Drug Interactions between glycerol phenylbutyrate and olanzapine / samidorphan

MONITOR: Coadministration of glycerol phenylbutyrate may lead to increased concentrations of CYP450 2D6 substrates. The proposed mechanism is inhibition of CYP450 2D6 by phenylbutyrate, the active moiety of glycerol phenylbutyrate, which has been shown to be an in vitro inhibitor of this isoenzyme. In in vitro studies, administration of phenylbutyrate at a concentration of 800 mcg/mL caused greater than 60% reversible inhibition of CYP450 2D6, 2C9, and 3A4/5. The clinical significance of these results has not been established; however, the manufacturer states that a potential interaction with CYP450 2D6 substrates cannot be ruled out.

MANAGEMENT: Caution is recommended if glycerol phenylbutyrate is administered with medicines that are substrates of CYP450 2D6, such as codeine, dextromethorphan, and some beta blockers (including metoprolol, carvedilol, labetalol, propranolol, and nebivolol). Dosage adjustments as well as clinical and laboratory monitoring may be appropriate.

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of samidorphan. According to the prescribing information, samidorphan is primarily metabolized by CYP450 3A4, with minor contributions from CYP450 2C8, 2C19, and 3A5. When olanzapine-samidorphan was coadministered with rifampin, a potent CYP450 3A4 inducer, samidorphan peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 44% and 73%, respectively. Olanzapine Cmax and AUC also decreased by 11% and 48%, respectively, most likely due to induction of CYP450 1A2 and/or uridine diphosphate glucuronosyltransferase (UGT) 1A4 by rifampin. The interaction has not been studied with other, less potent inducers.

MANAGEMENT: The potential for diminished pharmacologic effects of samidorphan and possibly also olanzapine should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.