Cisapride disposition in neonates and infants: in vivo reflection of cytochrome P450 3A4 ontogeny.
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 (t(max)), 4.4 +/- 2.8 hours (range, 0.9-12 hours); peak plasma concentration (C(max)), 29.3 +/- 16.6 ng/mL (range, 5.2-71.7 ng/mL); elimination half-life (t(1/2)), 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 (VD(ss)/F), 9.0 +/- 7.1 L/kg (range, 2.2-30.5 L/kg). The apparent renal clearance (CL(R)) 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) C(max) 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 t(max) 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 (lambda(z)) for cisapride (P <.001, r(2) = 0.47) but not with CL/F. For norcisapride, the mean apparent C(max) was highest and the t(max) was shortest in the oldest postconceptional age group, although no association between postconceptional age and the norcisapride/cisapride area under the curve ratio was observed. All infants tolerated a single dose of cisapride well without significant alteration in QTc.


CONCLUSIONS
(1) In neonates and infants, cisapride absorption and metabolism to its primary metabolite, norcisapride, were developmentally dependent; (2) approximately 99% of cisapride CL/F in neonates and young infants was nonrenal in nature; (3) CL/F of cisapride in neonates and infants noted in this study was reduced compared with data from older children and adults, likely as a result of developmental reductions in CYP3A4 activity; (4) as reflected by the correlation between postconceptional age and lambda(z), a rapid increase in total CYP3A4 activity occurs in the first 3 months of life.
Kearns
Gregory L
GL
Division of Pediatric Pharmacology and Medical Toxicology, Children's Mercy Hospitals and Clinics, 2401 Gillham Rd, Kansas City, MO 64108, USA. gkearns@cmh.edu
Robinson
Patricia K
PK
Wilson
John T
JT
Wilson-Costello
Deanna
D
Knight
Gail R
GR
Ward
Robert M
RM
van den Anker
John N
JN
D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D020117:Cisapride / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D005765:Gastrointestinal Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008657:Metabolic Clearance Rate
D005765:Gastrointestinal Agents; C072044:norcisapride; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D020117:Cisapride