Drug Interactions between cobicistat / darunavir / emtricitabine / tenofovir alafenamide and istradefylline

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations and risk of adverse effects of istradefylline, which is primarily metabolized by CYP450 3A4 and 1A1. In study subjects, administration of a single 40 mg dose of istradefylline with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 4 days) increased the total systemic exposure (AUC(inf)) of istradefylline by 2.5-fold.

MANAGEMENT: The manufacturer suggests that the maximum dose of istradefylline when coadministered with potent CYP450 3A4 inhibitors be reduced to 20 mg once daily. Patients should be monitored for adverse effects including dyskinesia, impulse control issues, dizziness, constipation, nausea, hallucinations, and insomnia.

MONITOR: Coadministration of tenofovir and darunavir-ritonavir or darunavir-cobicistat may result in increased plasma concentrations of tenofovir and darunavir. Increased tenofovir plasma concentration may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction is unknown; however, increased tenofovir concentrations may be related to inhibition of P-glycoprotein by darunavir, cobicistat, or ritonavir in the renal tubules. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. In 12 study subjects, administration of darunavir-ritonavir (300 mg-100 mg twice daily) with tenofovir (300 mg once daily) increased the systemic exposure (AUC) and trough plasma concentration (Cmin) of darunavir by 21% and 24%, respectively, compared to administration without tenofovir. Tenofovir AUC and Cmin also increased by 22% and 37%, respectively, in the presence of darunavir-ritonavir. Data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Caution and close monitoring of renal function is recommended if darunavir-ritonavir or darunavir-cobicistat is to be used in combination with tenofovir, particularly in patients with risk factors for renal impairment. No dose adjustments appear necessary during coadministration of darunavir-ritonavir with tenofovir. However, initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir) or is nephrotoxic.

MONITOR: Concomitant use of tenofovir with cobicistat may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction has not been described. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. When given concomitantly with cobicistat, the systemic exposure (AUC) and trough plasma concentrations (Cmin) of tenofovir was also increased by 23% and 55%, respectively. However, data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir), or is nephrotoxic. If concomitant therapy is necessary, monitoring of renal function is recommended, particularly in patients with risk factors for renal impairment.

MONITOR: Coadministration with istradefylline may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) transporter. The proposed mechanism is inhibition of P-glycoprotein-mediated drug efflux by istradefylline. When a single dose of the P-gp probe substrate digoxin (0.4 mg) was administered with istradefylline (40 mg daily for 21 days), the Cmax and total systemic exposure (AUC(inf)) of digoxin was increased by 33% and 21%, respectively, when compared with digoxin alone.

MANAGEMENT: Caution is advised when istradefylline is used concurrently with drugs that are known P-gp substrates, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever istradefylline is added to or withdrawn from therapy.

GENERALLY AVOID: Cobicistat may increase the plasma concentrations of antiretroviral agents. The plasma concentrations of cobicistat may also be increased or reduced in the presence of antiretroviral agents. The proposed mechanism is cobicistat inhibition of the CYP450 3A4 isoenzyme, of which antiretroviral agents may be substrates, and the inhibition or induction of CYP450 3A4 by concomitant antiretroviral medications. Cobicistat is a mechanism-based inhibitor and substrate of CYP450 3A4 with no antiretroviral activity of its own. Rather, it is indicated in its capacity as a pharmacokinetic booster of CYP450 3A4 to increase the systemic exposure of some antiretroviral medications such as atazanavir, darunavir, and elvitegravir, which are substrates of this isoenzyme. Concomitant use of other antiretroviral agents with cobicistat may also increase the plasma levels and risk of side effects associated with these medicines. In contrast, concomitant use of cobicistat-boosted atazanavir or darunavir with CYP450 3A4 inducers nevirapine, etravirine, or efavirenz may reduce the plasma concentrations of cobicistat, darunavir, and atazanavir, leading to a potential loss of therapeutic effect and development of resistance to darunavir and atazanavir. Pharmacokinetic data are not available.

MANAGEMENT: Cobicistat is not intended for use with more than one antiretroviral medication that requires pharmacokinetic enhancement, such as two protease inhibitors or elvitegravir in combination with a protease inhibitor. In addition, cobicistat should not be used concomitantly with ritonavir due to their similar effects on CYP450 3A4. According to some authorities, use of the antiretroviral combinations of atazanavir-cobicistat or darunavir-cobicistat concomitantly with the CYP450 3A4 inducers efavirenz, etravirine, or nevirapine is also not recommended. Other authorities consider the administration of atazanavir-cobicistat with efavirenz or nevirapine to be contraindicated. Since dosing recommendations have only been established for a number of antiretroviral medications, product labeling and current antiretroviral treatment guidelines should be consulted.

MONITOR: Coadministration with moderate inhibitors of CYP450 3A4 may increase the plasma concentrations of istradefylline, which is primarily metabolized by CYP450 3A4 and 1A1. In study subjects, administration of a single 40 mg dose of istradefylline with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 4 days) increased the total systemic exposure (AUC(inf)) of istradefylline by 2.5-fold. No data are available regarding the effects that other, less potent CYP450 3A4 inhibitors will have on the pharmacokinetics of istradefylline.

MANAGEMENT: Caution is advised if istradefylline is used with moderate CYP450 3A4 inhibitors. It is unknown if istradefylline will require a dosage adjustment if coadministered with a moderate CYP450 3A4 inhibitor. Clinical and laboratory monitoring of istradefylline should be considered whenever a moderate CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be monitored for adverse effects including dyskinesia, impulse control issues, dizziness, constipation, nausea, hallucinations, and insomnia.