Pharmacokinetics of First-Line Antituberculosis Drugs in HIV-Infected Children with Tuberculosis Treated with Intermittent Regimens in India

Abstract

The objective of this report was to study the pharmacokinetics of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) in HIV-infected children with tuberculosis (TB) treated with a thrice-weekly anti-TB regimen in the government program in India. Seventy-seven HIV-infected children with TB aged 1 to 15 years from six hospitals in India were recruited. During the intensive phase of TB treatment with directly observed administration of the drugs, a complete pharmacokinetic study was performed. Drug concentrations were measured by high-performance liquid chromatography. A multivariable regression analysis was done to explore the factors impacting drug levels and treatment outcomes. The proportions of children with subnormal peak concentrations (C max ) of RMP, INH, and PZA were 97%, 28%, and 33%, respectively. Children less than 5 years old had a lower median C max and lower exposure (area under the time-concentration curve from 0 to 8 h [AUC 0 -8 ]) of INH (C max , 2.5 versus 5.1 g/ml, respectively [P ‫؍‬ 0.016]; AUC 0 -8 , 11.1 versus 22.0 g/ml · h, respectively [P ‫؍‬ 0.047[) and PZA (C max , 34.1 versus 42.3 g/ml, respectively [P ‫؍‬ 0.055]; AUC 0 -8 , 177.9 versus 221.7 g/ml · h, respectively [P ‫؍‬ 0.05]) than those more than 5 years old. In children with unfavorable versus favorable outcomes, the median C max of RMP (1.0 versus 2.8 g/ml, respectively; P ‫؍‬ 0.002) and PZA (31.9 versus 44.4 g/ml, respectively; P ‫؍‬ 0.045) were significantly lower. Among all factors studied, the PZA C max influenced TB treatment outcome (P ‫؍‬ 0.011; adjusted odds ratio, 1.094; 95% confidence interval, 1.021 to 1.173). A high proportion of children with HIV and TB had a subnormal RMP C max . The PZA C max significantly influenced treatment outcome. These findings have important clinical implications and emphasize that drug doses in HIV-infected children with TB have to be optimized.

A Critical Review of the Current Evidence for Measuring Drug Concentrations of First-Line Agents Used to Treat Tuberculosis in Children

“…Ramachandran et al found similar results with only 10 % achieving concentrations [8 lg/mL across all age groups studied but specifically that all children aged \3 years did not achieve concentrations within the target range [14]. A more recent study by Ramachandran found 97 % of children (all HIV positive) did not achieve target concentrations [13]. Thee et al attempted to study the effect of dose on rifampin concentrations and noted that with the standard 10 mg/kg dosing, only 45 % had rifampin C max values [8 lg/mL but this number increased to 73 % after dosing based on 15 mg/kg [22].…”

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

“…In adult RMP dose-escalation studies of up to 35 mg/kg/day for 2 weeks, higher doses showed a disproportionate plasma exposure increase with dose and a greater fall in bacterial load (48). Multiple factors influence the relationship between drug concentrations and TB treatment outcome, including M. tuberculosis genotype, gene polymorphisms, extent of TB disease, bacillary burden, and immune status, including HIV infection status (46). A limitation of our study is that the study drug was administered only on the pharmacokinetic day, while routine drugs were used for the 6-month treatment; this limits the interpretation of drug concentrations on TB treatment outcome.…”

“…Age-dependent elimination of first-line antituberculosis drugs has been shown, with lower exposures documented in younger children for RMP (10,14,40), INH (14,40,46), PZA (8,14), and EMB (42). These findings have mainly been attributed to the more rapid clearance of drugs and to a relatively larger liver-to-body size ratio.…”

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

“…While our study was not designed to investigate the relationship between pharmacokinetics and TB treatment outcome, the lower median plasma exposure and C max of rifampin and ethambutol in the HIV-coinfected patients is concerning and raises the question of whether inadequate drug pharmacokinetics is a contributor to the higher risk of an unfavorable treatment response. At least one group reported a relationship between lower rifampin and pyrazinamide C max and unfavorable TB treatment outcome (death, failure, and default) in HIV-infected children (19) and in a combined group of HIV-infected and uninfected children in India treated with a thrice-weekly regimen (32). Thus, strategies to improve TB treatment outcomes in children, especially with HIV coinfection, should include optimized dosages of rifampin, pyrazinamide, and ethambutol.…”

“…In particular, low plasma exposure to the rifamycins in the setting of intermittent therapy in HIV-infected patients with TB has been associated with treatment failure and emergence of rifampin resistance (16)(17)(18). While there are limited data on the relationship between pharmacokinetic (PK) parameters and pharmacodynamics in children, one study from India reported an association between low plasma maximum concentrations (C max ) of rifampin and pyrazinamide and unfavorable clinical outcomes in HIV-infected children (19).…”