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The importance of clinical pharmacokinetic-pharmacodynamic studies in unraveling the determinants of early and late tuberculosis outcomes.

ABSTRACT: Tuberculosis remains a major infectious cause of morbidity and mortality worldwide. Current antibiotic regimens, constructed prior to the development of modern pharmacokinetic-pharmacodynamic (PK-PD) tools, are based on incomplete understanding of exposure-response relationships in drug susceptible and multidrug resistant tuberculosis. Preclinical and population PK data suggest that clinical PK-PD studies may enable therapeutic drug monitoring for some agents and revised dosing for others. Future clinical PK-PD challenges include: incorporation of PK methods to assay free concentrations for all active metabolites; selection of appropriate early outcome measures which reflect therapeutic response; elucidation of genetic contributors to interindividual PK variability; conduct of targeted studies on special populations (including children); and measurement of PK-PD parameters at the site of disease.

SUBMITTER: McCallum AD

PROVIDER: S-EPMC6161803 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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The importance of clinical pharmacokinetic-pharmacodynamic studies in unraveling the determinants of early and late tuberculosis outcomes.

McCallum Andrew D AD Sloan Derek J DJ

International journal of pharmacokinetics 20170712 3

Tuberculosis remains a major infectious cause of morbidity and mortality worldwide. Current antibiotic regimens, constructed prior to the development of modern pharmacokinetic-pharmacodynamic (PK-PD) tools, are based on incomplete understanding of exposure-response relationships in drug susceptible and multidrug resistant tuberculosis. Preclinical and population PK data suggest that clinical PK-PD studies may enable therapeutic drug monitoring for some agents and revised dosing for others. Futur ...[more]

PMID: 30283633

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Project description:Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC(50)] = 0.18 nM) or B/Yamagata (IC(50) = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC(0-24)), minimum concentration of OC in plasma (C(min)), and maximum concentration of OC in plasma (C(max)). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC(0-24 )evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC(0-24) threshold (~14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.

Dataset Information

The importance of clinical pharmacokinetic-pharmacodynamic studies in unraveling the determinants of early and late tuberculosis outcomes.

Publications

The importance of clinical pharmacokinetic-pharmacodynamic studies in unraveling the determinants of early and late tuberculosis outcomes.

Similar Datasets

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