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Abstract We conducted a clinical study to determine the effect of efavirenz and ritonavir on the pharmacokinetics of R‐ and S‐PZQ in healthy male participants. This was toward evaluating the risk of drug‐drug interactions, which may occur after PZQ administration to HIV patients on efavirenz or ritonavir containing regimens. A non‐randomized, open‐label, single‐dose, one sequence crossover study with 2 arms was conducted. We gave 26 healthy volunteers a single oral dose of 40 mg/kg PZQ followed by a daily oral dose of either 400 mg efavirenz or 100 mg ritonavir for 14 consecutive days. On day 14, they ingested a single 40 mg/kg dose of PZQ. We measured plasma levels up to 12 h on day 1 and day 14. Samples were analyzed by LC‐MS. Pharmacokinetic analysis was conducted in WinNonlin to determine the primary endpoints (plasma T1/2, Cmin, and AUC). Efavirenz had a significant effect on the pharmacokinetics of PZQ (p

Abstract Racemic praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis. R‐Praziquantel (R‐PZQ) has been shown as the therapeutic form, whereas S‐PZQ is less efficacious and responsible for the bitter taste of the tablet. This study aimed at investigating the metabolism of R‐ and S‐PZQ as this could have implications on efficacy and safety of racemate and R‐PZQ specific formulations under development. In vitro CYP reaction phenotyping assay using 10 recombinant CYP (rCYP) isoenzymes showed hepatic CYP1A2, 2C19, 2D6, 3A4, and 3A5 were the major enzymes involved in metabolism of PZQ. Enzyme kinetic studies were performed by substrate depletion and metabolite formation methods, by incubating PZQ and its R‐ or S‐enantiomers in human liver microsomes (HLM) and the rCYP enzymes. The effect of selective CYP inhibitors on PZQ metabolism was assessed in HLM. CYP1A2, 2C19, and 3A4 exhibited different catalytic activity toward PZQ, R‐ and S‐enantiomers. Metabolism of R‐PZQ was mainly catalyzed by CYP1A2 and CYP2C19, whereas metabolism of S‐PZQ was mainly by CYP2C19 and CYP3A4. Based on metabolic CLint obtained through formation of hydroxylated metabolites, CYP3A4 was estimated to contribute 89.88% to metabolism of S‐PZQ using SIMCYP® IVIVE prediction. Reanalysis of samples from a human PZQ‐ketoconazole (KTZ) drug‐drug interaction pharmacokinetic study confirmed these findings in that KTZ, a potent inhibitor of CYP3A, selectively increased area under the curve of S‐PZQ by 68% and that of R‐PZQ by just 9%. Knowledge of enantioselective metabolism will enable better understanding of variable efficacy of PZQ in patients and the R‐PZQ formulation under development.