Drug Interactions between nirmatrelvir / ritonavir and sotorasib

MONITOR: Coadministration with drugs that are inducers of CYP450 3A4 may decrease the plasma concentrations of protease inhibitors (PIs), which are primarily metabolized by the isoenzyme.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, protease inhibitors should be used cautiously with agents that induce CYP450 3A4, particularly if only one PI is used in the antiretroviral regimen. Coadministration of atazanavir without ritonavir and carbamazepine, phenobarbital, or phenytoin is not recommended. Antiretroviral response should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the antiretroviral regimen adjusted as necessary.

MONITOR: Coadministration with sotorasib may alter the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme as well as the P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) membrane transporters. Sotorasib may increase clearance via induction of CYP450 3A4, resulting in decreased plasma concentrations of substrates that are metabolized by the isoenzyme. However, sotorasib may also increase systemic bioavailability of P-gp and BCRP substrates via inhibition of transporter-mediated efflux in the intestine and possibly other organs such as the liver and kidney. When midazolam, a sensitive CYP450 3A4 substrate, was coadministered with sotorasib, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 48% and 53%, respectively. These results suggest moderate induction of CYP450 3A4 by sotorasib. On the contrary, coadministration of digoxin, a P-gp substrate, with sotorasib increased digoxin Cmax by 91% and AUC by 21%. Coadministration of rosuvastatin, a BCRP substrate, with sotorasib increased rosuvastatin Cmax by 70% and AUC by 34%. The P-gp and BCRP inhibiting effects of sotorasib may be most prominent with orally administered drugs. No formal studies have been conducted to evaluate the net pharmacokinetic effect on drugs that are substrates of CYP450 3A4 as well as P-gp and/or BCRP.

MANAGEMENT: Caution is advised when sotorasib is used concomitantly with drugs that are substrates of CYP450 3A4 as well as P-gp and/or BCRP, particularly sensitive substrates or those with a narrow therapeutic range. The prescribing information recommends avoiding coadministration of sotorasib with CYP450 3A4, P-gp, and/or BCRP substrates for which minimal concentration changes may lead to therapeutic failure or serious toxicities. If coadministration is required, dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever sotorasib is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a moderate CYP450 3A4 inducer and P-gp/BCRP inhibitor like sotorasib and for any dosage adjustments that may be required.