2019 Volume 50 Issue 3 Pages 89-95
Draft guidelines on population pharmacokinetics/pharmacodynamic analysis suggest that population pharmacokinetics (PPK) analysis would be a highly useful method for evaluating ethnic difference and appropriate dosages for individual patients. The results of such analyses are beginning to be included in package inserts and interview forms, but the validity of those data has not yet been evaluated. In the present study, we investigated and discussed the issue of whether PPK analysis can detect factors that are deduced from the pharmacokinetic characteristics of drugs or detected by clinical pharmacokinetic (CPK) studies.
Among 112 drugs that had been newly approved in Japan in 2016, we excluded blood products, vaccines, radiopharmaceuticals, in vivo diagnostic agents, high-molecular-weight drugs and drugs for which blood concentrations had not been determined. Clinical pharmacokinetic parameters (bioavailability, urinary excretion rate of unchanged drug, systemic clearance, volume of distribution, unbound fraction in plasma, and blood-to-plasma ratio) were extracted from the package insert, interview form, and review report and summary technical documentation. The results obtained from PPK and CPK analyses were compared based on the pharmacokinetic characteristics of each drug.
Twenty drugs were eligible for comparison, and PPK analysis was performed on all of them. Among 15 drugs in which CPK studies detected changes in blood concentrations in patients with liver or kidney dysfunction, significant covariates were detected by PPK analysis in only 6 drugs.
In order to increase the detection power of covariates by PPK analysis in patients with liver or kidney dysfunction, a proper study design should be developed based on information about expected factors related to the variability of blood drug concentrations, particularly the blood unbound drug concentrations, using pharmacokinetic data from healthy volunteers. When providing data from PPK analysis, it is necessary to clearly define the background and indicate the limitations.