Cisapride disposition in neonates and infants: in vivo reflection of cytochrome P450 3A4 ontogeny

• Published in: Clinical pharmacology and therapeutics 2003-10, Vol.74 (4), p.312-325
• Main Authors: Kearns, Gregory L., Robinson, Patricia K., Wilson, John T., Wilson‐Costello, Deanna, Knight, Gail R., Ward, Robert M., Anker, John N.
• Format: Article
• Language: English
• Subjects: Area Under Curve; Biological and medical sciences; Chromatography, High Pressure Liquid; Cisapride - analogs & derivatives; Cisapride - blood; Cisapride - metabolism; Cisapride - pharmacokinetics; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - metabolism; Digestive system; Female; Gastrointestinal Agents - blood; Gastrointestinal Agents - metabolism; Gastrointestinal Agents - pharmacokinetics; General pharmacology; Half-Life; Humans; Infant; Infant, Newborn; Male; Medical sciences; Metabolic Clearance Rate; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/S0009-9236(03)00225-X

Background Cisapride, a prokinetic agent and substrate for cytochrome P450 (CYP) 3A4, has been used to treat neonates and infants with feeding intolerance and apnea or bradycardia associated with gastroesophageal reflux. At age 1 month, CYP3A4 activity has been reported to be only 30% to 40% of adult activity. This known developmental delay in the expression of CYP3A4 prompted us to conduct a classical open‐label pharmacokinetic study of cisapride in neonates and young infants. Methods A total of 35 infants with a postconceptional age of 28 to 54 weeks at the time of the study received a single oral cisapride dose (0.2 mg/kg) at a postnatal age of 4 to 102 days, followed by repeated (n = 7) blood sampling over a 24‐hour period. Cisapride and norcisapride were quantitated from plasma by HPLC–tandem mass spectrometry and pharmacokinetic data determined (n = 32) by noncompartmental methods. Results The pharmacokinetic parameters (mean ± SD) were as follows: time to reach peak plasma concentration (tmax), 4.4 ± 2.8 hours (range, 0.9–12 hours); peak plasma concentration (Cmax), 29.3 ± 16.6 ng/mL (range, 5.2–71.7 ng/mL); elimination half‐life (t1/2), 10.7 ± 3.7 hours (range, 1.9–18.1 hours); apparent total body clearance (Cl/F), 0.62 ± 0.43 L · h−1 · kg−1 (range, 0.2–1.9 L · h−1 · kg−1); and apparent volume of distribution (VDss/F), 9.0 ± 7.1 L/kg (range, 2.2–30.5 L/kg). The apparent renal clearance (CLR) of cisapride in infants (n = 28) was estimated to be 0.003 ± 0.003 L · h−1 · kg−1. Substratification of the population based on postconceptional age demonstrated the following findings for cisapride: (1) The mean (±SD) Cmax for cisapride was higher in the oldest postconceptional age category (44.5 ± 19.6 ng/mL) than the middle and youngest categories (23.4 ± 11.7 ng/mL and 30.0 ± 17.5 ng/mL, respectively); (2) the tmax for cisapride was shortest in the oldest postconceptional age category (2.2 ± 1.1 hours) compared with the middle and youngest categories (4.4 ± 3.3 hours and 5.0 ± 2.6 hours, respectively); (3) the CL/F for cisapride in the youngest postconceptional age group was significantly lower (0.45 ± 0.26 L · h−1 · kg−1, P < .05) than in the middle and oldest categories (0.75 ± 0.46 L · h−1 · kg−1 and 0.85 ± 0.69 L · h−1 · kg−1, respectively); (4) a positive linear correlation was found between postconceptional age and the apparent terminal elimination rate constant (λz) for cisapride (P < .001, r2 = 0.47) but not with CL/F. For norcisapride, the mean app