Application of physiologically‐based pharmacokinetic modelling to guide oral ketamine prescription in analgesic doses

Aim This study aimed to apply physiologically based pharmacokinetic (PBPK) models of ketamine (KET) and its active metabolite norketamine (norKET) after oral administration to evaluate appropriate dosing protocols for racemic KET in ethnically diverse adult populations. Methods Clinical pharmacokinetic data of S‐ and R‐ketamine and their respective metabolites were obtained from published studies and used to construct PBPK models in Simcyp® Simulator . The models were validated using independent datasets through visual comparison of predicted and observed plasma concentration, time profiles and by calculating mean fold error (MFE) for pharmacokinetic parameters (AUC, Cmax and Tmax). Simulations of multiple oral dosing regimens (0.3–1.25 mg/kg, every 2–12 h) were conducted in virtual Caucasian, Japanese and Chinese populations to determine optimal analgesic ranges. Results The validated PBPK models accurately predicted plasma exposure for both KET and norKET within acceptable MFE ranges (0.5–2.0). Simulations revealed that in Asian adults, KET exposure was approximately 60% higher and norKET concentrations 25% lower compared with Caucasians. Among the tested regimens, oral doses of 0.75–1.0 mg/kg administered every 6–8 h achieved stable norKET plasma concentrations within the therapeutic range for analgesia, while avoiding levels associated with anaesthetic or adverse effects. Conclusion The developed PBPK models effectively simulated the pharmacokinetics of oral racemic KET and its metabolite across populations. NorKET appears to be the primary contributor to sustained analgesic activity and represents a suitable marker for plasma monitoring and individualized dose adjustment in clinical practice.