Pharmacokinetics of Isoniazid, Rifampin, and Pyrazinamide in Children Younger than Two Years of Age with Tuberculosis: Evidence for Implementation of Revised World Health Organization Recommendations

Abstract

There was no difference in the t max values achieved. Children less than 2 years of age achieve target concentrations of first-line anti-TB agents using revised WHO dosage recommendations. Our data provided supportive evidence for the implementation of the revised WHO guidelines for first-line anti-TB therapy in young children.Isoniazid (INH), rifampin (RMP), and pyrazinamide (PZA) are routinely used to treat tuberculosis (TB) in children (23, 44). Recommendations for pediatric dosages are based on a small number of pharmacokinetic studies, few of which included children younger than 2 years of age. During early life, children experience significant changes in the relative sizes of their body compartments and their ability to absorb, metabolize, and excrete drugs (5, 17). These changes are greatest within the first 2 years of life (4). Most published studies on first-line anti-TB drugs in children have not analyzed differences between older and younger children or the effect of HIV coinfection. The pharmacokinetics of INH are further complicated by genetic polymorphisms of N-acetyltransferase type 2 (NAT2) in the metabolic pathway of INH, which influences INH concentrations (18,26,46).In the absence of pharmacodynamic data for children and therefore data that demonstrate an association between serum drug concentration and clinical outcome, optimal anti-TB therapy should aim to produce the targeted serum drug concentrations that have been determined in adult pharmacokinetic and pharmacodynamic studies. For INH, the proposed optimal maximum serum drug concentration (C max ) for therapy is 3 to 5 g/ml (15, 27). Target serum RMP concentrations in adults after a standard oral dose of 600 mg are in the range of 8 to 24 g/ml; serum RMP concentrations below 8 g/ml are considered low, and those below 4 g/ml are considered very low (28,29). There is more uncertainty regarding the optimal therapeutic serum PZA concentration. In adults, serum PZA concentrations are targeted at 20 to 60 g/ml (11, 28). However, in a recent study of adults, poor treatment outcome of pulmonary TB was associated with serum PZA concentrations of Ͻ35 g/ml (8).Optimal anti-TB therapy is important in all children but particularly in young children (Ͻ2 years of age) and those HIV infected, where there is a high risk of progression to severe

Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines

“…A proposed PZA adult target range of 20 to 60 g/ml has been suggested (23), but a study from Botswana showed that a C max of less than 35 g/ml was associated with a poor outcome in adult pulmonary TB patients (39). Our results were similar to other pediatric studies reporting peak concentrations of 34.6 to 47.8 g/ml when dosed at 30 to 40 mg/kg (8,13,28,32).…”

“…RMP mean peak concentrations of 6.4 and 11.7 g/ml, when dosed at 10 and 15 mg/kg (P ϭ 0.005), respectively, were observed in 11 South African children younger than 2 years of age using a different RMP formulation. The authors noted that children with high drug concentrations at the lower RMP dose did not necessarily have comparatively high drug concentrations following the higher dose (13). RMP formulations are known for considerable intra-and interindividual variability, which may partly be explained by differences in RMP bioavailability.…”

“…Enzyme maturation, efflux transporter activity, increased drug clearance for body weight, and formulations and their preparations are all important factors determining drug exposure in young children (12). Few pharmacokinetic studies have been completed in children Ͻ2 years of age with TB (13,14), and none were specifically in infants. A study in Indian children found significantly lower maximum plasma concentrations (C max ) and areas under the concentration-time curves (AUC) for RMP, INH, and PZA in children Ͻ3 years of age compared to older children (ages 3.1 to 12.0 years) when the drugs were given thrice weekly, highlighting the need for age-dependent dosing considerations (14).…”

Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection

“…The pharmacokinetic sampling was done at five time points (time zero and 1, 2, 4, and 8 hours postdose) but not over the entire 24-hour dosing interval, and so we could not determine the trough concentrations of the drugs. However, such a sampling scheme has been used in other pediatric studies, when sampling at steady state is considered sufficient to estimate key pharmacokinetic parameters such as C max and AUC up to the time of the last sample (33,34). The factors selected in the multivariate analysis do not explain all the interindividual variability in the pharmacokinetics.…”

“…Blood samples were collected at time zero (predose) and at 1, 2, 4, and 8 hours postdose. This sampling scheme, when conducted at steady state, was considered sufficient to estimate key pharmacokinetic parameters such as maximum concentration (C max ) and area under the concentration-time curve (AUC) (33). The samples, collected in EDTA-coated tubes, were placed immediately on ice and centrifuged within 30 min at 3,000 ϫ g for 10 min.…”