Abstract

A previous study reported a 2- and 3-timepoint limited sampling strategy (LSS) model accurately predicted oral midazolam area under the concentration time curve (AUC), and thus cytochrome P450 (CYP) 3A activity. Objective: This study evaluated whether the LSS models predict midazolam AUC during CYP3A baseline, inhibition and induction/activation. Materials and methods: Plasma midazolam concentrations from 106 healthy adults from 6 published studies were obtained where oral midazolam was co-administered alone or with ketoconazole, double-strength grapefruit juice, Ginkgo biloba extract, pleconaril, or rifampin. Observed and predicted midazolam AUCs were determined. Bias and precision of the LSS models were determined. Results: Contrasting results were observed for the 2- and 3-timepoint LSS models in accurately predicting midazolam AUC during baseline CYP3A conditions. With the exception of 1 study (single dose, double-strength grapefruit juice), the 2- and 3-timepoint LSS models did not accurately predict midazolam AUC during conditions of CYP3A inhibition and induction/activation. Conclusion: The previously reported 2- and 3-timepoint oral midazolam LSS models are not applicable to the evaluated conditions of CYP3A baseline, inhibition, and induction/ activation.

Author Details

Authors

• J.D. Ma¹
• E.T. Nguyen¹
• S.M. Tsunoda¹
• H.E. Greenberg²
• J.C. Gorski³
• S.R. Penzak⁴
• L.S. Lee⁵

Departments

• ¹ University of California, San Diego (UCSD), Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA,
• ² Clinilabs, New York, NY,
• ³ Mylan Pharmaceuticals, Inc., Morgantown, WV,
• ⁴ Warren G. Magnuson Clinical Center, Pharmacy Department, National Institutes of Health, Bethesda, MD, and
• ⁵ Consultant, San Diego, CA, USA

Address

J.D. Ma, PharmD
UCSD, Skaggs School of Pharmacy and Pharmaceutical Sciences
9500 Gilman Drive, MC 0714
La Jolla, CA, 92093-0714, USA
Email: [email protected]

Citation