Pharmacometric and statistical considerations for dose optimization.

Abstract

The probability of target attainment (PTA) is a common metric in drug dose optimization, but it requires a specific known target concentration threshold. Such target thresholds are not always available for some treatments, and patient and disease groups, particularly when treating children. This study performed pharmacokinetic and pharmacokinetic-pharmacodynamic (PKPD) simulations to explore different statistical approaches for determining the optimal dose for unknown PK and PKPD targets. To determine an optimal dose, PK and PKPD outcomes in typical patients with a standard adult dosing regimen were simulated and set as the reference profile, and compared to simulated outcomes for different dosing regimens in the population of interest. Statistical distances between the empirical cumulative distribution functions of the outcomes from all possible dosing regimens were calculated and compared to the reference profile. An optimal dose for known PK and PKPD target outcomes was selected to maintain the outcome above the assigned target, while optimal dosing in a population of interest with an unknown target was selected to generate equivalent PK and PKPD outcomes as the typical population. All of the dose optimization methods with commonly used PK and PKPD models and covariates were implemented as an open source freely available Shiny web-application. The developed pharmacometric method for dose optimization in populations with known and unknown target levels were robust and reproducible, and the implementation of a freely accessible Shiny web-application ensures widespread use and could be a useful tool for dose optimization in populations of interest.