Drug Interactions between avacopan and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of avacopan. CYP450 3A4 is the primary enzyme responsible for the clearance of avacopan and for the formation and clearance of the major circulating metabolite M1, a mono-hydroxylated metabolite with similar pharmacologic activity as avacopan on the complement 5a receptor (C5aR). When avacopan was administered with the potent CYP450 3A4 inhibitor, itraconazole (200 mg once daily for 4 days), avacopan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.9-fold and 2.2-fold, respectively. The Cmax and AUC of M1 were not significantly altered.

MANAGEMENT: The dosage of avacopan should be reduced to 30 mg once daily when used concomitantly with potent CYP450 3A4 inhibitors. Patients should be monitored for serious adverse reactions such as hepatotoxicity and infections.

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

MONITOR: Concomitant use with avacopan oral capsules may increase the plasma concentrations of orally administered sensitive P-gp substrates with relatively low bioavailability, such as dabigatran etexilate. The mechanism has not been elucidated; however, avacopan oral capsules are formulated with the excipient PEG-40 hydrogenated castor oil (macrogolglycerol hydroxystearate), which may act as a P-gp inhibitor. Clinical data are not available.

MANAGEMENT: Caution is advised when avacopan oral capsules are used concomitantly with oral medications that are substrates of P-gp, particularly those with relatively low bioavailability or a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever avacopan capsules are added to or withdrawn from therapy.

Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of lopinavir, which is primarily metabolized by the isoenzyme. The magnitude and clinical significance of this interaction are unknown, particularly when in the presence of ritonavir as a pharmacokinetic booster. Limited data indicate that ketoconazole, a potent CYP450 3A4 inhibitor, does not substantially alter the plasma concentrations of lopinavir administered as lopinavir-ritonavir in a 4:1 ratio.