Evaluation of Pharmacokinetics and Safety Tolerability of Higher Doses of Rifampic
Condition: Clinical Trial
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Tuberculosis in children is a major public health problem and it contributes 10% of the total
      TB cases worldwide. TB treatment outcomes in children are challenged by insufficient
      consideration of the relationships between doses administered, concentrations achieved and
      eventual desirable and undesirable effects (pharmacodynamics) of TB drugs. Rifampicin is a
      pivotal TB drug and data from adults suggest that a much higher dose of rifampicin (35 mg/kg
      instead of 10 mg/kg), resulting in much higher rifampicin exposures in plasma, is safe and
      tolerable and may provide a higher efficacy. The dose needed in children to achieve the same
      exposure in plasma is unknown.
    

Detailed description: 
      Tuberculosis (TB) in children is a major public health problem . It has a global estimate of
      >100,000 deaths per year and is included in the top ten causes of mortality in children
      worldwide. Children contribute 10% of the total TB cases worldwide. More than 75% of the
      worldwide estimated cases of TB in children occur in the 30 high burden countries, Tanzania
      being one of them. The enormous burden of pediatric TB in these countries is due to the TB
      epidemic amongst adults and the simultaneous HIV pandemic and a child less than 14 years of
      age whether HIV infected or not is at a high risk of developing the disease. Subsequent
      dissemination of the mycobacterium and progression of the disease is also fast in children.

      Knowledge on the efficacy and safety of medicines for children is still very limited and
      sometimes children are still being treated as small adults. However, adult dosing cannot be
      logically extrapolated to children according to weight or age because of different
      pharmacokinetics, i.e. the relationship between doses administered and exposures (drug
      concentrations) achieved, in children as compared with adults . More specifically, these
      pharmacokinetic differences occur in the subsequent processes of absorption, distribution,
      metabolism and elimination of drugs, which are subject to physiological changes due to growth
      and development in children. Especially in young children, maturation of liver metabolism
      pathways and renal function are not completed.

      In contrast, the pharmacodynamics of a drug, i.e. the relationship between concentrations
      achieved and eventual response is generally considered similar between adults and children,
      although differences in drug metabolism between children and adults may lead to differences
      in susceptibility to some adverse drug reactions. Thus, because of the differences in
      pharmacokinetics in children with different ages, they should not receive the same drug doses
      on mg/kg base as adults, and drug dosage selection in children should rather be based upon
      stages of growth and development. These drug doses should target the exposures that are
      efficacious in adults.
    

Intervention name(s): Evaluation of high dose rifampicin in children
Intervention type(s): Drug
Intervention description(s): Evaluation of severity of adverse event from grade 1 to 5
Other intervention name(s): Safety monitoring
Intervention MeSH terms: Rifampin
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Intervention model description: Safety and tolerability study
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Tuberculosis, Pharmacokinetics, safety/torelability