A Combination Regimen Design Program Based on Pharmacodynamic Target Setting for Childhood Tuberculosis: Design Rules for the Playground

Abstract

Children with tuberculosis are treated with drug regimens copied from adults despite significant differences in antibiotic pharmacokinetics, pathology, and the microbial burden between childhood and adult tuberculosis. We sought to develop a new and effective oral treatment regimen specific to children of different ages. We investigated and validated the concept that target drug concentrations associated with therapy failure and death in children are different from those of adults. On that basis, we proposed a 4-step program to rapidly develop treatment regimens for children. First, target drug concentrations for optimal efficacy are derived from preclinical models of disseminated tuberculosis that recapitulate pediatric pharmacokinetics, starting with monotherapy. Second, 2-drug combinations were examined for zones of synergy, antagonism, and additivity based on a whole exposure–response surface. Exposures associated with additivity or synergy were then combined and the regimen was compared to standard therapy. Third, several exposures of the third drug were added, and a 3-drug regimen was identified based on kill slopes in comparison to standard therapy. Fourth, computer-aided clinical trial simulations are used to identify clinical doses that achieve these kill rates in children in different age groups. The proposed program led to the development of a 3-drug combination regimen for children from scratch, independent of adult regimens, in <2 years. The regimens and doses can be tested in animal models and in clinical trials.

Levofloxacin Population Pharmacokinetics in South African Children Treated for Multidrug-Resistant Tuberculosis

“…These are potentially important limitations to the targeting of PK/PD indices. Interesting work on the development of hollow-fiber models of pediatric TB to establish drug targets has recently been undertaken (38); however, in the absence of validation of the exposure targets generated by these hollow-fiber models, we believe that it is premature to define doses on the basis of that work. Therefore, despite the limitations, the use of exposures in adults associated with efficacy remains a reasonable approach to establishing pediatric doses for anti-TB drugs.…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…In some models these data have been found to accurately forecast therapeutic events with 94% accuracy. 183,[421][422][423][424][425] The bactericidal effect of isoniazid is an example that has been shown in several preclinical models and patients (table 10). 421 The pharmacokinetic-pharmacodynamic exposure patterns or indices important in preventing or amplifying acquired drug resistance have been established for several agents in preclinical models, and at least in the case of first-line antituberculosis drugs and quinolones, they have been validated in clinical studies.…”

“…183,[421][422][423][424][425] The bactericidal effect of isoniazid is an example that has been shown in several preclinical models and patients (table 10). 421 The pharmacokinetic-pharmacodynamic exposure patterns or indices important in preventing or amplifying acquired drug resistance have been established for several agents in preclinical models, and at least in the case of first-line antituberculosis drugs and quinolones, they have been validated in clinical studies. 380,426,419 Table 11 shows the pharmacokineticpharmacodynamic exposure and pharmacokineticpharmacodynamic index associated with the sup pression of acquired drug resistance for several drugs that are used in clinical practice; these often differ from those associated with opti mal microbial kill for the same drug.…”

“…380,426,419 Table 11 shows the pharmacokineticpharmacodynamic exposure and pharmacokineticpharmacodynamic index associated with the sup pression of acquired drug resistance for several drugs that are used in clinical practice; these often differ from those associated with opti mal microbial kill for the same drug. 173,180,191,192,196,380,395,417,[419][420][421][422][423][424][425][426][427][428][429][430][431] Mistakenly, many regi mens were designed for the treatment of tuberculosis with a focus on microbial kill, ignoring the problem of acquired drug resistance. The theory was that directly observing the patients swallowing the pills, and using one drug to prevent resistance to another, would solve the acquired drug resistance problem.…”

Tuberculosis in Children

“…Including children in pre-clinical and clinical pharmacokinetic studies and efficacy trials is imperative to meeting the goals for global TB control. 107,108 Equally urgent is the need for child-friendly first- and second-line drugs which are palatable and easily administered.…”