Persistence of a Posaconazole-Mediated Drug-Drug Interaction With Ranolazine After Cessation of Posaconazole Administration: Impact of Obesity and Implications for Patient Safety

Journal of Clinical Pharmacology
Christina R ChowDavid J Greenblatt

Abstract

The antianginal agent ranolazine (Ranexa®) is metabolized primarily by cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors, such as ketoconazole and posaconazole, is contraindicated due to risk of QT prolongation from high levels of ranolazine. This study evaluated the time course of recovery from the posaconazole drug interaction in normal-weight and otherwise healthy obese subjects. Subjects received single doses of ranolazine in the baseline control condition, again during coadministration of posaconazole, and at 4 additional time points during the 2 weeks after posaconazole discontinuation. With posaconazole coadministration, the geometric mean ratio of ranolazine area under the concentration curve (AUC) increased by a factor of 3.9 in normals and by 2.8 in obese subjects. Posttreatment washout of posaconazole was slow in normals (mean half-life 36 hours) and further prolonged in obese subjects (64 hours). Recovery of ranolazine AUC toward baseline was delayed. AUC remained significantly elevated above baseline in normal-weight and obese subjects for 7-14 days after stopping posaconazole. Current product labeling does not address the need for delay or a reduced dose of ranolazine after disconti...Continue Reading

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Citations

May 22, 2020·Journal of Clinical Pharmacology·Brit Silja Rohr, Gerd Mikus
Apr 24, 2020·Drugs·Lu ChenRoger J M Brüggemann
Jan 16, 2021·British Journal of Clinical Pharmacology·Christopher D BrunoDavid J Greenblatt
Aug 3, 2021·Journal of Clinical Pharmacology·Christopher D BrunoDavid J Greenblatt
Dec 20, 2021·Therapeutic Drug Monitoring·Benjamin KablyEliane M Billaud

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