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

GENERALLY AVOID: Coadministration with inducers of P-glycoprotein (P-gp) may decrease the oral bioavailability and plasma concentrations of tenofovir alafenamide (TAF), which is a substrate of the efflux transporter. In 26 healthy study subjects, administration of TAF (25 mg once daily) with the P-gp inducer carbamazepine (300 mg twice daily) decreased TAF plasma concentration (Cmax) and systemic exposure (AUC) by an average of 57% and 55%, respectively, compared to TAF administered alone. It is not known if, and to what extent, tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, may interact with P-gp inducers. The interaction has not been studied with TDF, and no information is found in the labeling of various products containing TDF, although it has been reported to be a P-gp substrate also.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of tenofovir alafenamide fumarate with P-gp inducers is not recommended. Whether this also applies to tenofovir disoproxil fumarate has not been established.

GENERALLY AVOID: Coadministration with cobicistat may significantly increase the plasma concentrations of rifabutin and its metabolite, 25-O-desacetylrifabutin. The proposed mechanism is cobicistat inhibition of rifabutin metabolism via CYP450 3A4. In 12 healthy volunteers, administration of rifabutin 150 mg once every other day in combination with 150 mg once daily each of cobicistat and elvitegravir had no significant effect on the pharmacokinetics of rifabutin, but increased mean 25-O-desacetyl-rifabutin peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by approximately 4.8-, 6.3- and 4.9-fold, respectively, compared to administration of rifabutin alone at 300 mg once daily. Uveitis and neutropenia secondary to rifabutin toxicity may occur. On the other hand, cobicistat plasma concentrations may be significantly decreased due to CYP450 3A4 induction by rifabutin. In the same study mentioned above, the Cmin of cobicistat decreased by 66%.

MANAGEMENT: Concomitant use of cobicistat-containing fixed combination antiretroviral products with rifabutin is not recommended. However, if concomitant use is needed, to minimize the risk of rifabutin toxicity including leucopenia, uveitis, arthralgias, and skin discoloration, some authorities recommend that the rifabutin dosage be reduced to 150 mg every other day or three times a week in patients treated with cobicistat. A further dosage reduction of rifabutin to 150 mg twice weekly may be necessary for patients in whom the 150 mg three times per week dose is not tolerated. A complete blood count should be performed at least weekly and as clinically indicated to monitor for development of neutropenia. Due to the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, close monitoring of antiretroviral response is also recommended. Current guidelines should be consulted for the appropriate treatment of tuberculosis in HIV-infected patients.

ADJUST DOSE: Coadministration of rifabutin and darunavir/ritonavir is expected to increase the plasma concentrations of rifabutin and its 25-O-desacetylrifabutin metabolite and may also increase the plasma concentrations of darunavir and ritonavir. The proposed mechanism involves ritonavir inhibition of rifabutin metabolism via CYP450 3A4. In 11 study subjects, administration of lower-dose rifabutin (150 mg every other day for 12 days) and darunavir/ritonavir (600 mg/100 mg twice daily for 12 days) resulted in non-significant changes in the peak plasma concentration (Cmax), systemic exposure (AUC), and trough plasma concentration (Cmin) of rifabutin, as compared to the standard dose of rifabutin alone (300 mg once daily). In the same study, Cmax, AUC, and Cmin of darunavir were increased by 57%, 42% and 75% respectively. Uveitis secondary to rifabutin toxicity has been reported in some cases.

MANAGEMENT: To minimize the risk of rifabutin toxicity including leukopenia, uveitis, arthralgias and skin discoloration, darunavir labeling recommends that rifabutin dosage be reduced to 150 mg every other day in patients treated with darunavir/ritonavir or darunavir/cobicistat. A complete blood count should be performed at least weekly and as clinically indicated to monitor for development of neutropenia. Local guidelines should be consulted for appropriate recommendations.

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.