Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

Abstract

Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and are currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. One-hundred Vietnamese children with TBM were treated with an 8-month anti-tuberculosis regimen. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic properties of the four drugs, and to simulate different dosing strategies. The pharmacokinetic properties of rifampicin and pyrazinamide in plasma were described successfully by one-compartment disposition models, while isoniazid and ethambutol in plasma were described by two-compartment disposition models. All drug models included allometric scaling of body weight and enzyme maturation during the first years of life. CSF penetration of rifampicin was relatively poor and increased with increasing protein levels in CSF, a marker of CSF inflammation. Isoniazid and pyrazinamide showed good CSF penetration. Currently recommended doses of isoniazid and pyrazinamide, but not ethambutol and rifampicin, were sufficient to achieve target exposures. Ethambutol dose cannot be increased because of ocular toxicity. Simulation results suggested that rifampicin dosing at 50 mg/kg/day would be required to achieve the target exposure. Moreover, low rifampicin plasma exposure was associated with an increased risk of neurological disability. Therefore, higher doses of rifampicin could be considered, but further studies are needed to establish the safety and efficacy of increased dosing.

Treatment Outcomes of Childhood Tuberculous Meningitis in a Real-World Retrospective Cohort, Bandung, Indonesia

“…This short-course, high-dose therapy has recently been added by WHO as an alternative treatment option for childhood TBM ( 41 ). Suboptimal plasma and CSF concentrations with standard doses of oral rifampin at 10–20 mg/kg/day in children with TBM have also been reported in recent pharmacokinetic studies ( 42 , 43 ), advocating the use of higher rifampin doses with further efficacy and safety evaluations.…”

Comparative Effectiveness of Regimens for Drug-Susceptible Tuberculous Meningitis in Children and Adolescents: A Systematic Review and Aggregate-Level Data Meta-Analysis

“…The higher doses of isoniazid and rifampicin used in this regimen, together with the greater CSF penetration of ethionamide compared with ethambutol, may contribute to the effectiveness of the 6-month intensive regimen [ 21 ]. Rifampicin dosing may be particularly important for successful treatment [ 22 ]: data from adults with TB meningitis show an association between higher rifampicin concentrations and survival, and a small pediatric trial has shown improved neurocognitive function with doses of 30 mg/kg compared to the standard dose of 15 mg/kg [ 23 , 24 ]. Nonpharmacological interventions also may have contributed to low mortality, but treatment success would not have been so high had the regimen been ineffective.…”

Influence of N-acetyltransferase 2 (NAT2) genotype/single nucleotide polymorphisms on clearance of isoniazid in tuberculosis patients: a systematic review of population pharmacokinetic models

“…Of the identified 12 studies, nine were carried out in adult TB population [25][26][27][28][29][30][31][32][33], two in pediatric TB [34,35] and one in pregnant TB population [36]. Five studies were conducted in Asian countries, of which two were from China [26,28], one each from Indonesia [25], Korea [27], and Vietnam [34].…”

“…Of the identified 12 studies, nine were carried out in adult TB population [25][26][27][28][29][30][31][32][33], two in pediatric TB [34,35] and one in pregnant TB population [36]. Five studies were conducted in Asian countries, of which two were from China [26,28], one each from Indonesia [25], Korea [27], and Vietnam [34]. Six studies were from African continent, with two studies from South Africa [32,36] and one study each from Rwanda [29], Uganda [31], Ghana [35], and Tanzania [33].…”

“…Anthropometric measurements such as body weight [25,26,28,29,31,34,35], lean body weight [27], and free-fat mass [32,33,36] were reported to affect the isoniazid clearance.…”