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Evaluation of intravenous midazolam limited sampling models to determine area under the concentration time curve during cytochrome P450 3A baseline, inhibition and induction or activation

Anh N. Nguyen, Justin T. Hoffman, Shirley M. Tsunoda, In-Jin Jang and Joseph D. Ma

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Volume 50 p. 468 - 475

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 7/2012 (468-475)

Evaluation of intravenous midazolam limited sampling models to determine area under the concentration time curve during cytochrome P450 3A baseline, inhibition and induction or activation

Anh N. Nguyen¹, Justin T. Hoffman¹, Shirley M. Tsunoda¹, In-Jin Jang² and Joseph D. Ma¹

¹University of California, San Diego (UCSD), Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA, and ²Seoul National University College of Medicine, Seoul, South Korea
Objective: This study evaluated if previously published limited sampling models (LSMs) accurately predict midazolam area under the concentration time curve (AUC) during cytochrome P450 (CYP) 3A baseline, inhibition and induction/activation. Materials and methods: Plasma midazolam concentrations (n = 108) were obtained where intravenous midazolam was co-administered alone or concomitantly with ketoconazole, itraconazole, aprepitant, rifampin, or pleconaril. Observed AUC was calculated using noncompartmental analysis. Predicted AUC was calculated from the LSMs. Bias and precision were determined by percent mean prediction error (%MPE), percent mean absolute error (%MAE), and percent root mean squared error (%RMSE). Results: Contrasting results were observed for LSMs in predicting CYP3A baseline activity, with the majority of studies resulting in unacceptable bias and precision. During CYP3A inhibition, unacceptable bias and precision were observed from single- and 2-time point LSMs. %MAE and %RMSE values exceeded acceptable limits during CYP3A induction with rifampin. Contrasting results were observed with pleconaril. Conclusion: The contrasting results during CYP3A baseline and induction/activation, as well as the unacceptable bias and precision during CYP3A inhibition, limits the widespread use of the previously published LSMs.Correspondence to:
Joseph D. Ma, PharmD, UCSD
Skaggs School of Pharmacy and Pharmaceutical Sciences
9500 Gilman Drive, MC 0714
La Jolla, CA 92093, USA
Email: [email protected]

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