10 research outputs found
Utility of Quantitative Analysis in Drug Development and Optimization of Anti-Infective Therapy
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
The Non-Linear Child: Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism
N-acetyltransferase 2 (NAT2) catalyzes the acetylation of isoniazid to N-acetylisoniazid. NAT2 polymorphism explains 88% of isoniazid clearance variability in adults. We examined the effects of clinical and genetic factors on Michaelis-Menten reaction kinetic constants of maximum velocity (Vmax) and affinity (Km) in children 0–10 years old. We measured the rates of isoniazid elimination and N-acetylisoniazid production in the blood of 30 children. Since maturation effects could be non-linear, we utilized a pharmacometric approach and the artificial intelligence method, multivariate adaptive regression splines (MARS), to identify factors predicting NAT2 Vmax and Km by examining clinical, genetic, and laboratory factors in toto. Isoniazid concentration predicted both Vmax and Km and superseded the contribution of NAT2 genotype. Age non-linearly modified the NAT2 genotype contribution until maturation at ≥5.3 years. Thus, enzyme efficiency was constrained by substrate concentration, genes, and age. Since MARS output is in the form of basis functions and equations, it allows multiscale systems modeling from the level of cellular chemical reactions to whole body physiological parameters, by automatic selection of significant predictors by the algorithm
A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02)
Tissue pharmacodynamic data.
<p>* <i>P</i>-value from significance test of relevant contrast from GEE model.</p><p>Tissue pharmacodynamic data.</p
PK/PD relationship between rectal tissue TFV and colorectal tissue supernatant HIV-1 p24 after use of the VF TFV gel, the RGVF TFV gel, and the RF TFV gel.
<p>The black line represents PK/PD relationship for the entire data set across all three formulations.</p
Pharmacokinetic data are summarized as median (interquartile range).*
<p>BLQ; Below the level of quantification</p><p>Pharmacokinetic data are summarized as median (interquartile range).*</p
Flow diagram of participant progress through the CHARM-01 study.
<p>Flow diagram of participant progress through the CHARM-01 study.</p