Pharmacokinetics of first-line anti-tuberculosis drugs in HIV-infected children with tuberculosis treated with intermittent regimens in India.

Ramachandran, G.; Kumar, A.K.; Bhavani, P.K.; Kannan, T.; Kumar, S.R.; Gangadevi, N.P.; Banurekha, V.V.; Sekar, L.; Ravichandran, N.; Mathevan, G.; Sanjeeva, G.N.; Dayal, R.; Swaminathan, S.

Antimicrobial Agents & Chemotherapy; 2015; 59; 1162-1167.   

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 m g/ml, respectively [ P= 0.016]; AUC 0–8 , 11.1 versus 22.0 m g/ml ·h, respectively [ P= 0.047]) and PZA ( C max , 34.1 versus 42.3 m g/ml, respectively [ P= 0.055]; AUC 0–8 , 177.9 versus 221.7 m 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 m g/ml, respectively; P= 0.002) and PZA (31.9 versus 44.4 m 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.

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