EVALUATION OF TESTS BASED ON INDIVIDUAL VERSUS POPULATION MODELING TO COMPARE DISSOLUTION CURVES

Abstract

This study is aimed at comparing dissolution curves obtained for several batches of sustained release formulations of octreotide, a somatostatin analog used in acromegaly. We evaluated four tests to compare the parameters of two series of curves: a Mann-Whitney-Wilcoxon test comparing individual estimates; a likelihood ratio test after population analysis (NONMEM), and two Wald tests using population parameters estimated by two-stage methods. The four approaches were evaluated by simulations. The Mann-Whitney- Wilcoxon test and the population approach had adequate type-I error, and the latter provided the highest power under the alternatives simulated. The two-stage method including the uncertainty on individual estimates was disappointing.

Keywords:

• Dissolution curves
• Nonlinear regression
• Nonlinear mixed effect models
• Comparison of parameters
• Empirical type-I error

ACKNOWLEDGMENTS

This work was supported by research agreement No 96 145 between Inserm, France, and Novartis Pharma, Department of Drug Metabolism and Pharmacokinetics, Basel, Switzerland. We thank Novartis Pharma, and especially Dr. Ryosei Kawai, Dr. Peter Marbach, Dr. Gengenbacher, and Dr. Vonderscher, for the use of the data from in vitro dissolution tests, and for their assistance during this work.

We are indebted to Dr. Sylvie Huet, Department of Biometrics, INRA, Jouy-en-Josas, France, who developed with her colleagues the n1s2 functions [12], and kindly gave us advice and help. These functions are available at http:// www-bia.inra.fr/ or by ftp www-bia.inra.fr in pub/log/n1s2. We would also like to thank Dr. Jean-Louis Foulley for his help with the estimation of the asymptotic variance-covariance matrix in the case of linear mixed-effects models.