolone would be expected. In a case of a methylprednisolone dependent asthmatic patient, asthma control was lost after rifampin was added, leading to an ineffective switch to prednisone. Only discontinuation of rifampin restored good asthma control [51]. Monitoring for signs of steroid failure when rifampin is added to medication regimens of patients with steroid dependent conditions is necessary, with the potential for development of rejection and graft failure if immunosuppressive doses are not adequately adjusted. Though an alternative agent such as rifabutin may also interact with steroids, reports of specific drug–drug interactions are lacking.
In one study of single dose prednisolone and weekly dose isoniazid, prednisolone was shown to significantly decrease isoniazid plasma concentrations in slow and rapid acetylators by 25% and 40%, respectively, as increased renal clearance of isoniazid after prednisolone administration was observed in both groups [52].
Macrolides
Given the frequent combination of macrolide and steroid use in asthma, much of the data regarding macrolide interaction with steroids comes from the asthma literature. Macrolides are considered to be “steroid-sparing” agents in patients with asthma due, in part, to their inhibition of P-gp and CYP3A4 [53]. In six patients with asthma, oral erythromycin significantly decreased mean IV methylprednisolone clearance by 46% (
Antivirals
RITONAVIR:
Ritonavir is commonly utilized in combination for the treatment of HCV and human immunodeficiency virus (HIV). Although ritonavir has antiviral activity, it is often utilized as a “booster” for other medications contained within the treatment regimen [9,56]. Ritonavir exhibits this effect through inhibition of CYP enzymes increasing the area under the cure for the active antiviral agents. There have been greater than 30 cases of Cushing’s syndrome and/or secondary adrenal insufficiency secondary to administration of orally or nasally inhaled fluticasone in combination with ritonavir utilized for HIV or HCV treatment [57–59]. In a study of 18 healthy individuals who received fluticasone propionate nasal spray (200 mcg daily) and ritonavir (100 mg twice daily) for seven day increased the fluticasone AUC by 350-fold and increased the Cmax by 25-fold compared to baseline. These pharmacokinetic effects resulted in an 86% reduction in plasma cortisol AUC levels [56]. Cushing’s syndrome and/or secondary adrenal insufficiency has also been observed in patients who have received intra-articular, intramuscular, and epidural triamcinolone injections [60–64].
The pharmacokinetic effects of ritonavir (200 mg twice daily) on prednisone (20 mg once) were evaluated in 10 healthy individuals at day 4 and day 14. The AUC for the active metabolite prednisolone increased from baseline by 37% on day 4 and 28% on day 14. The half-life was increased by approximately one hour and there were no differences between Cmax and Tmax observed [65]. A pharmacokinetic evaluation of inhaled beclomethasone (160 mcg twice daily) and ritonavir (100 mg twice daily) in 20 healthy individuals demonstrated a statically significant increase of 223% in the AUC of 17-monopropionate, beclomethasone’s active metabolite. Despite this significant increase, there was not a significant reduction in serum cortisol levels seen [66]. There is sufficient evidence to recommend the avoidance of use of corticosteroids with significant CYP3A4 metabolism, such as fluticasone and triamcinolone, in combination with ritonavir due to the risk of Cushing’s syndrome and adrenal suppression. Alternative steroids, such as beclomethasone and prednisone, should be utilized and a reduction of 25% should be considered for long-term therapy. While other protease inhibitors (e.g., boceprevir, simeprevir, and telaprevir) pharmacokinetic and dynamic effects on corticosteroids have not specifically been evaluated, many possess CYP3A4 inhibitory properties and signs and symptoms of Cushing’s syndrome and adrenal suppression should be evaluated in these patients.
COBICISTAT:
Cobicistat is a potent CYP3A4 inhibitor utilized as a “booster” in the management of HIV. A case report of a 39-year-old man utilizing fluticasone nasal drops (800 mcg twice daily) initiated on HIV therapy containing cobicistat, demonstrated adrenal suppression and morning cortisol < 50 nmol/L. The nasal drops were transitioned to beclomethasone nasal spray and the man’s morning cortisol levels rebounded to 149 nmol/L six weeks later [67]. This is currently the only case report of adrenal suppression with cobicistat. Due to cobicistat’s pharmacologic properties intended to create advantageous pharmacokinetic interactions, similar recommendations to avoid corticosteroids metabolized by CYP3A4 and dose reduce or monitor for side effects, similar to ritonavir, should be followed when using corticosteroids.
Conclusions
Interactions of immunosuppressants with specific antimicrobials agents may result in high levels of immunosuppressants leading to toxicity, or sub-therapeutic levels leading to graft rejection. Many untoward interactions can be prevented by substitution of alternative anti-infective agents or by judicious adjustments in immunosuppressant dosing after considering known effects of anti-infective agents. There are two keys to success in this approach: cognizance by all clinicians caring for the SOT recipient and continued education of the patient regarding the potential for drug interactions that may affect their overall immunosuppression.
References
1. Fishman JA, Infection in organ transplantation: Am J Transplant, 2017; 17(4); 856-79, pmid: 28117944
2. Lindenfeld J, Miller GG, Shakar SF, Drug therapy in the heart transplant recipient: Part II: Immunosuppressive drugs: Circulation, 2004; 110(25); 3858-65, pmid: 15611389
3. Kobashigawa JA, Meiser BM, Review of major clinical trials with mycophenolate mofetil in cardiac transplantation: Transplantation, 2005; 80(2 Suppl); S235-43, pmid: 16251856
4. Eisen HJ, Kobashigawa J, Keogh A, Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients: J Heart Lung Transplant, 2005; 24(5); 517-25, pmid: 15896747
5. Germani G, Pleguezuelo M, Villamil F, Azathioprine in liver transplantation: A reevaluation of its use and a comparison with mycophenolate mofetil: Am J Transplant, 2009; 9(8); 1725-31, pmid: 19538488
6. Wagner M, Earley AK, Webster AC, Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients: Cochrane Database Syst Rev, 2015(12); Cd007746, pmid: 26633102
7. Pelaez A, Lyon GM, Force SD, Efficacy of oral ribavirin in lung transplant patients with respiratory syncytial virus lower respiratory tract infection: J Heart Lung Transplant, 2009; 28(1); 67-71, pmid: 19134533
8. Vu DL, Bridevaux PO, Aubert JD, Respiratory viruses in lung transplant recipients: A critical review and pooled analysis of clinical studies: Am J Transplant, 2011; 11(5); 1071-78, pmid: 21521473
9. AASLD/IDSA HCV Guidance Pane, Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus: Hepatology, 2015; 62(3); 932-54, pmid: 26111063
10. Gish RG, Treating HCV with ribavirin analogues and ribavirin-like molecules: J Antimicrob Chemother, 2006; 57(1); 8-13, pmid: 16293677
11. Chaparro M, Trapero-Marugan M, Moreno-Otero R, Gisbert JP, Azathioprine plus ribavirin treatment and pancytopenia: Aliment Pharmacol Ther, 2009; 30(9); 962-63, pmid: 19807727
12. Thevenot T, Mathurin P, Moussalli J, Effects of cirrhosis, interferon and azathioprine on adverse events in patients with chronic hepatitis C treated with ribavirin: J Viral Hepat, 1997; 4(4); 243-53, pmid: 9278222
13. Peyrin-Biroulet L, Cadranel JF, Nousbaum JB, Interaction of ribavirin with azathioprine metabolism potentially induces myelosuppression: Aliment Pharmacol Ther, 2008; 28(8); 984-93, pmid: 18657132
14. Kelly P, Kahan BD, Review: Metabolism of immunosuppressant drugs: Current Drug Metab, 2002; 3(3); 275-87
15. Sperker B, Backman JT, Kroemer HK, The role of beta-glucuronidase in drug disposition and drug targeting in humans: Clin Pharmacokinet, 1997; 33(1); 18-31
16. Christians U, Strom T, Zhang YL, Active drug transport of immunosuppressants: New insights for pharmacokinetics and pharmacodynamics: Ther Drug Monit, 2006; 28(1); 39-44, pmid: 16418692
17. Bullingham RE, Nicholls AJ, Kamm BR, Clinical pharmacokinetics of mycophenolate mofetil: Clin Pharmacokinet, 1998; 34(6); 429-55, pmid: 9646007
18. Lemaitre F, Ben Ali Z, Tron C, Managing drug–drug interaction between ombitasvir, paritaprevir/ritonavir, dasabuvir, and mycophenolate mofetil: Ther Drug Monit, 2017; 39(4); 305-7, pmid: 28700519
19. Ratna P, Mathew BS, Annapandian VM, Pharmacokinetic drug interaction of mycophenolate with co-amoxiclav in renal transplant patients: Transplantation, 2011; 91(6); e36-38, pmid: 21383599
20. Kodawara T, Masuda S, Yano Y, Inhibitory effect of ciprofloxacin on beta-glucuronidase-mediated deconjugation of mycophenolic acid glucuronide: Biopharm Drug Dispos, 2014; 35(5); 275-83, pmid: 24615849
21. Naderer OJ, Dupuis RE, Heinzen EL, The influence of norfloxacin and metronidazole on the disposition of mycophenolate mofetil: J Clin Pharmacol, 2005; 45(2); 219-26, pmid: 15647415
22. Naderer OJ, Dupuis RE, Wiwattanawongsa K, Reduction of plasma mycophenolic acid (MPA) andits glucouronide (MPAG) concentrations with antibiotic treatment [abstract]: Clin Pharmacol Ther, 1999; 65(2); 159
23. Picard N, Ratanasavanh D, Premaud A, Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism: Drug Metab Dispos, 2005; 33(1); 139-46, pmid: 15470161
24. Rae JM, Johnson MD, Lippman ME, Flockhart DA, Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: Studies with cDNA and oligonucleotide expression arrays: J Pharmacol Exp Ther, 2001; 299(3); 849-57, pmid: 11714868
25. Magnarin M, Morelli M, Rosati A, Induction of proteins involved in multidrug resistance (P-glycoprotein, MRP1, MRP2, LRP) and of CYP 3A4 by rifampicin in LLC-PK1 cells: Eur J Pharmacol, 2004; 483(1); 19-28, pmid: 14709322
26. Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y, Drug interaction between mycophenolate mofetil and rifampin: Possible induction of uridine diphosphate-glucuronosyltransferase: Clin Pharmacol Ther, 2005; 78(1); 81-88, pmid: 16003296
27. Barau C, Barrail-Tran A, Hemerziu B, Optimization of the dosing regimen of mycophenolate mofetil in pediatric liver transplant recipients: Liver Transpl, 2011; 17(10); 1152-58, pmid: 21695772
28. Groll AH, Desai A, Han D, Pharmacokinetic assessment of drug–drug interactions of isavuconazole with the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults: Clin Pharmacol Drug Dev, 2017; 6(1); 76-85, pmid: 27273343
29. Rybak JM, Marx KR, Nishimoto AT, Rogers PD, Isavuconazole: Pharmacology, pharmacodynamics, and current clinical experience with a new triazole antifungal agent: Pharmacotherapy, 2015; 35(11); 1037-51, pmid: 26598096
30. Szefler SJ, Glucocorticoid therapy for asthma: Clinical pharmacology: J Allergy Clin Immunol, 1991; 88(2); 147-65, pmid: 1880315
31. Tiao GM, Martin J, Weber FL, Addisonian crisis in a liver transplant patient due to fluconazole withdrawal: Clin Transplant, 1999; 13(1 Pt 1); 62-64, pmid: 10081637
32. Yu DT, Peterson JF, Seger DL, Frequency of potential azole drug–drug interactions and consequences of potential fluconazole drug interactions: Pharmacoepidemiol Drug Saf, 2005; 14(11); 755-67, pmid: 15654717
33. Glynn AM, Slaughter RL, Brass C, Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion: Clin Pharmacol Therap, 1986; 39(6); 654-59, pmid: 3709030
34. Kandrotas RJ, Slaughter RL, Brass C, Jusko WJ, Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol: Clin Pharmacol Therap, 1987; 42(4); 465-70, pmid: 3311551
35. Ludwig EA, Slaughter RL, Savliwala M, Steroid-specific effects of ketoconazole on corticosteroid disposition: Unaltered prednisolone elimination: DICP, 1989; 23(11); 858-61, pmid: 2596127
36. Yamashita SK, Ludwig EA, Middleton E, Jusko WJ, Lack of pharmacokinetic and pharmacodynamic interactions between ketoconazole and prednisolone: Clin Pharmacol Ther, 1991; 49(5); 558-70, pmid: 1827622
37. Zurcher RM, Frey BM, Frey FJ, Impact of ketoconazole on the metabolism of prednisolone: Clin Pharmacol Ther, 1989; 45(4); 366-72, pmid: 2639662
38. Varis T, Kaukonen KM, Kivisto KT, Neuvonen PJ, Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole: Clin Pharmacol Ther, 1998; 64(4); 363-68, pmid: 9797792
39. Varis T, Kivisto KT, Backman JT, Neuvonen PJ, Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers: Pharmacol Toxicol, 1999; 85(1); 29-32, pmid: 10426160
40. Lebrun-Vignes B, Archer VC, Diquet B, Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects: Br J Clin Pharmacol, 2001; 51(5); 443-50, pmid: 11422002
41. Linthoudt H, Van Raemdonck D, Lerut T, The association of itraconazole and methylprednisolone may give rise to important steroid-related side effects: J Heart Lung Transplant, 1996; 15(11); 1165, pmid: 8956126
42. Varis T, Kivisto KT, Neuvonen PJ, The effect of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone: Eur J Clin Pharmacol, 2000; 56(1); 57-60, pmid: 10853878
43. Varis T, Kivisto KT, Backman JT, Neuvonen PJ, The cytochrome P450 3A4 inhibitor itraconazole markedly increases the plasma concentrations of dexamethasone and enhances its adrenal-suppressant effect: Clin Pharmacol Ther, 2000; 68(5); 487-94, pmid: 11103751
44. Edwards OM, Courtenay-Evans RJ, Galley JM, Changes in cortisol metabolism following rifampicin therapy: Lancet (London, England), 1974; 2(7880); 548-51
45. McAllister WA, Thompson PJ, Al-Habet SM, Rogers HJ, Rifampicin reduces effectiveness and bioavailability of prednisolone: Br Med J (Clin Res Ed), 1983; 286(6369); 923-25
46. Powell-Jackson PR, Gray BJ, Heaton RW, Adverse effect of rifampicin administration on steroid-dependent asthma: Am Rev Respir Dis, 1983; 128(2); 307-10, pmid: 6349444
47. Buffington GA, Dominguez JH, Piering WF, Interaction of rifampin and glucocorticoids. Adverse effect on renal allograft function: JAMA, 1976; 236(17); 1958-60, pmid: 787563
48. Carrie F, Roblot P, Bouquet S, Rifampin-induced nonresponsiveness of giant cell arteritis to prednisone treatment: Arch Intern Med, 1994; 154(13); 1521-24, pmid: 8018008
49. Hendrickse W, McKiernan J, Pickup M, Lowe J, Rifampicin-induced non-responsiveness to corticosteroid treatment in nephrotic syndrome: Br Med J, 1979; 1(6159); 306
50. Udwadia ZF, Sridhar G, Beveridge CJ, Soutar C, McHardy GJ, Leitch AG, Catastrophic deterioration in asthma induced by rifampicin in steroid-dependent asthma: Respir Med, 1993; 87(8); 629, pmid: 8290748
51. Lin FL, Rifampin-induced deterioration in steroid-dependent asthma: J Allergy Clin Immunol, 1996; 98(6 Pt 1); 1125, pmid: 8977517
52. Sarma GR, Kailasam S, Nair NG, Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid: Antimicrob Agents Chemother, 1980; 18(5); 661-66, pmid: 7447424
53. Czock D, Keller F, Rasche FM, Haussler U, Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids: Clin Pharmacokinet, 2005; 44(1); 61-98, pmid: 15634032
54. LaForce CF, Szefler SJ, Miller MF, Inhibition of methylprednisolone elimination in the presence of erythromycin therapy: J Allergy Clin Immunol, 1983; 72(1); 34-39, pmid: 6602160
55. Fost DA, Leung DY, Martin RJ, Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy: J Allergy Clin Immunol, 1999; 103(6); 1031-35, pmid: 10359882
56. Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, Department of Health and Human Services Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf
57. Josephson F, Drug–drug interactions in the treatment of HIV infection: focus on pharmacokinetic enhancement through CYP3A inhibition: J Intern Med, 2010; 268(6); 530-39, pmid: 21073558
58. Nelson B, Cluck D, Alexander K, Need for awareness about interaction between nonprescription intranasal corticosteroids and pharmacokinetic enhancers: Am J Health Syst Pharm, 2015; 72(13); 1086-88, pmid: 26092956
59. Saberi P, Phengrasamy T, Nguyen DP, Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: A review of pharmacokinetics, case reports and clinical management: HIV Med, 2013; 14(9); 519-29, pmid: 23590676
60. Albert NE, Kazi S, Santoro J, Dougherty R, Ritonavir and epidural triamcinolone as a cause of iatrogenic Cushing’s syndrome: Am J Med Sci, 2012; 344(1); 72-74, pmid: 22543594
61. Fessler D, Beach J, Keel J, Stead W, Iatrogenic hypercortisolism complicating triamcinolone acetonide injections in patients with HIV on ritonavir-boosted protease inhibitors: Pain Physician, 2012; 15(6); 489-93, pmid: 23159966
62. Hall JJ, Hughes CA, Foisy MM, Iatrogenic Cushing syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted darunavir: Int J STD AIDS, 2013; 24(9); 748-52, pmid: 23970582
63. Levine D, Ananthakrishnan S, Garg A, Iatrogenic Cushing syndrome after a single intramuscular corticosteroid injection and concomitant protease inhibitor therapy: J Am Acad Dermatol, 2011; 65(4); 877-78, pmid: 21920248
64. Yombi JC, Maiter D, Belkhir L, Iatrogenic Cushing’s syndrome and secondary adrenal insufficiency after a single intra-articular administration of triamcinolone acetonide in HIV-infected patients treated with ritonavir: Clin Rheumatol, 2008; 27(Suppl 2); S79-82, pmid: 18827959
65. Penzak SR, Formentini E, Alfaro RM, Prednisolone pharmacokinetics in the presence and absence of ritonavir after oral prednisone administration to healthy volunteers: J Acquir Immune Defic Syndr, 2005; 40(5); 573-80, pmid: 16284534
66. Boyd SD, Hadigan C, McManus M, Influence of low-dose ritonavir with and without darunavir on the pharmacokinetics and pharmacodynamics of inhaled beclomethasone: J Acquir Immune Defic Syndr, 2013; 63(3); 355-61, pmid: 23535292
67. Lewis J, Turtle L, Khoo S, Nsutebu EN, A case of iatrogenic adrenal suppression after co-administration of cobicistat and fluticasone nasal drops: AIDS, 2014; 28(17); 2636-37, pmid: 25574967
68. Page RL, Miller GG, Lindenfeld J, Drug therapy in the heart transplant recipient: Part IV: Drug–drug interactions: Circulation, 2005; 111(2); 230-39, pmid: 15657387
69. Borrows R, Chusney G, James A, Determinants of mycophenolic acid levels after renal transplantation: Ther Drug Monit, 2005; 27(4); 442-50, pmid: 16044100
Abstract
ABSTRACT: Infections account for 15–20% of deaths in transplant recipients, requiring rapid and appropriate therapeutic interventions. Many anti-infective agents interact with immunosuppressive regimens used in transplantation, placing patients at increased risk for adverse drug reactions and prolonged hospitalizations. There is established data regarding the level of evidence and magnitude of interactions between calcineurin inhibitors and mammalian target of rapamycin inhibitors with anti-infective agents. Less is known about the interactions with anti-proliferative agents and corticosteroids, with gaps in knowledge on the appropriate management of these interactions. The objective of this review was to highlight the pharmacokinetic drug–drug interactions between antimetabolites and corticosteroids with commonly used anti-infective agents.
Keywords: Anti-Infective Agents, Antimetabolites, Drug Interactions, corticosteroids
Background
Infections remain a significant complication after solid organ transplantation (SOT). Use of various induction regimens, administration of novel immunosuppressive agents, and incorporation of newer prophylactic strategies continue to change the spectrum and severity of infections in SOT recipients [1]. Corticosteroids and anti-proliferative agents, azathioprine (AZA), and mycophenolic acid (MPA) are cornerstone therapies for rejection prevention in patients undergoing SOT [2]. Corticosteroids are utilized for immunosuppression induction to prevent acute rejection, and for chronic anti-rejection maintenance therapy. Anti-proliferative agents are primarily utilized for anti-rejection maintenance prophylaxis [2]. The use of these treatments in conjunction with specific antimicrobial agents introduces the potential for drug–drug interactions. This review highlights clinically important pharmacokinetic interactions between these classes of immunosuppressants and select antimicrobials, focusing on mechanisms, magnitude of effects, and management strategies.
Interactions with Antimetabolites
In general, long-term data demonstrating a decrease in the risk of rejection and improved survival with mycophenolate mofetil (MMF) compared with AZA has prompted many transplant centers to replace routine use of AZA with MMF [3–6]. Azathioprine is a prodrug converted rapidly by plasma esterases or non-enzymatically via glutathione to 6-mercaptopurine, which is further converted to thioinosine-monophosphate, its active metabolite. Only about 10% of AZA is eliminated as unchanged drug in the urine. The majority of AZA’s metabolism is based on plasma esterases or non-enzymatic processes [2].
Antivirals
RIBAVIRIN:
Ribavirin is a nucleoside analogue, which inhibits viral replication of a wide spectrum of RNA and DNA viruses. In solid organ transplant patients, ribavirin is utilized for the treatment of patients infected with hepatitis C (HCV), respiratory syncytial virus, and other viral infections [7–9]. Ribavirin has a well-established inhibitory effect on inosine monophosphate dehydrogenase (IMPDH). This enzyme is key to the metabolism of AZA. Inhibition of IMPDH leads to an increase in 6-methyl-thioinosine monophosphate, which has been associated with myelotoxicity [10].
Several case reports have described patients with normal thiopurine methyltransferase genotype, and who received chronic AZA treatment and developed severe pancytopenia resulting in the discontinuation of ribavirin and AZA [11,12]. A case series of eight patients on AZA treated for HCV with ribavirin showed significant pancytopenia with a mean cell count nadir of 4.6±1.6 weeks following initiation of ribavirin. Three of the patients underwent bone marrow aspiration and were found to be profoundly hypocellular. Following the withdrawal of ribavirin and AZA, full blood count recovery was seen at 5±1 week and hematologic toxicity was not seen following reintroduction of ribavirin or AZA alone in any patient. Within the case series, two patients’ plasma concentrations of methylated derivatives and 6-thioguanine nucleotide were evaluated. From baseline to cell count nadir there was an average threefold increase in methylated derivatives plasma concentration and 44% reduction in plasma 6-thioguanine nucleotide concentrations [13]. The concomitant use of AZA and ribavirin should be avoided given the significant risks for pancytopenia.
Mycophenolate mofetil is a 2-morpholinoethyl ester prodrug, with a complex metabolism pathway (Figure 1). After absorption from the stomach, MMF is rapidly hydrolyzed by esterases to its active metabolite MPA. This represents the first MPA peak plasma concentration. Once in the liver, MPA is metabolized primarily by uridine diphosphate-glucuronosyltransferases (UGTs), specifically UGT1A9, to form MPA’s phenolic glucuronide metabolite, MPAG, which is devoid of pharmacologic activity. MPAG is excreted via renal mechanisms as well as into the bile and ultimately into the distal small bowel and colon [14]. Colonic and intestinal gram-negative aerobic and anaerobic flora produce β-glucuronidase, which cleaves MPAG’s glucuronide conjugate converting it back to MPA. Once de-conjugated, MPA may be reabsorbed back into the circulation [15]. The biliary excretion of MPAG and the subsequent MPA enterohepatic recirculation involve several transport mechanisms including P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP), and multi-drug resistant protein 2 (MRP2) [16]. This recirculation results in MPA’s second peak plasma concentration and may account for as much as 40% of the MPA exposure measured by the area under the curve (AUC) [14].
While a limited number of pharmacokinetic drug–drug interactions have been reported with MMF, potential mechanisms involve alterations in absorption or enterohepatic recycling, competition of renal tubular excretion of MPAG, and changes in UGT activity [17]. Although antiretroviral and HCV therapies can influence these pathways, no pharmacokinetic drug interactions have been reported to date. A pharmacokinetic analysis of MMF before, during, and after treatment with ombitasvir, paritaprevir/ritonavir and dasabuvir found no significant changes in MPA concentrations [18]. Regardless, caution and clinical monitoring is prudent when co-administering MMF with antivirals that may influence MPA elimination pathway.
Antibiotics and Alteration of Intestinal Flora
Oral antibiotics, including fluoroquinolones, metronidazole, and amoxicillin-clavulanate, can inhibit or eliminate normal intestinal bacterial flora, which express enzymes responsible for MPAG de-glucuronidation, leading to alterations in MPA levels (Table 1). Two case reports showed a 39% and 63% drop in MPA AUC with amoxicillin-clavulanate and a doubling of the MPA exposure five days following the discontinuation of amoxicillin-clavulanate [19]. While use of oral fluoroquinolones have resulted in decreased MPA levels secondary to destruction of normal intestinal flora, further interruption of the pathway converting MPAG to MPA has been shown,
Anti-Tubercular Agents
Rifampin is a potent inducer of cytochrome P450 (CYP) 3A4, P-gp, monoamine oxidase B, and glutathione S-transfereases. Rifampin increases UGT expression, particularly intestinal UGT1A7 and UGT1A8, as well as hepatic and intestinal UGT1A9, which accounts for 55% of MPAG production [23–25]. Rifampin induces MRP2 and P-gp, which are responsible for MPAG’s biliary and renal excretion, as well as MPA’s enterohepatic recirculation [24,25].
One case report showed a three-fold increase in MMF dosing was needed to maintain a MPA concentration of 2.5 mcg/mL following rifampin administration [26]. The corresponding dose-corrected 12 hour MPA AUC increased 221% while MPA total body clearance decreased by 68.9% after rifampin discontinuation [26]. These findings may have been due to intestinal, hepatic, and renal UGT1A9 augmentation, increased renal MRP2, and possible interruption of intestinal flora. Rifampin may increase MPAG levels in the circulation and gut lumen, subsequently increasing renal elimination, and ultimately reducing MPA reabsorption from the distal gut [26,27].
Antifungals
ISAVUCONAZOLE:
Isavuconazole is second-generation triazole indicated for the treatment of invasive aspergillosis and mucormycosis infections. A prospective pharmacokinetic interaction study of 22 patients evaluated interactions between isavuconazole and MMF [28]. Isavuconazole increased MPA mean AUC0–∞ by 35% and decreased Cmax by 11%. Conversely, MPAG mean AUC0–∞ decreased by 24% and Cmax decreased by 32%. Isavuconazole pharmacokinetics were largely unchanged with the addition of MMF.
Isavuconazole’s secondary metabolism is mediated in part by the UGT pathway and is also a mild inhibitor of this pathway. The increased MMF exposure in conjunction with isavuconazole administration is likely the result of the inhibition of the UGT pathway. Effects of other antifungal agents on MMF concentrations are not reported but are unlikely due to the lack of interaction with the UGT pathway [29]. A dose reduction of MMF by 25% and/or close monitoring for signs and symptoms of toxicity are reasonable approaches when administering isavuconazole.
Corticosteroids
Corticosteroids may undergo 6β-hydroxylation via the CYP3A4 metabolic pathway, and are inducers of MRP2, as well as substrates, inhibitors, and inducers of OATP and P-gp [16]. Detection of pharmacokinetic interactions with corticosteroids is difficult as serum concentrations are not routinely measured and patients are often receiving concomitant inhibitors and/or inducers of drug transporters and CYP enzymes. Therefore, potential interactions are derived from pharmacokinetic studies conducted in non-SOT patients or healthy volunteers.
Prednisone and methylprednisolone are the two most commonly used synthetic corticosteroids in SOT recipients [2]. While structurally similar, differences exist. Prednisone is an inactive prodrug, converted through first pass metabolism to the active drug, prednisolone. While methylprednisolone is active, it differs from prednisolone by the presence of a methyl group at the 6α position and a hydrogen-bond donor at position C-11. These minor structural modifications enhances its P-gp affinity and cellular efflux, increasing its susceptibility to pharmacokinetic drug–drug interactions [23,30].
Anti-Fungal Agents
FLUCONAZOLE:
Although pharmacokinetic confirmation is lacking, an Addisonian crisis has been reported after discontinuation of prophylactic fluconazole in a liver transplant patient taking prednisone [31]. One large tertiary care hospital investigated the clinical impact of combination of fluconazole with prednisone. The study found 70.3% (n=2,941) of patients prescribed an azole experienced a potential drug interaction. The most common potential interaction was of fluconazole with prednisone (n=745) [32]. No steroid related adverse events were noted by chart review, with 47 patients administered fluconazole with prednisone, suggesting little clinical significance of this interaction at commonly prescribed doses; however, monitoring for signs and symptoms of an interaction when initiating or discontinuing fluconazole in the setting of a steroid is warranted.
KETOCONAZOLE:
One study reported that six healthy participants who were given ketoconazole 200 mg/day for six days had decreased intravenous (IV) methylprednisolone clearance by 60% and increased the AUC by 135%, leading to a reduced 24-hour cortisol AUC [33]. In a follow-up study, eight healthy participants were given IV methylprednisolone (15 or 30 mg) alone, then they were given ketoconazole 200 mg daily for seven days, and showed oral methylprednisolone clearance decreased by 46% with the administration of ketoconazole, leading to recommendations for a 50% reduction in methylprednisolone dose when used in conjunction with ketoconazole [34].
In a similar study involving four healthy participants, ketoconazole 200 mg/day for six days did not significantly alter prednisolone pharmacokinetics after administration of oral prednisone at 20 mg. No significant changes were noted in renal excretion of prednisone or prednisolone. In addition, 24 hour cortisol AUC ratios (with prednisone: baseline) were not significantly altered with ketoconazole administration [35]. This was confirmed in a subsequent study evaluating six healthy volunteers receiving IV prednisolone (14.8 mg) after six days of ketoconazole 200 mg daily [36].
In contrast, Zurcher et al. evaluated 10 healthy participants receiving ketoconazole at 200 mg/day for seven days with oral prednisone (0.8 mg/kg) and IV prednisolone (0.8 mg/kg) on separate occasions, and showed a two-fold decrease in urinary excretion of 6-beta-OH-prednisolone in all participants suggesting ketoconazole inhibits 6-beta-hydroxylase, a major metabolism pathway of prednisolone. In addition, the ratio of 6-beta-OH-cortisol/17-OH-corticosteroids declined by more than 50%. However, AUC ratios of prednisolone/prednisone after oral prednisone and IV prednisolone were found to be independent of ketoconazole suggesting the conversion of prednisone to prednisolone is not affected by ketoconazole. Therefore, it was concluded that ketoconazole increases exposure to prednisolone [37]. There is insufficient evidence for empiric dose reduction with concomitant use of ketoconazole and prednisone or prednisolone. Clinicians should monitor for steroid-related adverse effects.
ITRACONAZOLE:
Being a potent CYP3A4 inhibitor, itraconazole has been shown to inhibit metabolism of both oral and IV methylprednisolone. In a double-blind, placebo-controlled crossover study, 10 healthy individuals received itraconazole at 200 mg (or placebo) orally for four days, then 16 mg of oral methylprednisolone. Oral methylprednisolone AUC increased 3.9-fold, Cmax 1.9-fold, and half-life 2.4-fold following itraconazole when compared to placebo. This led to mean cortisol plasma levels of only 13% when compared to methylprednisolone alone [38]. In a similar study design, itraconazole increased IV methylprednisolone total AUC 2.6-fold, 12–24 hour AUC 12.2-fold, half-life from 2.1 to 4.8 hours and decreased clearance by 60%. This led to morning cortisol level reduction by 91% when compared to methylprednisolone alone [39]. This interaction was again confirmed in a study of 14 healthy males receiving oral methylprednisolone at 48 mg, then prednisone at 60 mg after a washout period with and without four days of itraconazole (400 mg on day one, then 200 mg daily for three days). The study showed itraconazole increased methylprednisolone 24 hour AUC, Cmax, and half-life by 2.5, 1.6, and 1.7-fold, respectively [40]. Furthering this point, the effect of itraconazole at 200 mg twice daily on methylprednisolone (12 mg orally) pharmacokinetics resulted in case reports of patient harm [41]. A dose reduction of 50% in methylprednisolone should be considered when starting itraconazole.
In a similar study design, only small changes in measured prednisolone AUC, Cmax, or half-life were observed following prednisone administration with or without itraconazole [40]. Contradictory to these findings, Varis et al. evaluated itraconazole at 200 mg daily for four days on 20 mg of oral prednisolone pharmacokinetics in 10 healthy participants in a double-blind placebo-controlled crossover study. Itraconazole statistically significantly increased prednisolone total AUC by 24% and half-life by 29% compared to placebo. This related to a statistically significant decrease in mean morning cortisol concentrations by 27% compared to placebo. The study authors concluded that though statistically different, these relatively small changes in prednisolone pharmacokinetics may not be clinically relevant [42]. Taken together, the effect of itraconazole on prednisolone pharmacokinetics may be less pronounced than the effect of methylprednisolone.
In a double-blind crossover study of eight health patients, itraconazole 200 mg daily for four days increased oral dexamethasone AUC, Cmax, and half-life by 3.7 fold, 1.7 fold, and 2.8 fold, respectively. Intravenous dexamethasone AUC and half-life increased by 3.3 fold and 3.2 fold, respectively; whereas, systemic clearance decreased by 68% when given with itraconazole. Morning cortisol concentrations where significantly lower at 47 hours and 71 hours after both oral and IV dexamethasone administration with itraconazole compared to the same dose of dexamethasone and four days of placebo [43]. The combination of dexamethasone and itraconazole may result in prolonged steroid-related adrenal suppression.
Administration of voriconazole and posaconazole may result in similar drug interactions since inhibition of similar CYP enzymes are expected. Monitoring for steroid related side-effects is warranted when using these combinations.
ISAVUCONAZOLE:
A prospective pharmacokinetic interaction study of 20 patients evaluated interactions between isavuconazole at 200 mg three times daily for two days followed by 200 mg daily, and prednisone at 20 mg once on day 9, found no clinically significant changes in prednisolone mean AUC0–∞ or Cmax [28]. The Cmax of isavuconazole was increased by approximately 26% and the AUCτ was unchanged. No dose adjustments for prednisone or isavuconazole are anticipated with concomitant use based on this study.
ANTI-TUBERCULAR AGENTS:
Rifampin increases the metabolism of cortisol, thereby [44] lowering prednisolone AUC by 66% and increasing clearance by 45% [45]. In another study, rifampin significantly decreased the plasma half-life and bioavailability of prednisolone in patients with asthma. Even with dose increases of 93% of prednisolone, asthma control remained inferior. One patient was withdrawn from the study due to poor asthma control after a five-fold increase in prednisolone dose [46].
Other case reports of harm occurring due to loss of steroid efficacy with rifampin range in diseases such as nephrotic syndrome, giant cell arteritis, immunosuppression for renal transplant, and asthma [47–50]. A pharmacokinetic study of two patients with giant cell arteritis treated with prednisone and rifampin found that prednisolone clearance increased by greater than 200% and half-life decreased by 40% to 60% compared to prednisolone administration without rifampin. Authors suggest a doubling of prednisone dose when used with rifampin [48]. Though not as well characterized, a similar interaction between rifampin and methylprednisolone would be expected. In a case of a methylprednisolone dependent asthmatic patient, asthma control was lost after rifampin was added, leading to an ineffective switch to prednisone. Only discontinuation of rifampin restored good asthma control [51]. Monitoring for signs of steroid failure when rifampin is added to medication regimens of patients with steroid dependent conditions is necessary, with the potential for development of rejection and graft failure if immunosuppressive doses are not adequately adjusted. Though an alternative agent such as rifabutin may also interact with steroids, reports of specific drug–drug interactions are lacking.
In one study of single dose prednisolone and weekly dose isoniazid, prednisolone was shown to significantly decrease isoniazid plasma concentrations in slow and rapid acetylators by 25% and 40%, respectively, as increased renal clearance of isoniazid after prednisolone administration was observed in both groups [52].
Macrolides
Given the frequent combination of macrolide and steroid use in asthma, much of the data regarding macrolide interaction with steroids comes from the asthma literature. Macrolides are considered to be “steroid-sparing” agents in patients with asthma due, in part, to their inhibition of P-gp and CYP3A4 [53]. In six patients with asthma, oral erythromycin significantly decreased mean IV methylprednisolone clearance by 46% (
Antivirals
RITONAVIR:
Ritonavir is commonly utilized in combination for the treatment of HCV and human immunodeficiency virus (HIV). Although ritonavir has antiviral activity, it is often utilized as a “booster” for other medications contained within the treatment regimen [9,56]. Ritonavir exhibits this effect through inhibition of CYP enzymes increasing the area under the cure for the active antiviral agents. There have been greater than 30 cases of Cushing’s syndrome and/or secondary adrenal insufficiency secondary to administration of orally or nasally inhaled fluticasone in combination with ritonavir utilized for HIV or HCV treatment [57–59]. In a study of 18 healthy individuals who received fluticasone propionate nasal spray (200 mcg daily) and ritonavir (100 mg twice daily) for seven day increased the fluticasone AUC by 350-fold and increased the Cmax by 25-fold compared to baseline. These pharmacokinetic effects resulted in an 86% reduction in plasma cortisol AUC levels [56]. Cushing’s syndrome and/or secondary adrenal insufficiency has also been observed in patients who have received intra-articular, intramuscular, and epidural triamcinolone injections [60–64].
The pharmacokinetic effects of ritonavir (200 mg twice daily) on prednisone (20 mg once) were evaluated in 10 healthy individuals at day 4 and day 14. The AUC for the active metabolite prednisolone increased from baseline by 37% on day 4 and 28% on day 14. The half-life was increased by approximately one hour and there were no differences between Cmax and Tmax observed [65]. A pharmacokinetic evaluation of inhaled beclomethasone (160 mcg twice daily) and ritonavir (100 mg twice daily) in 20 healthy individuals demonstrated a statically significant increase of 223% in the AUC of 17-monopropionate, beclomethasone’s active metabolite. Despite this significant increase, there was not a significant reduction in serum cortisol levels seen [66]. There is sufficient evidence to recommend the avoidance of use of corticosteroids with significant CYP3A4 metabolism, such as fluticasone and triamcinolone, in combination with ritonavir due to the risk of Cushing’s syndrome and adrenal suppression. Alternative steroids, such as beclomethasone and prednisone, should be utilized and a reduction of 25% should be considered for long-term therapy. While other protease inhibitors (e.g., boceprevir, simeprevir, and telaprevir) pharmacokinetic and dynamic effects on corticosteroids have not specifically been evaluated, many possess CYP3A4 inhibitory properties and signs and symptoms of Cushing’s syndrome and adrenal suppression should be evaluated in these patients.
COBICISTAT:
Cobicistat is a potent CYP3A4 inhibitor utilized as a “booster” in the management of HIV. A case report of a 39-year-old man utilizing fluticasone nasal drops (800 mcg twice daily) initiated on HIV therapy containing cobicistat, demonstrated adrenal suppression and morning cortisol < 50 nmol/L. The nasal drops were transitioned to beclomethasone nasal spray and the man’s morning cortisol levels rebounded to 149 nmol/L six weeks later [67]. This is currently the only case report of adrenal suppression with cobicistat. Due to cobicistat’s pharmacologic properties intended to create advantageous pharmacokinetic interactions, similar recommendations to avoid corticosteroids metabolized by CYP3A4 and dose reduce or monitor for side effects, similar to ritonavir, should be followed when using corticosteroids.
Conclusions
Interactions of immunosuppressants with specific antimicrobials agents may result in high levels of immunosuppressants leading to toxicity, or sub-therapeutic levels leading to graft rejection. Many untoward interactions can be prevented by substitution of alternative anti-infective agents or by judicious adjustments in immunosuppressant dosing after considering known effects of anti-infective agents. There are two keys to success in this approach: cognizance by all clinicians caring for the SOT recipient and continued education of the patient regarding the potential for drug interactions that may affect their overall immunosuppression.
References
1. Fishman JA, Infection in organ transplantation: Am J Transplant, 2017; 17(4); 856-79, pmid: 28117944
2. Lindenfeld J, Miller GG, Shakar SF, Drug therapy in the heart transplant recipient: Part II: Immunosuppressive drugs: Circulation, 2004; 110(25); 3858-65, pmid: 15611389
3. Kobashigawa JA, Meiser BM, Review of major clinical trials with mycophenolate mofetil in cardiac transplantation: Transplantation, 2005; 80(2 Suppl); S235-43, pmid: 16251856
4. Eisen HJ, Kobashigawa J, Keogh A, Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients: J Heart Lung Transplant, 2005; 24(5); 517-25, pmid: 15896747
5. Germani G, Pleguezuelo M, Villamil F, Azathioprine in liver transplantation: A reevaluation of its use and a comparison with mycophenolate mofetil: Am J Transplant, 2009; 9(8); 1725-31, pmid: 19538488
6. Wagner M, Earley AK, Webster AC, Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients: Cochrane Database Syst Rev, 2015(12); Cd007746, pmid: 26633102
7. Pelaez A, Lyon GM, Force SD, Efficacy of oral ribavirin in lung transplant patients with respiratory syncytial virus lower respiratory tract infection: J Heart Lung Transplant, 2009; 28(1); 67-71, pmid: 19134533
8. Vu DL, Bridevaux PO, Aubert JD, Respiratory viruses in lung transplant recipients: A critical review and pooled analysis of clinical studies: Am J Transplant, 2011; 11(5); 1071-78, pmid: 21521473
9. AASLD/IDSA HCV Guidance Pane, Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus: Hepatology, 2015; 62(3); 932-54, pmid: 26111063
10. Gish RG, Treating HCV with ribavirin analogues and ribavirin-like molecules: J Antimicrob Chemother, 2006; 57(1); 8-13, pmid: 16293677
11. Chaparro M, Trapero-Marugan M, Moreno-Otero R, Gisbert JP, Azathioprine plus ribavirin treatment and pancytopenia: Aliment Pharmacol Ther, 2009; 30(9); 962-63, pmid: 19807727
12. Thevenot T, Mathurin P, Moussalli J, Effects of cirrhosis, interferon and azathioprine on adverse events in patients with chronic hepatitis C treated with ribavirin: J Viral Hepat, 1997; 4(4); 243-53, pmid: 9278222
13. Peyrin-Biroulet L, Cadranel JF, Nousbaum JB, Interaction of ribavirin with azathioprine metabolism potentially induces myelosuppression: Aliment Pharmacol Ther, 2008; 28(8); 984-93, pmid: 18657132
14. Kelly P, Kahan BD, Review: Metabolism of immunosuppressant drugs: Current Drug Metab, 2002; 3(3); 275-87
15. Sperker B, Backman JT, Kroemer HK, The role of beta-glucuronidase in drug disposition and drug targeting in humans: Clin Pharmacokinet, 1997; 33(1); 18-31
16. Christians U, Strom T, Zhang YL, Active drug transport of immunosuppressants: New insights for pharmacokinetics and pharmacodynamics: Ther Drug Monit, 2006; 28(1); 39-44, pmid: 16418692
17. Bullingham RE, Nicholls AJ, Kamm BR, Clinical pharmacokinetics of mycophenolate mofetil: Clin Pharmacokinet, 1998; 34(6); 429-55, pmid: 9646007
18. Lemaitre F, Ben Ali Z, Tron C, Managing drug–drug interaction between ombitasvir, paritaprevir/ritonavir, dasabuvir, and mycophenolate mofetil: Ther Drug Monit, 2017; 39(4); 305-7, pmid: 28700519
19. Ratna P, Mathew BS, Annapandian VM, Pharmacokinetic drug interaction of mycophenolate with co-amoxiclav in renal transplant patients: Transplantation, 2011; 91(6); e36-38, pmid: 21383599
20. Kodawara T, Masuda S, Yano Y, Inhibitory effect of ciprofloxacin on beta-glucuronidase-mediated deconjugation of mycophenolic acid glucuronide: Biopharm Drug Dispos, 2014; 35(5); 275-83, pmid: 24615849
21. Naderer OJ, Dupuis RE, Heinzen EL, The influence of norfloxacin and metronidazole on the disposition of mycophenolate mofetil: J Clin Pharmacol, 2005; 45(2); 219-26, pmid: 15647415
22. Naderer OJ, Dupuis RE, Wiwattanawongsa K, Reduction of plasma mycophenolic acid (MPA) andits glucouronide (MPAG) concentrations with antibiotic treatment [abstract]: Clin Pharmacol Ther, 1999; 65(2); 159
23. Picard N, Ratanasavanh D, Premaud A, Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism: Drug Metab Dispos, 2005; 33(1); 139-46, pmid: 15470161
24. Rae JM, Johnson MD, Lippman ME, Flockhart DA, Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: Studies with cDNA and oligonucleotide expression arrays: J Pharmacol Exp Ther, 2001; 299(3); 849-57, pmid: 11714868
25. Magnarin M, Morelli M, Rosati A, Induction of proteins involved in multidrug resistance (P-glycoprotein, MRP1, MRP2, LRP) and of CYP 3A4 by rifampicin in LLC-PK1 cells: Eur J Pharmacol, 2004; 483(1); 19-28, pmid: 14709322
26. Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y, Drug interaction between mycophenolate mofetil and rifampin: Possible induction of uridine diphosphate-glucuronosyltransferase: Clin Pharmacol Ther, 2005; 78(1); 81-88, pmid: 16003296
27. Barau C, Barrail-Tran A, Hemerziu B, Optimization of the dosing regimen of mycophenolate mofetil in pediatric liver transplant recipients: Liver Transpl, 2011; 17(10); 1152-58, pmid: 21695772
28. Groll AH, Desai A, Han D, Pharmacokinetic assessment of drug–drug interactions of isavuconazole with the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults: Clin Pharmacol Drug Dev, 2017; 6(1); 76-85, pmid: 27273343
29. Rybak JM, Marx KR, Nishimoto AT, Rogers PD, Isavuconazole: Pharmacology, pharmacodynamics, and current clinical experience with a new triazole antifungal agent: Pharmacotherapy, 2015; 35(11); 1037-51, pmid: 26598096
30. Szefler SJ, Glucocorticoid therapy for asthma: Clinical pharmacology: J Allergy Clin Immunol, 1991; 88(2); 147-65, pmid: 1880315
31. Tiao GM, Martin J, Weber FL, Addisonian crisis in a liver transplant patient due to fluconazole withdrawal: Clin Transplant, 1999; 13(1 Pt 1); 62-64, pmid: 10081637
32. Yu DT, Peterson JF, Seger DL, Frequency of potential azole drug–drug interactions and consequences of potential fluconazole drug interactions: Pharmacoepidemiol Drug Saf, 2005; 14(11); 755-67, pmid: 15654717
33. Glynn AM, Slaughter RL, Brass C, Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion: Clin Pharmacol Therap, 1986; 39(6); 654-59, pmid: 3709030
34. Kandrotas RJ, Slaughter RL, Brass C, Jusko WJ, Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol: Clin Pharmacol Therap, 1987; 42(4); 465-70, pmid: 3311551
35. Ludwig EA, Slaughter RL, Savliwala M, Steroid-specific effects of ketoconazole on corticosteroid disposition: Unaltered prednisolone elimination: DICP, 1989; 23(11); 858-61, pmid: 2596127
36. Yamashita SK, Ludwig EA, Middleton E, Jusko WJ, Lack of pharmacokinetic and pharmacodynamic interactions between ketoconazole and prednisolone: Clin Pharmacol Ther, 1991; 49(5); 558-70, pmid: 1827622
37. Zurcher RM, Frey BM, Frey FJ, Impact of ketoconazole on the metabolism of prednisolone: Clin Pharmacol Ther, 1989; 45(4); 366-72, pmid: 2639662
38. Varis T, Kaukonen KM, Kivisto KT, Neuvonen PJ, Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole: Clin Pharmacol Ther, 1998; 64(4); 363-68, pmid: 9797792
39. Varis T, Kivisto KT, Backman JT, Neuvonen PJ, Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers: Pharmacol Toxicol, 1999; 85(1); 29-32, pmid: 10426160
40. Lebrun-Vignes B, Archer VC, Diquet B, Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects: Br J Clin Pharmacol, 2001; 51(5); 443-50, pmid: 11422002
41. Linthoudt H, Van Raemdonck D, Lerut T, The association of itraconazole and methylprednisolone may give rise to important steroid-related side effects: J Heart Lung Transplant, 1996; 15(11); 1165, pmid: 8956126
42. Varis T, Kivisto KT, Neuvonen PJ, The effect of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone: Eur J Clin Pharmacol, 2000; 56(1); 57-60, pmid: 10853878
43. Varis T, Kivisto KT, Backman JT, Neuvonen PJ, The cytochrome P450 3A4 inhibitor itraconazole markedly increases the plasma concentrations of dexamethasone and enhances its adrenal-suppressant effect: Clin Pharmacol Ther, 2000; 68(5); 487-94, pmid: 11103751
44. Edwards OM, Courtenay-Evans RJ, Galley JM, Changes in cortisol metabolism following rifampicin therapy: Lancet (London, England), 1974; 2(7880); 548-51
45. McAllister WA, Thompson PJ, Al-Habet SM, Rogers HJ, Rifampicin reduces effectiveness and bioavailability of prednisolone: Br Med J (Clin Res Ed), 1983; 286(6369); 923-25
46. Powell-Jackson PR, Gray BJ, Heaton RW, Adverse effect of rifampicin administration on steroid-dependent asthma: Am Rev Respir Dis, 1983; 128(2); 307-10, pmid: 6349444
47. Buffington GA, Dominguez JH, Piering WF, Interaction of rifampin and glucocorticoids. Adverse effect on renal allograft function: JAMA, 1976; 236(17); 1958-60, pmid: 787563
48. Carrie F, Roblot P, Bouquet S, Rifampin-induced nonresponsiveness of giant cell arteritis to prednisone treatment: Arch Intern Med, 1994; 154(13); 1521-24, pmid: 8018008
49. Hendrickse W, McKiernan J, Pickup M, Lowe J, Rifampicin-induced non-responsiveness to corticosteroid treatment in nephrotic syndrome: Br Med J, 1979; 1(6159); 306
50. Udwadia ZF, Sridhar G, Beveridge CJ, Soutar C, McHardy GJ, Leitch AG, Catastrophic deterioration in asthma induced by rifampicin in steroid-dependent asthma: Respir Med, 1993; 87(8); 629, pmid: 8290748
51. Lin FL, Rifampin-induced deterioration in steroid-dependent asthma: J Allergy Clin Immunol, 1996; 98(6 Pt 1); 1125, pmid: 8977517
52. Sarma GR, Kailasam S, Nair NG, Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid: Antimicrob Agents Chemother, 1980; 18(5); 661-66, pmid: 7447424
53. Czock D, Keller F, Rasche FM, Haussler U, Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids: Clin Pharmacokinet, 2005; 44(1); 61-98, pmid: 15634032
54. LaForce CF, Szefler SJ, Miller MF, Inhibition of methylprednisolone elimination in the presence of erythromycin therapy: J Allergy Clin Immunol, 1983; 72(1); 34-39, pmid: 6602160
55. Fost DA, Leung DY, Martin RJ, Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy: J Allergy Clin Immunol, 1999; 103(6); 1031-35, pmid: 10359882
56. Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, Department of Health and Human Services Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf
57. Josephson F, Drug–drug interactions in the treatment of HIV infection: focus on pharmacokinetic enhancement through CYP3A inhibition: J Intern Med, 2010; 268(6); 530-39, pmid: 21073558
58. Nelson B, Cluck D, Alexander K, Need for awareness about interaction between nonprescription intranasal corticosteroids and pharmacokinetic enhancers: Am J Health Syst Pharm, 2015; 72(13); 1086-88, pmid: 26092956
59. Saberi P, Phengrasamy T, Nguyen DP, Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: A review of pharmacokinetics, case reports and clinical management: HIV Med, 2013; 14(9); 519-29, pmid: 23590676
60. Albert NE, Kazi S, Santoro J, Dougherty R, Ritonavir and epidural triamcinolone as a cause of iatrogenic Cushing’s syndrome: Am J Med Sci, 2012; 344(1); 72-74, pmid: 22543594
61. Fessler D, Beach J, Keel J, Stead W, Iatrogenic hypercortisolism complicating triamcinolone acetonide injections in patients with HIV on ritonavir-boosted protease inhibitors: Pain Physician, 2012; 15(6); 489-93, pmid: 23159966
62. Hall JJ, Hughes CA, Foisy MM, Iatrogenic Cushing syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted darunavir: Int J STD AIDS, 2013; 24(9); 748-52, pmid: 23970582
63. Levine D, Ananthakrishnan S, Garg A, Iatrogenic Cushing syndrome after a single intramuscular corticosteroid injection and concomitant protease inhibitor therapy: J Am Acad Dermatol, 2011; 65(4); 877-78, pmid: 21920248
64. Yombi JC, Maiter D, Belkhir L, Iatrogenic Cushing’s syndrome and secondary adrenal insufficiency after a single intra-articular administration of triamcinolone acetonide in HIV-infected patients treated with ritonavir: Clin Rheumatol, 2008; 27(Suppl 2); S79-82, pmid: 18827959
65. Penzak SR, Formentini E, Alfaro RM, Prednisolone pharmacokinetics in the presence and absence of ritonavir after oral prednisone administration to healthy volunteers: J Acquir Immune Defic Syndr, 2005; 40(5); 573-80, pmid: 16284534
66. Boyd SD, Hadigan C, McManus M, Influence of low-dose ritonavir with and without darunavir on the pharmacokinetics and pharmacodynamics of inhaled beclomethasone: J Acquir Immune Defic Syndr, 2013; 63(3); 355-61, pmid: 23535292
67. Lewis J, Turtle L, Khoo S, Nsutebu EN, A case of iatrogenic adrenal suppression after co-administration of cobicistat and fluticasone nasal drops: AIDS, 2014; 28(17); 2636-37, pmid: 25574967
68. Page RL, Miller GG, Lindenfeld J, Drug therapy in the heart transplant recipient: Part IV: Drug–drug interactions: Circulation, 2005; 111(2); 230-39, pmid: 15657387
69. Borrows R, Chusney G, James A, Determinants of mycophenolic acid levels after renal transplantation: Ther Drug Monit, 2005; 27(4); 442-50, pmid: 16044100
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