The cornerstone of anti-infective therapy is attainment of the effective target concentration of the drug at the site of infection; achieving this goal requires integration of the pharmacokinetic and pharmacodynamics properties of the anti-infective drug. In this interplay, systemic and local quantitative analysis of the drug plays an integral part in providing information about the pharmacokinetic and pharmacodynamic properties of the anti-infective; this information is critical for drug development as well as evaluation of adequacy of established therapies. In this thesis, we will demonstrate the role of systemic and local quantitative analysis in the development of preventative strategies for HIV and also, the role of quantitative analysis in assessing adequacy of therapy in pediatric tuberculosis (TB).
The projects in this thesis highlight the various points that are key for successful use of anti-infective drugs. The first two projects, CHARM-01 and CHARM-02, focus on use of anti-infectives for prophylaxis; specifically the development of tenofovir (TFV)-containing gels as locally applied (rectal) microbicides. Since these gels are locally-dosed, there are several factors that have to be considered such as the mucosal safety of the formulations, the ability of the formulations to cover all potentially HIV-exposed mucosa, and the ability to reach the optimal concentration of the active drug, TFV diphosphate (TDF-DP) to prevent HIV infection.
In contrast, the PHATISA project looks at systemic (oral) dosing of anti-TB drugs in children for treatment. Children are a unique population in that optimal therapy has to account for the differences in absorption, distribution, metabolism and excretion of xenobiotic in the growing, ever-changing child. For instance, children have a less acidic gastric environment and their gastric motility is slow, which may affect the absorption of drugs. Children, mainly neonates and infants, have different water body composition as compared to older children and adults, which may affect the volume of distribution of drugs. The ontogeny of metabolic enzymes may affect the degree of metabolism that goes on at a specific age, and immaturity of the kidneys will affect the excretion of drugs. Unfortunately, most drug regimens used in children are extrapolated from adult dosing, which does not consider the abovementioned factors that are unique to children9. In the PHATISA study, we sought to evaluate whether a revised WHO-recommendation for TB drugs is able to achieve the presumed optimal concentrations for treatment of TB in children
