Drug Interaction Report

Coadministration with osimertinib may alter the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4. In vitro, osimertinib has been shown to be a competitive inhibitor as well as inducer of CYP450 3A4. However, a clinically significant inhibitory effect on CYP450 3A4 has not been demonstrated in clinical drug interaction studies. In a pharmacokinetic study of 49 patients with non-small cell lung cancer, coadministration of osimertinib with the sensitive CYP450 3A4 substrate simvastatin decreased the area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) of simvastatin by approximately 9% and 23%, respectively. These reductions are also not considered clinically significant. Based on these observations, osimertinib may be administered with CYP450 3A4 substrates without the need for increased clinical monitoring.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of buspirone. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

ADJUST DOSING INTERVAL: In a small, randomized, crossover study, the consumption of large amounts of grapefruit juice (compared to water) was associated with significantly increased plasma buspirone concentrations, slightly prolonged elimination half-lives, and delayed times to reach peak drug concentration. The perceived pharmacodynamic effect of buspirone, as measured by subjective drowsiness and overall subjective drug effect, was also enhanced by grapefruit juice. These alterations may stem from the delay of gastric emptying as well as inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving buspirone should be advised to avoid consumption of alcohol. Patients also should preferably avoid the consumption of large amounts of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. If this is not possible, the buspirone dose should be taken at least 2 hours before or 8 hours after grapefruit or grapefruit juice. Monitoring for increased CNS depression is recommended.