Drug Interactions between pirtobrutinib and Stribild

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of pirtobrutinib, which is primarily metabolized by the isoenzyme. When pirtobrutinib (200 mg single dose) was administered with itraconazole, a potent CYP450 3A4 inhibitor, pirtobrutinib systemic exposure (AUC) increased by 49%. Increased exposure to pirtobrutinib may increase the risk of infection, bruising, bleeding, fatigue, musculoskeletal pain, diarrhea, edema, and dyspnea.

MANAGEMENT: Coadministration of pirtobrutinib with potent CYP450 3A4 inhibitors should be avoided. If concomitant use of a potent CYP450 3A4 inhibitor is unavoidable, reduce the pirtobrutinib dose by 50 mg. If the current dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of potent CYP450 3A4 inhibitor use. After discontinuation of a potent CYP450 3A4 inhibitor for 5 half-lives, resume the pirtobrutinib dose that was taken prior to initiating the potent CYP450 3A4 inhibitor.

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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.

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MONITOR: Coadministration with pirtobrutinib may increase the plasma concentrations of drugs that are substrates of CYP450 2C8, 2C19, 3A4, P-glycoprotein (P-gp), and/or breast cancer resistance protein (BCRP). The peak plasma concentration (Cmax) and systemic exposure (AUC) of repaglinide, a CYP450 2C8 substrate, increased by 98% and 130%, respectively, and the Cmax and AUC of omeprazole, a CYP450 2C19 substrate, increased by 49% and 56%, respectively, when administered with pirtobrutinib. The Cmax and AUC of oral midazolam, a CYP450 3A4 substrate, increased by 58% and 70%, respectively, while exposure to IV midazolam was not significantly affected, when administered with pirtobrutinib. The Cmax and AUC of digoxin, a P-gp substrate, increased by 51% and 17%, respectively, when administered with a single pirtobrutinib dose (200 mg), and 55% and 35%, respectively, when administered with multiple pirtobrutinib doses (200 mg daily). The Cmax and AUC of rosuvastatin, a BCRP substrate, increased by 146% and 140%, respectively, when administered with pirtobrutinib. The risk of adverse reactions related to these substrates may be increased.

MANAGEMENT: Caution is advised if pirtobrutinib is used concomitantly with substrates of CYP450 2C8, 2C19, 3A4, P-gp, and/or BCRP, particularly sensitive substrates or those with a narrow therapeutic range. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.

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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.

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