Optimal Dosing of 1st Line Antituberculosis and Antiretroviral Drugs in Children (a Pharmacokinetic Study)
Condition: Tuberculosis; HIV
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 4

Summary: 
      The aims of this project are to:

        1. To evaluate the pharmacokinetics of first line antituberculosis drugs (isoniazid,
           rifampicin, pyrazinamide and ethambutol) when applying the 2010 WHO/IUATLD dosing
           guidelines across pediatric populations (0-12 years of age, HIV infected and uninfected,
           and with varied nutritional status) in Cape Town, South Africa and Blantyre, Malawi.

        2. To evaluate an 8-hourly weight band-based dosing strategy for lopinavir/ritonavir using
           the commercially available lopinavir/ritonavir (4:1 ratio) in children in South Africa
           receiving rifampicin-based antituberculosis treatment.

        3. To evaluate the pharmacokinetics of nevirapine in children in Malawi receiving
           rifampicin-based antituberculosis treatment.
    

Detailed description: 
      HIV and tuberculosis are a major public health problem in children. Challenges to treat
      children with tuberculosis include a lack of knowledge about optimal dosing of first line
      antituberculosis drugs across ages, nutritional status and HIV infection status, the absence
      of an appropriate regimen to co-administer rifampin and lopinavir/ritonavir, the key first
      line drugs for tuberculosis and HIV, and uncertainty about NVP exposure in young children
      during rifampin-based tuberculosis therapy.

      In total, 240 children < 12 years of age with tuberculosis will be enrolled at Red Cross
      Children's Hospital in Cape Town and Queen Elizabeth Central Hospital, Blantyre. In the
      second month of antituberculosis treatment, one dose of the drugs in their first-line
      regimens will be administered according to 2010 WHO/IUATLD guidelines (study drugs) and blood
      will be sampled for pharmacokinetic analysis over the following 8-10 hours.

      Children on antiretroviral treatment (started prior to or during TB treatment) will receive 2
      weeks of antiretrovirals (lopinavir/ritonavir or nevirapine) according in the study doses
      (adjusted 8 hourly doses of lopinavir/ritonavir, or nevirapine doses according to WHO's
      recommended weight band-based doses) in combination with antituberculosis treatment, prior to
      pharmacokinetic assessments of both antiretroviral and antituberculosis drugs. Children
      receiving nevirapine will also undergo pharmacokinetic evaluation 1 month after completion of
      antituberculosis treatment to evaluate nevirapine concentrations in the absence of
      antituberculosis drugs. In addition to the 240 children with tuberculosis, 25 HIV infected
      South African children without tuberculosis will be recruited to evaluate lopinavir
      concentrations in the absence of antituberculosis drugs.

      A population approach will be used to estimate the optimal doses of rifampicin, isoniazid,
      pyrazinamide and ethambutol in children according to covariates (e.g. age, weight, HIV
      status, nutritional status) found to have an important influence on the drug concentrations.
      Similarly population models will be used to describe lopinavir/ritonavir and nevirapine
      pharmacokinetics in children receiving rifampicin-based antituberculosis treatment, evaluate
      the dosing approaches and to simulate alternative optimal dosing approaches as indicated.
    

Intervention name(s): 8 hourly LPV/r during TB treatment; Nevirapine; Lopinavir/Ritonavir
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 8 hourly LPV/r during TB treatment
Intervention MeSH terms: Ritonavir; Lopinavir; Nevirapine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment