The effect of ketoconazole on praziquantel pharmacokinetics and the role of CYP3A4 in the formation of X-OH-praziquantel and not 4-OH-praziquantel

摘要

AimThe study sought to determine the effect of ketoconazole (KTZ) on the pharmacokinetics of praziquantel (PZQ) and on the formation of its major hydroxylated metabolites, cis- and trans-4-OH-PZQ, and X-OH-PZQ in healthy subjects.MethodsTwo treatments were evaluated by single-dose PK studies; the reference treatment was a 20mg/kg dose of praziquantel given alone. The test treatment was a 20mg/kg dose of praziquantel given in combination with 200mg of ketoconazole. The study had a balanced and randomised cross-over design. Serial blood samples were collected between 0 and 12h after each drug administration. PZQ, and cis- and trans-4-OH-PZQ and X-OH-PZQ concentrations in plasma were determined by LC-MS. A non-compartmental approach was used for pharmacokinetic analysis. Data were analysed using ANOVA and assessment of the 90% confidence interval of the geometric means of the log-transformed PK parameters obtained for each treatment.ResultsThe pharmacokinetics of PZQ following the two treatments, PZQ alone and PZQ + KTZ, were not equivalent based on the assessment of the 90% CI of the geometric mean ratios of the AUC and C-max (alpha=0.05). The geometric mean ratios of the AUC and C-max were found to be 176.8% and 227% respectively. The 90% CI of the AUC and C-max were found to be 129.8%-239.8% and 151.4%-341.4% respectively. The AUC of PZQ was increased by 75% with KTZ co-administration (3516 vs 6172ngh/ml) (p<0.01). Meanwhile, the mean AUC of trans-4-OH-PZQ increased by 67% (61,749ngh/ml vs 103,105ngh/ml) (p<0.01). X-OH-PZQ levels were reduced by about 57% (semi-quantified as 7311ngh/ml vs 3109ngh/ml by using trans-4-OH as standards) (p<0.01) with KTZ co-administration.ConclusionsThe relative bioavailability of praziquantel was increased by concomitant KTZ administration. KTZ preferentially inhibited the formation of X-OH-PZQ rather than 4-OH-PZQ, confirming in vitro data which implicates CYP3A4 in the formation of X-OH-PZQ rather than 4-OH-PZQ. The 4-hydroxylation of PZQ was shown to be the major metabolic pathway of PZQ, as evidenced by larger quantities of 4-OH-PZQ produced, thus explaining the modest albeit significant effect of ketoconazole on PZQ pharmacokinetics.