Mamoru Narukawa | PubMed Health

PubMed2005

A note on population pharmacokinetic studies with a single sampling design.

The choice of sampling time point in a population pharmacokinetic study with severe limitation on the number of samples per study subject (single sampling design) is critical in obtaining reliable parameter estimates. The authors have investigated the relationship between the timing as well as the degree of distribution of a sampling point among study subjects and the reliability of the estimates of pharmacokinetic parameters in a population pharmacokinetic study. This was achieved through a simulation, assuming an intravenously administered drug whose pharmacokinetic profile follows a 1-compartment model. The convergence rate of the NLMIXED procedure as well as the values of bias and MSE for the estimated parameters showed great variability depending on the sampling schedules. The results indicate that, in the case of a single sampling design, the sampling points should be distributed as widely as possible over a time range along the concentration-time profile to obtain reliable parameter estimates.

Blood Specimen Collection↗

PubMed2004

Observation of time-dependent adverse events and the influence of drop-out thereon in long-term safety studies--simulation study under the current practice of post-marketing safety evaluation in Japan.

Safety assessment of a new drug should be continuously carried out in the premarketing phase as well as in the postmarketing phase. Considering the actual conditions and problems of postmarketing safety studies in Japan, i.e., the lack of attention to the extent of patients' exposure to the drug (duration and the number of patients), we simulated the number of adverse events to be observed after specified intervals of exposure. This was done by applying different sets of hazard functions for a Weibull distribution under the circumstances that a certain number of patients has dropped out, focusing on rare and delayed adverse events associated with chronically used drugs. By using the result of these simulations, we point out potential problems of underestimating adverse event rates in situations where the hazard rate of the event escalates over time. Patients drop-out from the study also deteriorates the ability to observe such time-dependent adverse events. The simulation can also serve as a useful tool to examine the necessary sample size and the duration of exposure in order to observe and characterize potentially expected adverse events. It is important to take the two key factors into consideration: the change of hazard function over time and the effect of drop-out in designing, analyzing, and evaluating safety studies for new drugs.

Computer Simulation↗