Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85–90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, with most focusing on CLO-TH. Although CLO-CA is inactive, its predominant (compared to its parent drug and metabolites) presence in plasma underscores the importance of characterizing its formation and pharmacokinetic profile. This study aimed to characterize the process of the absorption of CLO and its conversion to CLO-CA via developing a population pharmacokinetic model. Individual participants’ data from two bioequivalence studies were utilized. Extensive blood samples were collected at predetermined intervals, including 841 concentrations of CLO and 1149 of CLO-CA. A nonlinear, mixed-effects modelling approach using NONMEM^® software (v 7.5) was applied. A one-compartment model was chosen for CLO, while a two-compartment proved optimal for CLO-CA. Absorption from the depot compartment was modeled via two transit compartments, incorporating transit rate constants (K_tr). A semi-physiological model explained the first-pass effect of CLO, integrating a liver compartment. The estimated mean transit times (MTTs) for the studies were 0.470 and 0.410 h, respectively. The relative bioavailability for each study’s generic medicine compared to the reference were 1.08 and 0.960, respectively. Based on the estimated parameters, the fractions metabolized to inactive metabolites (F_iaM_st1 and F_iaM_st2) were determined to be 87.27% and 86.87% for the two studies, respectively. The appropriateness of the final model was confirmed. Our model offers a robust framework for elucidating the pharmacokinetic profiles of CLO and CLO-CA.

Generic substitution has been introduced in the healthcare systems of many countries to reduce the costs and ensure the continuity of drug market supply. Common and country-specific strategies on this topic have been presented for several European countries, as well as for the Republic of Serbia. The factors that need to be considered when assessing the interchangeability of medicines may be related to the medicine or the individual patient. Particular caution is required with narrow therapeutic index drugs, drugs with non-linear pharmacokinetics, antiepileptic drugs, medicines with prolonged release formulations, medicines administered in a specific way or with a medical device. Factors such as the different appearance of the medicines, excipients, packaging, indications, but also the patient's condition, age, concomitant diseases, pregnancy, hand function, vision, ability to swallow, and the patient's attitude towards the alternative medicines should also be taken into account. When substituting two generic medicines, it should be noted that those medicines may not be bioequivalent, since bioequivalence is confirmed between a generic medicine and a reference (usually original) medicine, and thus pose an additional risk to the patient's safety. Some countries have opted to form lists of interchangeable medicines and/or detailed guidelines regarding interchangeability to assist healthcare professionals in making decisions on drug substitution.