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

MONITOR: Coadministration with darunavir may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by darunavir.

MANAGEMENT: Caution is advised if darunavir must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever darunavir is added to or withdrawn from therapy.

MONITOR: Coadministration with potent inhibitors of CYP450 2C8, 2C9, and/or 3A4 may increase the plasma concentrations and toxicities of tretinoin, which is a substrate of these isoenzymes. There have been isolated reports of pseudotumour cerebri, hypercalcemia, and acute renal failure in patients receiving tretinoin with fluconazole, itraconazole or voriconazole, all of which are considered potent inhibitors of at least one CYP450 isoenzyme involved in the metabolism of tretinoin. The conditions resolved following interruption of tretinoin therapy and/or discontinuation of the azole antifungal agent. As tretinoin is thought to undergo autoinduction of its own metabolism, CYP450 inhibitors have been investigated for use to boost plasma tretinoin concentrations and to overcome treatment resistance that often occurs with continued tretinoin therapy. In a study of two patients with acute promyelocytic leukemia, tretinoin systemic exposure (AUC) was found to be reduced significantly from baseline after one week of treatment. Following two daily doses of fluconazole administered 1 hour before tretinoin, the AUC of tretinoin increased by about 2- to 4-fold compared to day eight of tretinoin treatment alone, but similar to AUCs reported at baseline. In 13 patients who had received tretinoin daily for 4 consecutive weeks, administration of ketoconazole (400 to 1200 mg oral dose) 1 hour before the tretinoin dose on day 29 led to a 72% increase in tretinoin mean plasma AUC. Likewise, in 6 patients with lung cancer, a single 400 mg dose of ketoconazole (but not a 200 mg dose) one hour before tretinoin on day 29 increased tretinoin AUC by 115% compared to day 28 when tretinoin was given alone. No effect was observed when ketoconazole was given on day 2 relative to tretinoin alone on day one. By contrast, one study showed that prolonged ketoconazole administration (400 mg initially, then 200 mg daily for 14 days) in patients receiving tretinoin (45 mg/m2 twice daily for 14 days) had no effect on tretinoin auto-induction, but was associated with more vomiting.

MANAGEMENT: Caution is advised when tretinoin is prescribed in combination with potent inhibitors of CYP450 2C8, 2C9, and/or 3A4. Patients should be closely monitored and advised to seek medical attention immediately if they develop early symptoms of pseudotumour cerebri such as headache, nausea, vomiting, visual disturbances, photosensitivity, and tinnitus.

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.

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.