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. 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 Cmax,ss and AUCτ 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.
Footnotes
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This study was funded by Laboratorios Almirall, S.A.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.010835.
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ABBREVIATIONS: MS/MS, tandem mass spectrometry; QT, duration in milliseconds from the beginning of Q wave to the end of the T wave; CTP, cinitapride; KET, ketoconazole; PL, placebo; AUCτ, area under the plasma concentration-time curve within a dosing interval; QTc, QT interval corrected for heart rate; ECG, electrocardiogram; FI, fluctuation index; RR, duration in milliseconds between two R peaks of two consecutive QRS complexes; PR, duration in milliseconds from the beginning of wave P to onset of ventricular depolarization (Q and R); QRS, duration in milliseconds of the QRS complex; QTcB, QT interval corrected by the Bazett formula (QT/RR1/2); QTcF, QT interval corrected by the Fridericia formula (QT/RR1/3); QTcL, QT linear correction model [QT + α × (1 – RR)]; QTcI, QT parabolic log/log correction model (QT/RRα); hERG, human ether-a-go-go-related gene; ANOVA, analysis of variance; CI, confidence interval; AE, adverse event.
- Received April 27, 2006.
- Accepted April 13, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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