PMID: 8592662Nov 1, 1995Paper

Evaluation of bioequivalence of highly variable drugs using Monte Carlo simulations. I. Estimation of rate of absorption for single and multiple dose trials using Cmax

Pharmaceutical Research
Ahmed El-TahtawyT M Ludden

Abstract

A Monte Carlo simulation study was done to investigate the effects of high intrasubject variation in clearance (CL), and volume of distribution (V) on the calculation of the 90% confidence interval (CI) for Cmax for single dose and multiple dose studies. Simulations were done for both immediate release and sustained release scenarios. The simulated data were compared with clinical data from bioequivalence studies performed on indomethacin and verapamil. Previous reviews and simulations have shown that the probability of failure for the Cmax for single dose studies was always greater than that for multiple dose studies. However, the results for the simulated scenarios currently investigated indicate that if intra-subject (period-to-period) variation in CL and V is high (% CV's above 25%, and 12%, respectively), multiple dose studies can exhibit a higher probability of failure for Cmax than do single dose studies. Furthermore, Cmax values from studies performed with a sustained release scenario are more sensitive to changes in Ka, CL, and V than are results of studies on immediate release products. As an example, the probability of failure for immediate release products in simulated single dose studies is about 11% and 21% when t...Continue Reading

Citations

Jun 7, 2013·Therapeutic Delivery·Xinyuan ZhangLawrence X Yu
Oct 13, 2009·Clinical Pharmacokinetics·Laszlo TothfalusiAlfredo Garcia Arieta
Jun 3, 2000·Annual Review of Pharmacology and Toxicology·N H HolfordC C Peck
Dec 2, 2010·Expert Opinion on Drug Metabolism & Toxicology·Vangelis KaralisPanos Macheras
Aug 23, 2012·The AAPS Journal·Laszlo Endrenyi, Laszlo Tothfalusi
Jun 12, 2012·Expert Opinion on Drug Metabolism & Toxicology·Vangelis Karalis, Panos Macheras

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