Influence of body composition on disposition of the highly fat distributed compound as analysed by physiologically based pharmacokinetic (PBPK) modeling and simulation

摘要

Abstract A recent study suggested that the pharmacokinetics (PK) of highly fat distributed compounds can be affected by acute changes in the volume of adipose tissue. The present study investigates possible influences of body composition on the disposition of the highly lipophilic compound TAK‐357 in two rat strains. Physiologically based PK (PBPK) modeling and simulation was applied on single and multiple dose PK data of TAK‐357 in obese Wistar fatty rats and Wistar lean rats having approximately 45% and 13% body fat, respectively. The observed effects of an elevated fat mass in Wistar fatty rats on the plasma concentrations appeared to be partly compensated for by other differences between the two rat strains. A decrease in the tissue to blood partition coefficients under high body fat conditions was identified as another factor contributing to the difference in PK. A higher lipid content in the plasma in high body fat animals may result in relatively lower tissue to blood partition coefficients. PBPK‐based simulations indicate that the plasma concentrations of lipophilic compounds in high body fat conditions can differ by up to two‐times at steady‐state. This confirms that there is only a small impact of body composition change on the plasma concentration of highly lipophilic drugs and that the need for therapeutic dose adjustments may be limited.