Assessment of Intrasubject Variability of Pharmacokinetic Parameters in Clinical Studies
- PDF / 558,490 Bytes
- 11 Pages / 504 x 720.24 pts Page_size
- 94 Downloads / 170 Views
0092-8615i97 Copyright 0 1997 Drug lnformation Association Inc.
ASSESSMENT OF INTRASUBJECT VARIABILITY OF PHARMACOKINETIC PARAMETERS IN CLINICAL STUDIES CHENG-TAO CHANG,PHD Ohmeda Inc., Liberty Comer, New Jersey
ROBERTL. WONG,MD Morns Plains, New Jersey
According to the current bioavailabilityhioequivalence regulations by the Food arid Drug Administration (FDA), comparison of mean bioequivalence values between two formulations of the same drug in pharmacokinetic studies is suflcient for approval of the new formulation in a new drug application. Intrasubject variability ofpharmacokinetic parameters may still statistically differ between two bioequivalent formulations which cannot be proven based on the typical 2 x 2 crossover design if no repeated measures for the same formulation can be evaluated. When repeated meaures are required in a study protocol, a parallel group study design may be preferred over a crossover study design due to a pharmacological a d o r clinical reason. This paper evaluates two issues regarding intrasubject variability based on a parallel group design with repeated measures by two different approaches: 1. Conventional analysis of variance and 2. Individual subjects with respect to: an estimation procedure for variance and coefficient of variation (CV) with an emphasis on the different estimates for the CC: and different methods (parametric or nonparametric)for the comparison of variability with regard to variance and CK Key Words: Intrasubject variance; Intrasubject coefficient of variation (CV); Repeated measures; Parallel group design with repeated measures; Nonpararnetric analysis
INTRODUCTION I N BIOAVAILABILITY/BIOEQUIVALENCE studies, a 2 x 2 crossover trial design is normally used to determine whether the average bioavailability of a new (or tested) drug formulation is bioequivalent to the standard (or marketed) formulation (eg, if a generic drug is bioequivalent to the innovator drug) (1). In such a trial design, an “intrasubject” variance for any given pharmacokinetic (PK) parameter is estimated from the mean squared error in the analysis of variance. The “intrasubject” variance is used as the error term in constructing the 90% confidence intervals for the difference of the two formulation means as well as employing Schuirmann’s two one-sided t-tests.
Presented at the DIA “First International Taipei Symposium,” August 29-30, 1996, Taipei, Taiwan. Reprint address: Cheng-Tao Chang, PhD, Ohmeda Inc., PO Box 804/110 Allen Rd, Liberty Comer, NJ 079380804.
1203 Downloaded from dij.sagepub.com at NANYANG TECH UNIV LIBRARY on May 27, 2015
Cheng-Tao Chang and Robert L Wong
1204
This type of “intrasubject” variance is not actually the intrasubject variance since the ideal intrasubject variance should be computed from a series of observations collected over a period of time for the same subject under the same treatment. Since evaluation of each subject in a typical 2 x 2 crossover design is made on two different occasions under two different treatments, intrasubject variability for ea
Data Loading...
