Minimal Physiologically-Based Pharmacokinetic Modeling of Atenolol and Metoprolol Absorption in Malnourished Rats

Background and Objective: The pharmacokinetics of drugs can be altered by pathophysiological changes in the body that result from malnutrition. The objective of this study was to evaluate the profiles derived from in vivo studies conducted on non-malnourished (control) and malnourished rats using minimal physiologically based pharmacokinetic (mPBPK) models. Methods: Single oral doses of atenolol (ATN) and metoprolol (MET) were administered to non-malnourished and malnourished rats. We demonstrate how plasma profiles can be evaluated using mPBPK models with high and low tissue-to-plasma partition coefficients (K_p) and elimination by either kidney or liver. A decrease in blood flow and cardiac output due to beta-blocker administration was assumed. Reference IV profiles from the literature were included to inform the mPBPK model and to help assess the absorption phases of individual oral profiles. Absorption was captured as two or three sequential zero-order processes for both drugs, and IV and oral profiles were assessed by joint fitting. Modeling was performed using both naïve pooling (ADAPT) and population (Monolix) analyses. Results: The experimental data show increased AUC values of MET and ATN in malnourished rats. Accordingly, an increased bioavailability (from 0.43 to 0.67) for ATN and an increased bioavailability (from 0.42 to 0.84) for MET in the malnourished group were related to higher absorption rates in both absorption phases. Conclusions: This study demonstrated advantageous use of mPBPK modeling with malnutrition primarily altering drug absorption in this animal model. Also, our analysis offers a blend of known and assumed components assembled mechanistically to suggest a reasonable interpretation of the PK profiles.