Volume 39, Issue 12 p. 1212-1220

Concurrent Administration of the Erythromycin Breath Test (EBT) and Oral Midazolam as In Vivo Probes for CYP3A Activity

Dr. Jacqueline McCrea PharmD

Corresponding Author

Dr. Jacqueline McCrea PharmD

Merck Research Laboratories, West Point, Pennsylvania, and Rahway, New Jersey

Clinical Pharmacology, Merck Research Laboratories, BL 1–13, Blue Bell, PA 19422.Search for more papers by this author
Dr. Thomayant Prueksaritanont PhD

Dr. Thomayant Prueksaritanont PhD

Merck Research Laboratories, West Point, Pennsylvania, and Rahway, New Jersey

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Dr. Barry J. Gertz MD, PhD

Dr. Barry J. Gertz MD, PhD

Merck Research Laboratories, West Point, Pennsylvania, and Rahway, New Jersey

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Dr. Alexandra Carides PhD

Dr. Alexandra Carides PhD

Merck Research Laboratories, West Point, Pennsylvania, and Rahway, New Jersey

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Ms. Lisa Gillen MS

Ms. Lisa Gillen MS

Thomas Jefferson University, Philadelphia, Pennsylvania

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Ms. Suzanne Antonello BS

Ms. Suzanne Antonello BS

Merck Research Laboratories, West Point, Pennsylvania, and Rahway, New Jersey

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Ms. Mary Jo Brucker BS

Ms. Mary Jo Brucker BS

Merck Research Laboratories, West Point, Pennsylvania, and Rahway, New Jersey

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Ms. Cynthia Miller-Stein BS

Ms. Cynthia Miller-Stein BS

Merck Research Laboratories, West Point, Pennsylvania, and Rahway, New Jersey

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Ms. Barbara Osborne RN

Ms. Barbara Osborne RN

Thomas Jefferson University, Philadelphia, Pennsylvania

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Dr. S. Waldman MD, PhD

Dr. S. Waldman MD, PhD

Thomas Jefferson University, Philadelphia, Pennsylvania

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First published: 08 March 2013
Citations: 52

Abstract

Given the prominent role of CYP3A in the metabolism of drugs, it is important to identify whether new chemical entities will affect this enzyme system and produce clinically relevant drug interactions. This study evaluated concomitant administration of intravenous [14C N-methyl] erythromycin (3μCi) (erythromycin breath test; EBT) and 2 mg oral midazolam as probes of systemic and of systemic plus presystemic CYP3A activity, respectively Twelve males received the probes in a two-period crossover fashion: one period included the probes on two occasions, 5 days apart; in the second period, 200 mg ketoconazole was given orally 2 hours prior to the probes. The within-subject CV for EBT (%14CO2/h) and midazolam AUC0-last was 4.9% and 16.9%, respectively. Ketoconazole reduced %14CO2/h by 43% and increased midazolam AUC0-last by approximately fivefold. In a nonrandomized third period (N = 5), ketoconazole was given simultaneously with midazolam (no EBT); midazolam AUC0-last was similar whether ketoconazole was given 2 hours prior to or simultaneously with the midazolam. The low midazolam dose was generally well tolerated; mild sedation was occasionally seen. Concurrent administration of the EBT and oral midazolam is a sensitive and reproducible tool to screen new chemical entities for potentially important CYP3A interactions.