Development and Validation of Sensitive RP‐HPLC Bioanalytical Method of Diclofenac Sodium and Its Predictive In‐Silico Physiologically Based Pharmacokinetic Modeling in Hepatic and Renal Impairment

ABSTRACT Diclofenac sodium is a widely prescribed NSAID for inflammatory and rheumatoid diseases, and the dose adjustment, especially for elderly patients suffering from renal or hepatic impairment, is not a routine practice. In this study, a sensitive RP‐HPLC bioanalytical method was developed and validated for quantifying diclofenac in human plasma. After quality assessment of different diclofenac sodium brands, a pharmacokinetic study was performed in 12 healthy human subjects and compared with predicted in silico PBPK models in healthy subjects and in patients with renal or hepatic impairment. The bioanalytical method demonstrated sensitivity and linearity from 20 to 3000 ng/mL, with 99.9% accuracy. Stability tests on plasma samples stored long term and subjected to freeze–thaw cycles showed considerable stability at −20°C. Pharmacokinetic parameters included C max , T max , AUC 0–t and AUC 0–∞ . In silico PBPK modelling indicated that routine monitoring might not be necessary for patients with mild to moderate hepatic or renal impairment. However, significantly higher AUC 0–t values were observed in severe cases, end‐stage renal disease, cirrhosis B and cirrhosis C, suggesting a need for dose adjustments to mitigate dose‐dependent toxicities. This study provides a comprehensive framework for generic manufacturers, regulatory agencies and clinicians for dose optimization, safety prediction and clinical decision support.