Additional Notes on Clinical Repeated-Dose Pharmacokinetic Trials Applying a Peak-and-Trough Sampling Design to Estimate Oral Clearance

抄録

  In the previous study, we performed a simulation of a clinical pharmacokinetic trial, in which blood was sampled at two time points corresponding to the peak concentration (C_peak) and trough concentration (C_trough) following repetitive oral administration at the dose, D, and dosing interval, τ. The approximate oral clearance (CL/F_approx), estimated as 2·D/(C_peak·τ+C_trough·τ), is accurate for drugs with an elimination half-life comparative to or longer than τ; however, it was suggested that we might not use CL/F_approx for drugs with a considerably short elimination half-life relative to τ. In the present study, we evaluated the accuracy of the alternative oral clearance (CL/F_exp) estimated by the simple monoexponential model. In contrast to CL/F_approx, CL/F_exp was accurate for drugs with a short elimination half-life relative to τ. The present finding in conjunction with our previous study suggested that the peak-and-trough sampling design is promising for the clinical repeated-dose pharmacokinetic trial for drugs with not only slow but also rapid elimination from the body. We think that the accuracy and precision of the two analysis methods to estimate oral clearance (CL/F_approx and CL/F_exp) for a target drug should be evaluated carefully before and after a real clinical trial.