Optimal sampling times for a drug and its metabolite using SIMCYP(®) simulations as prior information.

Background: Since 2007, it is mandatory for the pharmaceutical companies to submit a Paediatric Investigation Plan to the Paediatric Committee at the European Medicines Agency for any drug in development in adults, and it often leads to the need to conduct a pharmacokinetic study in children. Pharmacokinetic studies in children raise ethical and methodological issues. Because of limitation of sampling times, appropriate methods, such as the population approach, are necessary for analysis of the pharmacokinetic data. The choice of the pharmacokinetic sampling design has an important impact on the precision of population parameter estimates. Approaches for design evaluation and optimization based on the evaluation of the Fisher information matrix (M(F)) have been proposed and are now implemented in several software packages, such as PFIM in R.

Objectives: The objectives of this work were to (1) develop a joint population pharmacokinetic model to describe the pharmacokinetic characteristics of a drug S and its active metabolite in children after intravenous drug administration from simulated plasma concentration-time data produced using physiologically based pharmacokinetic (PBPK) predictions; (2) optimize the pharmacokinetic sampling times for an upcoming clinical study using a multi-response design approach, considering clinical constraints; and (3) evaluate the resulting design taking data below the lower limit of quantification (BLQ) into account.

Methods: Plasma concentration-time profiles were simulated in children using a PBPK model previously developed with the software SIMCYP(®) for the parent drug and its active metabolite. Data were analysed using non-linear mixed-effect models with the software NONMEM(®), using a joint model for the parent drug and its metabolite. The population pharmacokinetic design, for the future study in 82 children from 2 to 18 years old, each receiving a single dose of the drug, was then optimized using PFIM, assuming identical times for parent and metabolite concentration measurements and considering clinical constraints. Design evaluation was based on the relative standard errors (RSEs) of the parameters of interest. In the final evaluation of the proposed design, an approach was used to assess the possible effect of BLQ concentrations on the design efficiency. This approach consists of rescaling the M(F), using, at each sampling time, the probability of observing a concentration BLQ computed from Monte-Carlo simulations.

Results: A joint pharmacokinetic model with three compartments for the parent drug and one for its active metabolite, with random effects on four parameters, was used to fit the simulated PBPK concentration-time data. A combined error model best described the residual variability. Parameters and dose were expressed per kilogram of bodyweight. Reaching a compromise between PFIM results and clinical constraints, the optimal design was composed of four samples at 0.1, 1.8, 5 and 10 h after drug injection. This design predicted RSE lower than 30 % for the four parameters of interest. For this design, rescaling M(F) for BLQ data had very little influence on predicted RSE.

Conclusion: PFIM was a useful tool to find an optimal sampling design in children, considering clinical constraints. Even if it was not forecasted initially by the investigators, this approach showed that it was really necessary to include a late sampling time for all children. Moreover, we described an approach to evaluate designs assuming expected proportions of BLQ data are omitted.