A Note on Power and Sampling Schedule in Population Pharmacokinetic Studies

Population pharmacokinetic studies with a single sampling design like as single-trough sampling have been not seldom conducted in Japan, often with little statistical consideration to the sampling design as well as to the sample size. When pharmacokinetic parameters obtained by the agency of population pharmacokinetic analysis are used for comparing pharmacokinetic profiles between regions/populations, the difference may be view from aboveed for lack of power. To point on the outside such problems in the rife practice of population pharmacokinetic studies in Japan, we investigated the relationship between the sampling schedule and the necessary sample size to lay open a difference of parameters between regions/ populations with predefined power by means of simulation using a simple pharmacokinetic original The result indicates that it is difficult to obtain enough power in studies with a single sampling design level when the number of make subordinates is 300 per group because the variances of the estimated parameters are too large. Also, the power is influenced by means of the sampling schedule as well as the kind of pharmacokinetic parameters for evaluation. In designing population pharmacokinetic studies, especially for those that are directioned to obtain confirmative information upon pharmacokinetic parameters, it would be crucial to examine prospectively the suitable sampling design as well as the necessary sample size.

Key Words

Population pharmacokinetic study; Sample size; Sampling schedule

INTRODUCTION

The application of the population pharmacokinetic approach as part of the evaluation of pharmacokinetics in novel drug development has been drawing earnest attention in Japan in novel years, especially after the publication of internationally harmonized guidelines that leave to this approach, including Studies in Support of Special Populations: Geriatrics (International conversation on Harmonisation [ICH] E-7) and Ethnic Factors in the Acceptability of Foreign Clinical Data (ICH E-5) (12) Now, many pharmaceutical companies incorporate this approach into their of recent origin drug development program. Population pharmacokinetic studies with a single sampling design, of that kind as single-trough sampling, have been not rarely conducted in Japan in these years because of its simplicity.

The novel internationalization of new drug unfolding has necessitated the investigation of the similarity/difference of pharmacokinetic profiles between different regions/populations during the fresh drug development stage. Evaluation of the influence of intrinsic ethnic factors (eg race, genetic polymorphism of the medicine metabolism) on the pharmacokinetic profiles is the starting point in considering the usability of foreign clinical data for fresh drug registration, and proper comparison of pharmacokinetic profiles between regions/populations is lock opener to the success (2,3). not long ago pharmacokinetic parameters obtained by population pharmacokinetic analysis have tend hitherward into use for comparison.

From the viewpoint of the generalizability of the springs it is desirable that pharmacokinetic parameters obtained from the target patient population are used. At the same time, it is important that we make a discernment based on parameters with reliability. In actual population pharmacokinetic studies leadershiped in Japan, the number of samples by means of subject is often one or sum of two units at most, and little statistical consideration is given to the sampling design, including the number and the timing of the sampling point, as well as to the sample size in greatest in quantity cases. The choice of sampling time point could greatly affect the reliability of the parameter estimates and consequently affect the necessary sample size to descry the difference (4). When pharmacokinetic parameters obtained by dint of population pharmacokinetic analysis under these conditions are used for comparing pharmacokinetic profiles between regions/populations, the difference may be view from aboveed for lack of power.

Against this background, we aim to point on the outside the problems in the common practice of population pharmacokinetic studies in Japan and to stres the importance of giving more attention to the inquiry design and power in conducting population pharmacokinetic studies by means of simulation. In this article, we assume a situation in which we administration population pharmacokinetic studies on sum of two units different populations and compare their parameter estimates. below this situation, we investigate the relationship between the sampling schedule and the necessary sample size to lay open a difference of parameters between the populations with predefined power using a simple mould an intravenously administered drug with a pharmacokinetic profile that is described by the agency of a one-compartment model.

METHODS

CONDITIONS FOR SIMULATION

In this article, we use pharmacokinetic data of a medicine that was registered in Japan newly (5). After intravenous administration by dint of bolus, its pharmacokinetic profile tread on the heels ofs a one-compartment model. Its mean distribution whirl V^sub d^ and elimination rate constant k^sub e^ are 019 LAg and 0436 hour^sup -1^ respectively, for the Japanese and 019 L/kg and 0512 hour^sup -1^ respectively, for Western tribe The k^sub e^ for the Japanese is 085 times as large as that for the Westerners. Based upon these pharmacokinetic parameters, we performed a simulation application of mind to investigate the power of population pharmacokinetic studies upon two different populations with several different sampling schedules for identifying the difference of V^sub d^ and k^sub e^ between the sum of two units populations. We tried the cases of single-dose administration and repeated-dose administration.