The prokinetic cinitapride has no clinically relevant pharmacokinetic interaction and effect on QT during coadministration with ketoconazole.
The present clinical trial was designed to evaluate the possible pharmacokinetic and electrocardiographic interactions of the gastroenteric prokinetic drug cinitapride with ketoconazole. The safety and tolerability of the study treatments were also evaluated. After a placebo-controlled, double-blind, crossover design, 16 healthy male (n = 8) and female (n = 8) volunteers were randomized into four treatment groups of four subjects (two males and two females): cinitapride (CTP; 1 mg t.i.d.) + ketoconazole (KET; 200 mg b.i.d.), CTP + placebo (PL), PL+KET, and PL+PL. Treatments were given for 7 days with a washout period of 14 days between crossover treatments. Cinitapride is rapidly absorbed after oral administration and is metabolized by the cytochrome P450 CYP3A4 and CYP2C8 isozymes. At steady state, coadministration with ketoconazole, a potent CYP3A4 inhibitor, increased mean C(max,ss) and AUC(tau) by 1.63- and 1.98-fold, respectively. Measurement of mean QTc interval or baseline-corrected QTc intervals on day 7 showed small increases that were due to the effects of ketoconazole alone. Comparing CTP+KET versus PL+KET, the differences between mean increases in the QTc parameters were always less than 2 ms. Finally, no outlier increase of the QTc interval versus baseline >60 ms was identified after any treatment. The study showed that cinitapride, either given alone or after coadministration with ketoconazole 200 mg b.i.d., had no effect on cardiac repolarization as measured by changes in the heart rate-corrected QT interval on the surface electrocardiogram.
Robert
Marta
M
Laboratorios Almirall, S.A., Research Centre, Barcelona, Spain. mrobert@almirall.es
Salvà
Miquel
M
Segarra
Rosa
R
Pavesi
Marco
M
Esbri
Ramón
R
Roberts
David
D
Golor
Georg
G
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004311:Double-Blind Method; D004347:Drug Interactions; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D012016:Reference Values
D001549:Benzamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C045316:cinitapride; D007654:Ketoconazole