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Isoniazid pharmacokinetics in children according to acetylator phenotype
E Rey1, D Gendrel, J M Treluyer
1Pharmacologie Périnatale et Pédiatrique, Hôpital St Vincent de Paul, Université René Descartes Paris V, France. elisabeth.rey@svp.ap-hop-paris.fr
Insights
Slow acetylator children exhibit altered isoniazid pharmacokinetics, with lower clearance and longer half-life. This suggests potential need for individualized dosing in pediatric tuberculosis treatment.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Tuberculosis Treatment
Background:
- Isoniazid (INH) is a cornerstone of tuberculosis treatment.
- Individual pharmacokinetic variability in children can impact treatment efficacy and safety.
- Acetylator phenotype influences drug metabolism and response.
Purpose of the Study:
- To investigate the pharmacokinetics of isoniazid in children based on their acetylator phenotype.
- To determine if acetylator status affects isoniazid clearance, volume of distribution, and half-life in pediatric populations.
Main Methods:
- Studied 34 children (0-196 months) divided into slow (n=17) and fast (n=17) acetylator groups.
- Acetylator phenotype was determined by the metabolic acetyl INH/INH plasma concentration ratio (MR) 3 hours post-oral INH administration.
- Analyzed apparent plasma clearance (Cl), volume of distribution (Vd), and half-life (t1/2).
Main Results:
- Slow acetylators showed significantly lower Cl (0.298 L/h/kg) and longer t1/2 (3.88 h) compared to fast acetylators (Cl: 0.528 L/h/kg; t1/2: 1.64 h).
- The apparent volume of distribution was higher in slow acetylators (1.56 L/kg) than in fast acetylators (1.06 L/kg).
- Isoniazid half-life demonstrated a decrease with increasing age, with impaired elimination suggested in infants under three months.
Conclusions:
- Children's acetylator phenotype significantly influences isoniazid pharmacokinetics.
- Slow acetylator phenotype is associated with reduced isoniazid clearance and prolonged half-life.
- Findings support the consideration of individualized isoniazid dosing, particularly in infants under three months, to optimize tuberculosis treatment outcomes.
Abstract:
The pharmacokinetics of isoniazid (INH) was studied in children (0-196 months old) according to their acetylator phenotype, estimated from the metabolic acetyl INH/INH molar plasma concentration ratio (MR) measured 3 h after INH oral administration. There were 17 slow (MR < 0.48) and 17 fast acetylators (MR > or = 0.48). The mean apparent plasma clearance was significantly lower, the mean apparent volume of distribution higher and the half-life longer in the slow acetylator group (C1, 0.298 +/- 0.099 L/h/kg; Vd, 1.56 +/- 0.65 L/kg; t1/2, 3.88 +/- 01.89 h) than in the fast acetylator group (Cl, 0.528 +/- 0.234 L/h/kg; Vd, 1.06 +/- 0.45; t1/2, 1.64 +/- 1.1 h). The half-life decreased with age. An impaired isoniazid elimination was suggested in children less than three months old, which may be in favour of an individual dose adjustment in this population.