Drug Interactions between ivacaftor / lumacaftor and maraviroc

ADJUST DOSE: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of maraviroc, which is primarily metabolized by the isoenzyme. According to the product labeling, administration of maraviroc (100 mg twice a day) with the potent CYP450 3A4 inducer rifampin (600 mg once a day) reduced the mean maraviroc peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 66%, 63% and 78%, respectively, compared to administration alone. When the same dosage of maraviroc was administered with efavirenz (600 mg once a day), maraviroc Cmax, AUC, and Cmin decreased by approximately 50% each. In contrast, maraviroc Cmax increased by 25% and AUC increased by 153% during coadministration with efavirenz (600 mg once a day) plus the potent CYP450 3A4 inhibitors lopinavir/ritonavir (400 mg/100 mg twice a day). An even greater increase of 2.3-fold in Cmax and 5-fold in AUC was observed during coadministration of maraviroc (300 mg twice a day) and efavirenz plus saquinavir/ritonavir (1000 mg/100 mg twice a day).

CONTRAINDICATED: Patients with severe renal impairment or end-stage renal disease (CrCl <30 mL/min) given maraviroc may have an increased risk of postural hypotension due to increased maraviroc exposure. Moreover, these patients often have cardiovascular comorbidities that could predispose them to adverse cardiovascular events triggered by postural hypotension. No studies have been performed in subjects with severe renal impairment or ESRD co-treated with maraviroc and potent CYP450 3A4 inducers. Hence, no dosage recommendation for maraviroc is available for these patients.

MANAGEMENT: Maraviroc should be administered at a dosage of 600 mg twice daily during coadministration with potent CYP450 3A4 inducers. However, if a potent CYP450 3A4 inhibitor such as itraconazole, ketoconazole, delavirdine, clarithromycin, telithromycin, nefazodone, or any protease inhibitor (except tipranavir plus ritonavir) is also used in combination with the inducer, then maraviroc dosage should be reduced to 150 mg twice daily. Maraviroc is contraindicated for use with potent CYP450 3A4 inducers in patients with severe renal impairment or end-stage renal disease (CrCl <30 mL/min).

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MONITOR: Coadministration with inhibitors of the CYP450 3A4 isoenzyme and/or P-glycoprotein efflux transporter may increase the plasma concentrations of maraviroc, which is a substrate of both. According to the product labeling, administration of maraviroc (100 mg twice a day) with the potent CYP450 3A4/P-glycoprotein inhibitor ketoconazole (400 mg once a day) increased the mean maraviroc peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 3.5- and 5-fold, respectively, compared to administration alone. When the same dosage of maraviroc was administered with ritonavir (100 mg twice a day), maraviroc Cmax increased by nearly 1.3-fold and AUC by 2.6-fold. An even greater increase of nearly 5-fold in Cmax and 10-fold in AUC was observed during coadministration of maraviroc and saquinavir/ritonavir (1000 mg/100 mg twice a day). At 300 mg twice a day, mean maraviroc Cmax increased by approximately 2-fold and AUC by 3.6-fold during coadministration with atazanavir (400 mg once a day). When the same dosage of maraviroc was given with atazanavir/ritonavir (300 mg/100 mg once a day), maraviroc Cmax increased by 2.7-fold and AUC increased by nearly 5-fold. During coadministration with lopinavir/ritonavir (400 mg/100 mg twice a day), maraviroc Cmax and AUC increased by 2-fold and 4-fold, respectively.

MANAGEMENT: Caution is advised when maraviroc is used with inhibitors of CYP450 3A4 and/or P-glycoprotein. Dosage adjustment for maraviroc may be necessary if an interaction is suspected.

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