Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children

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Tuberculosis (TB) and human immunodeficiency virus (HIV) infections are major causes of morbidity and mortality in children. Children are highly susceptible to the dual epidemics of HIV and TB infections especially in Africa. HIV-infected children are at a higher risk of developing active TB and dying of TB. The high risk of death in children with TB/HIV coinfection is in part due to delayed therapy or suboptimal drug treatment of one or both infections. In particular, suboptimal pharmacokinetics (PK) due to inappropriate drug formulations or dosing may contribute to the high mortality in children. The lack of PK data of new pediatric formulations rolled out for the treatment of TB and HIV in children in Africa represents a major obstacle to optimized outcomes. Our long-term goal is to generate novel PK data of the new fixed-dose combination (FDC) formulations of anti- TB and antiretroviral drugs used in children and adolescents in Africa. Our primary objective is to determine the PK and covariates associated with interindividual variability in the PK of the new child-friendly FDC formulation of isoniazid/rifampin/pyrazinamide for children as well as generic FDC antiretrovirals used in adolescents. The overarching hypothesis is that previous studies have underestimated the effect of developmental and genetic factors in drug metabolism, drug-drug interactions, as well as the risk for suboptimal drug concentrations in children. Our goal will be pursued through three specific aims. Aim 1 will evaluate the PK of the new pediatric isoniazid/rifampin/pyrazinamide FDC formulation, and use the PK data to develop a population PK model and stimulations to predict optimal weight-band dosages for children. Aim 2 will examine the effect of rifampin- containing anti-TB therapy on virological response in children with TB/HIV coinfection compared to those with HIV alone treated with efavirenz-based therapy. Aim 3 will determine the intracellular PK of tenofovir diphosphate and emtricibaine triphosphate in adolescents aged 10 to 19 years old, as well as examine the effect of age and TB coinfection on the PK of these anabolities. As new pediatric formulations of anti-TB and ARVs are scaled up in sub-Saharan Africa, PK and PK-PD data in African children are needed to either validate the formulations and dosing guidelines or provide relevant data for guidelines revisions. This innovative proposal has the potential to provide critical data for optimization of treatment regimens for childhood TB, HIV and TB/HIV coinfection.