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Are Literature References Sufficient for Dose Recommendations? An FDA Case Study of Efavirenz and Rifampin

From the Office of Clinical Pharmacology, Division IV (Dr DiGiacinto, Dr Robertson, Dr Reynolds) and the Office of New Drugs, Division of Anti-Viral Products (Dr Chan-Tack, Dr Struble), US Food and Drug Administration, Silver Spring, Maryland.

One of the numerous regulatory functions of the Food and Drug Administration (FDA) is the evaluation of drug-drug interactions and the determination of appropriate dose adjustments, if necessary, to ensure the safe and effective use of medications. The FDA considers several data sources when determining the significance of drug-drug interactions. The majority of dose adjustment recommendations are based on specific drug-drug interactions studies. The FDA reviews individual patient pharmacokinetic and safety data from drug interaction studies, determines appropriate dose adjustments, and provides recommendations to update the respective product labeling. Sometimes literature references are submitted to the FDA to support dosing recommendations. Determining an appropriate dose adjustment recommendation based on literature reports is a challenge for the FDA due to the lack of individual patient pharmacokinetic or safety data from these studies. Recently, the FDA encountered a challenging regulatory situation when evaluating literature reports to determine the appropriate dose of efavirenz and rifampin. Although numerous studies were found in the literature about this combination, a dosing recommendation cannot be concluded from the reported data. This article reviews the process the FDA used to evaluate literature to support potential dose adjustments for efavirenz when coadministered with rifampin and the challenges encountered during the process.

Key Words: Tuberculosis • HIV • rifampin • efavirenz • drug interaction

Address for correspondence: Kimberly A. Struble, PharmD, WO 22, Rm 6374, 10903 New Hampshire Ave, Silver Spring, MD 20993; e-mail: kimberly.struble{at}fda.hhs.gov.

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