Comprehensive PBPK Evaluation of Phenytoin and Indomethacin: Dose, Age, Pregnancy and Drug–Drug Interaction Insights

Background/Objectives: Understanding the pharmacokinetics (PK) of antiepileptic and anti-inflammatory drugs under different physiological conditions is essential for optimizing therapy. Phenytoin, a widely used antiepileptic, and indomethacin, a nonsteroidal anti-inflammatory drug, are frequently prescribed in women of reproductive age. This study aimed to evaluate the influence of age, pregnancy, and dosing regimens on the PK of both drugs, as well as to investigate potential drug–drug interactions (DDIs). Methods: PK parameters of phenytoin and indomethacin were systematically analyzed in women aged 20–45 years under non-pregnant and pregnant conditions. Different dosing regimens were compared, and coadministration studies were conducted to assess DDI. Results: Phenytoin demonstrated stable absorption and bioavailability across ages and during pregnancy. Single daily dosing (300 mg once daily) yielded slightly higher peak concentration (Cmax) values, while fractionated dosing (100 mg q8h) produced significantly higher drug exposure (AUC) and absorption fraction, particularly with prolonged administration, reflecting saturable metabolism. During pregnancy, systemic exposure (Cmax and AUC) was modestly reduced, while absorption and distribution remained unchanged. Indomethacin showed minimal age-related variability and linear pharmacokinetics across dosing regimens. In pregnancy, exposure was reduced (lower Cmax and AUC) with delayed Tmax, indicating slower absorption. Importantly, no PK DDI was observed, as indomethacin parameters remained unchanged except for Tmax, which was lower in the interaction scenario compared with baseline, suggesting a faster absorption rate without affecting overall exposure or peak concentration in the presence of phenytoin. Conclusions: Phenytoin and indomethacin exhibit stable and predictable PK across ages and during pregnancy, with dose-dependent characteristics that align with their known metabolic profiles. The absence of clinically relevant DDI supports their safe concomitant use. These findings provide preliminary reassuring evidence for clinicians and contribute to a better understanding of their pharmacological behavior in diverse patient populations.