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[Pharmacokinetics of clofibrate in jaundiced newborn infants at term]
P Bourget1, I Broise, V Quinquis-Desmaris
1Service de pharmacie clinique, groupe hospitalier Necker-Enfants-Malades, Paris, France.
Insights
Clofibrate (CFB) is slowly eliminated in jaundiced newborns, with prolonged active metabolite (CFA) levels. A 50 mg/kg dose of CFB appears suitable for neonatal jaundice treatment.
Area of Science:
- Pharmacology
- Neonatal Medicine
- Drug Metabolism
Context:
- Neonatal hyperbilirubinemia is a common condition.
- Clofibrate (CFB) has been investigated for its potential to increase bilirubin elimination in neonates.
- The pharmacokinetic profile of CFB in newborns was previously unknown.
Purpose:
- To characterize the pharmacokinetics of an oil formulation of clofibrate (CFB) in term neonates with jaundice.
- To determine the disposition of CFB and its active metabolite, clofibric acid (CFA), in this population.
Summary:
- Two groups of eight jaundiced neonates received single oral doses of 100 mg/kg or 50 mg/kg CFB.
- Serum concentrations of CFB and CFA were measured over 50 hours.
- Pharmacokinetic analysis revealed slow CFA formation, prolonged elimination (half-life often >100 hours), and excellent tolerance.
Impact:
- Neonatal CFB metabolism is reduced, likely due to decreased hydrolysis and hepatic conjugation capacity.
- A single oral dose of 50 mg/kg CFB is suggested as a suitable regimen for treating neonatal jaundice.
- Findings provide crucial data for understanding CFB disposition in neonates.
Background:
Clofibrate (CFB) has been proposed to increase elimination of bilirubin in neonates with hyperbilirubinemia. Nevertheless, its disposition, at this age, remains unknown. The aim of this work was to characterize pharmacokinetics of an oil formulation of CFB in neonates at term with jaundice.
Patients And Methods:
Two groups (G1 and G2) of eight neonates, presenting with jaundice, entered an open, non randomized and comparative study. Five blood samples were collected over 50 hours following a single oral administration of 100 mg/kg or 50 mg/kg CFB, respectively, in G1 and G2. Serum concentrations of both CFB and clofibric acid (CFA) were measured by HPLC and the pharmacokinetic analysis was made by a non-compartmental method. Data were compared to those obtained in adults receiving 2 g dose of CFB.
Results:
Tolerance to the treatment was excellent. Pharmacokinetic profiles were similar in both groups of infants. There was a slow and prolonged formation of CFA whose serum concentrations remained high 50 hours after drug administration. Non-hydrolyzed CFB was found in the blood of three neonates. Elimination of CFA was prolonged corresponding to a terminal half-life (t1/2m) often above 100 hours and sometimes incalculable. MRTo-->50 (h) was similar in both groups (ie 26.2 +/- 2.0 vs 25.5 +/- 1.3, respectively). The decrease of t1/2m was related to the decrease of the clearance of CFA.
Conclusions:
The decrease in CFB's metabolism in newborns is probably the result of at least two concurrent phenomenons: partial hydrolysis of CFA, especially at high doses, and decrease in the hepatic capacity to conjugate the active metabolite. A single oral administration of 50 mg/kg CFB seems to be a suitable schedule.