Received for publication June 20, 2006.
Revised April 13, 2007.
Accepted for publication April 13, 2007.

The prokinetic cinitapride has no clinically relevant pharmacokinetic interaction and effect on QT during co-administration with ketoconazole

Abstract

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. Following 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 (2 males and 2 females): cinitapride (1 mg t.i.d., CTP) + ketoconazole (200 mg b.i.d., KET), CTP + placebo (PL), PL+KET and PL+PL. Treatments were given for 7 days with a wash-out period of 14 days between crossover treatments. Cinitapride is rapidly absorbed following oral administration and is metabolized by the cytochrome P450 CYP3A4 and CYP2C8 isozymes. At steady state, co-administration with ketoconazole, a potent CYP3A4 inhibitor, increased mean C_max^ss and AUC 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 vs. 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 vs. baseline > 60 ms was identified after any treatment. The study showed that cinitapride, either given alone or following co-administration 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.

Key words: clinical pharmacokinetics, CYP2C, CYP3A, drug interactions, pharmacokinetics, safety evaluation