INTERACTIONS BETWEEN AZOLE ANTIFUNGALS AND ANTIRETROVIRALS Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole Kinetic Substrate of Substrate of CYP3A4. Substrate of p- Inhibits CYP3A4. Substrate of Substrate of CYP3A4 6 Characteristics 1 CYP3A4 , p- Inhibits CYP3A4 glycoprotein, Induces CYP3A, 2B CYP2C19 (major), (11%) , p- 2 2 glycoprotein . Inhibits (potent), 2C9, 1A2, p- UGT1A4. Inhibits (preliminary data in CYP3A4, CYP2C9. glycoprotein . Inhibits 6 7 4, 5 8 3 CYP3A4 , p- glycoprotein , UGT. CYP3A4, p- animal studies). Inhibits CYP3A4 , CYP3A4, 2C9 , 2 2C19 3, UGT 4, 5 glycoprotein . glycoprotein. 2C9, 2C19. CCR5 Inhibitor Maraviroc Potential for Potential for When given with Potential for Potential for ↑ fluconazole to ↑ itraconazole to ↑ ketoconazole 400 mg posaconazole to ↑ maraviroc (metabolized by maraviroc maraviroc QD, maraviroc AUC ↑ maraviroc concentrations due to CYP3A4 and p- concentrations via concentrations via 5-fold, Cmax ↑ 3.4- concentrations via CYP3A4 inhibition by 9 glycoprotein. ) CYP3A4 inhibition. CYP3A4 inhibition. fold. 10 Reduction of CYP3A4 inhibition. voriconazole. Since Administration of the Reduction of maraviroc dose by Reduction of voriconazole is standard maraviroc maraviroc dose by 50% in the presence maraviroc dose by considered a dose (300 mg BID) 50% in the presence of protease 50% in the presence moderate CYP3A4 should be done with of protease inhibitors/potent of protease inhibitor, the caution.9 inhibitors/potent CYP3A4 inhibitors is inhibitors/potent magnitude of the CYP3A4 inhibitors is recommended. 9 CYP3A4 inhibitors is interaction is likely recommended. 9 recommended. 9 less than with more potent inhibitors. Monitor closely for maraviroc-related toxicity if maraviroc 300mg twice daily dose is used.9 It is unclear whether a dosage ↓of maraviroc to 150 mg twice daily is recommended as it is with other more potent CYP3A4 inhibitors (i.e. ketonazole, itraconazole, clarithromycin). 9 Integrase Inhibitor Dolutegravir Interactions are Interactions are Interactions are Interactions are Interactions are Interactions are (metabolized by unlikely based on unlikely based on unlikely based on unlikely based on unlikely based on unlikely based on UGT1A1 with some dolutegravir dolutegravir dolutegravir dolutegravir dolutegravir dolutegravir contribution by metabolism. Use metabolism. Use metabolism. Use metabolism. Use metabolism. Use metabolism. Use CYP3A4. Inhibits standard doses of standard doses of standard doses of standard doses of standard doses of standard doses of renal OCT2 both drugs. both drugs. both drugs. both drugs. both drugs. both drugs. transporter; no other inhibitory or Academic copyright: Alice Tseng, PharmD, Toronto General Hospital, Michelle Foisy, PharmD and Christine Hughes, PharmD, Northern Alberta HIV Program, Alberta Health Services. www.hivclinic.ca September 2014 1 of 21 Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole inductive potential in vitro. 11 ) Elvitegravir Potential for ↑ Potential for ↑ In a healthy volunteer Potential for ↑ Potential for ↑ Potential for ↑ (metabolized by fluconazole and/or itraconazole and/or study, subjects posaconazole and/or ravuconazole and/or voriconazole and/or CYP3A4, elvitegravir and elvitegravir and received elvitegravir elvitegravir and ↑/↓ elvitegravir and elvitegravir and UGT1A1/3, cobicistat cobicistat 150/ritonavir 100 mg cobicistat cobicistat cobicistat moderate 2C9 concentrations. concentrations. Do daily alone and then concentrations. concentrations. concentrations. 12 inducer) not exceed maximum with ketoconazole 200 Boosted by daily dose of mg BID, each for 10 cobicistat (3A4, itraconazole 200 mg12 days, followed by 4 2D6 substrate, more days of inhibitor of 3A4, ketoconazole 200 mg 2D6, P- BID alone. In the glycoprotein) presence of ketoconazole, modest increases in elvitegravir exposures were observed: 17% ↑ Cmax, 48% ↑ AUC, 67% ↑Cmin. A maximum ketoconazole dose of 200 mg once daily is recommended when coadministering with boosted elvitegravir. 13 Raltegravir Interactions are Interactions are Interactions are Interactions are Interactions are Interactions are unlikely based on unlikely based on unlikely based on unlikely based on unlikely based on unlikely based on (metabolized by raltegravir raltegravir raltegravir raltegravir raltegravir raltegravir UGT1A1 and has metabolism. Use metabolism. Use metabolism. Use metabolism. Use metabolism. Use metabolism. Use no inhibitory or standard doses of standard doses of standard doses of standard doses of standard doses of standard doses of inductive potential both drugs. both drugs. both drugs. both drugs. both drugs. both drugs. in vitro. 14 ) NNRTIs Delavirdine A dual inhibition A dual inhibition A dual inhibition Possible ↑ delavirdine interaction is possible interaction is possible interaction is possible concentrations due to (metabolized via via CYP 3A4 inhibition via CYP 3A4 inhibition via CYP 3A4 inhibition CYP3A4 inhibition by CYP3A4; also by delavirdine and by delavirdine and by delavirdine and posaconazole. inhibits 3A4, as well fluconazole. No itraconazole. Monitor ketoconazole. No Monitor for delavirdine as 2C9, 2C19. 15 ) interaction noted. 16 for both delavirdine delavirdine dosage toxicity. Use standard doses and itraconazole adjustment of both drugs. toxicity (i.e. recommended with hepatotoxicity). inhibitors of CYP3A4 or CYP2D6. 16 Monitor for both delavirdine and ketoconazole Academic copyright: Alice Tseng, PharmD, Toronto General Hospital, Michelle Foisy, PharmD and Christine Hughes, PharmD, Northern Alberta HIV Program, Alberta Health Services. www.hivclinic.ca September 2014 2 of 21 Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole toxicity (i.e. hepatotoxicity). Efavirenz Potential for dual In a pharmacokinetic In a pharmacokinetic Posaconazole AUC ↓ Dual induction/inhibition study of healthy study of 12 HIV- 50% by efavirenz, 24, 25 induction/inhibition (In vitro is a potent interaction due to subjects, efavirenz infected patients, the likely via efavirenz- interaction likely due inducer and efavirenz-mediated 600 mg plus kinetics of single-dose mediated induction of to efavirenz-mediated inhibitor of CYP3A4 induction itraconazole 200 mg ketoconazole 400 mg posaconazole CYP3A4, 2C9, 2C19 CYP3A4. Induces and fluconazole- BID for 14 days led to was measured alone glucuronidation. induction of 2B6. 17 Also inhibits related CYP3A4 a 39% ↓ AUC of and after 14 days of voriconazole and CYP2C9, 2C19. 3) inhibition. No itraconazole and 37% efavirenz/3TC/d4T. In Avoid combination voriconazole-related interaction noted with ↓ AUC of its hydroxyl- the presence of unless the benefits CYP3A4 inhibition of 18 combination. Use metabolite; EFV steady-state clearly outweigh the efavirenz metabolism. standard doses of exposures were not efavirenz, risks of antifungal 80% ↓ voriconazole both drugs. affected. 19 ketoconazole Cmax ↓ failure. Consider AUC; 43% ↑ efavirenz 44% and AUC ↓ posaconazole TDM to AUC when given as 72%. 23 Avoid dose-adjust. 22 voriconazole 400 mg Case report of HIV- every 12 hours (day positive male with concomitant use; 1), then 200 mg disseminated consider alternate every 12 hours and histoplasmosis with antiretroviral or antifungal therapy. efavirenz 400 mg undetectable 26 daily x 9 days. itraconazole 55% ↓ voriconazole concentrations and AUC; 1% ↑ efavirenz persistently elevated AUC when given as urinary Histoplasma voriconazole 300 mg antigen levels while every 12 hours and on efavirenz and efavirenz 300 mg itraconazole 200 mg daily. 27 BID. Therapeutic itraconazole levels 7% ↓ voriconazole and a decrease in AUC; 17% ↑ urinary Histoplasma efavirenz AUC when antigen levels were given as observed after voriconazole 400 mg efavirenz was every 12 hours and replaced with 20 efavirenz 300 mg atazanavir/ritonavir. daily . These values are similar to In a retrospective monotherapy with cohort analysis, either agent alone. 27 itraconazole levels were assessed in 10 Case report in 40 HIV-positive patients year-old male with with disseminated mild HCV-related histoplasmosis; 4 cirrhosis and patients were on PI cryptococcal Academic copyright: Alice Tseng, PharmD, Toronto General Hospital, Michelle Foisy, PharmD and Christine Hughes, PharmD, Northern Alberta HIV Program, Alberta Health Services. www.hivclinic.ca September 2014 3 of 21 Fluconazole Itraconazole Ketoconazole Posaconazole Ravuconazole Voriconazole therapy, 4 on NNRTIs, meningitis requiring a and 2 on both PIs and dosage adjustment of NNRTI therapy. All oral voriconazole NNRTI patients had titrated to 200 mg undetectable twice daily and itraconazole efavirenz 300mg concentrations, vs.1/4 once daily to yield PI patients. Two therapeutic patients who switched concentrations of both from NNRTI to PI drugs and positive therapy subsequently clinical outcomes. 28 had therapeutic itraconazole levels. 21 Contraindicated at No data using higher standard doses. 18 doses of itraconazole. Recommended dosage adjustment: Avoid this ↑ voriconazole maintenance dose to combination if possible. If 400 mg twice daily (from 200mg twice coadministered, closely monitor daily) and ↓ efavirenz itraconazole dose to 300mg once concentration and daily (from 600mg adjust dose once daily). Use the accordingly. 22 capsule formulation to obtain this dose since efavirenz 600mg Use of alternate tablets should not be antifungal treatment broken. 18 may be necessary or replacement of Short-term co- efavirenz with a non- administration