Exploring Pharmacokinetic Discrepancies of Chiral Drugs with Unidirectional Enantiomeric Conversion

Many chiral drugs are routinely formulated as racemic mixtures, containing bio-active S(+)- and bio-inactive R(-)-enantiomers, and the latter can unidirectionally convert into the former. Their biological differences can significantly affect the effective concentration in plasma, which further impact therapeutic efficacy and safety. In this study, we aim to investigate the pharmacokinetic discrepancies of above-mentioned chiral drugs induced by these two enantiomers, using published compartment pharmacokinetic models following intravenous bolus and extravascular administrations. As a result, the analytical solutions for drug concentration-time profiles, key pharmacokinetic surrogates and discrepancies between the total measured and the effective concentrations are qualitatively derived. Taking ibuprofen as a case, quantitative characterization by simulations demonstrate that the discrepancies can be significant. For particular extravascular administration, the effective peak concentration is lower and the corresponding peak timing is delayed compared with the measured counterparts. Sensitivity analysis further reveals that the discrepancies in peak concentrations and corresponding peak times are significantly affected by model parameters. Goodness-of-fit demonstrates the necessity for enantiomer-specific models for chiral drugs. These findings provide a theoretical basis for pharmacokinetic dynamics of such chiral drugs and decision making for optimizing dosing strategies.