Pharmacokinetic interaction between ketoconazole and praziquantel in healthy volunteers.
BACKGROUND
Praziquantel, a broad-spectrum anthelminthic, has been reported to undergo extensive first-pass metabolism by cytochrome P450 (CYP) enzymes in vivo. Ketoconazole, a potent CYP3A4 inhibitor, is known to markedly increase plasma concentrations of many co-administered drugs. However, no data are available on the potential pharmacokinetic drug interaction between ketoconazole and praziquantel in humans.


OBJECTIVE
To investigate the potential pharmacokinetic interaction of ketoconazole with praziquantel in healthy adult Thai male volunteers.


METHODS
In an open-label, randomized two-phase crossover study, separated by a 2-week period, 10 healthy adult Thai male volunteers ingested a single dose of 20 mg/kg praziquantel alone or with co-administration of 400-mg ketoconazole orally daily for 5 days. Venous blood samples were collected at specific times for a 24-h period. Plasma concentrations of praziquantel were determined using high-performance liquid chromatography. A non-compartmental model was applied for pharmacokinetic parameter analysis of praziquantel.


RESULTS
Concurrent administration of ketoconazole with praziquantel significantly increased the mean area under the curve from time zero to infinity (AUC(0-alpha)) and maximum plasma concentration (Cmax) of praziquantel by 93% (955.94 +/- 307.74 vs. 1843.10 +/- 336.39 ng h/mL; P < 0.01) and 102% (183.38 +/- 43.90 vs. 371.31 +/- 44.63 ng/mL; P < 0.01), respectively, whereas the mean total clearance (Cl/F) of praziquantel was significantly decreased by 58% (2.65 +/- 0.64 vs. 1.11 +/- 0.35 mL/h/kg; P < 0.01).


CONCLUSIONS
Ketoconazole co-administration alters the pharmacokinetics of praziquantel in humans, possibly through inhibition of CYP3A, particularly CYP3A4, first-pass metabolism of praziquantel. Our data suggest that when praziquantel is co-administered with ketoconazole, the dose of praziquantel could be reduced to half the standard dose of praziquantel to reduce the cost of therapy.
Ridtitid
W
W
Clinical Pharmacology Laboratory, Department of Pharmacology, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, Thailand. wibool.r@psu.ac.th
Ratsamemonthon
K
K
Mahatthanatrakul
W
W
Wongnawa
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000328:Adult; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D011223:Praziquantel / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065607:Cytochrome P-450 Enzyme Inhibitors; D011223:Praziquantel; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole