Optimal clinical doses of Faropenem, Linezolid, and Moxifloxacin in children with disseminated tuberculosis: Goldilocks.

Srivastava, S.; Deshpande, D.; Pasipanodya, J.; Nuermberger, E.; Swaminathan, S.; Gumbo, T.

Clinical Infectious Diseases; 2016; 63; S102-S109.

Background: When treated with the same antibiotic dose, children achieve different 0- to 24-hour area under the concentration time curves (AUC 0–24 ) because of maturation and between-child physiological variability on drug clearance. Children are also infected by Mycobacterium tuberculosis isolates with different antibiotic minimum inhibitory concentrations (MICs). Thus, each child will achieve different AUC 0–24 /MIC ratios when treated with the same dose.

Methods: We used 10 000-subject Monte Carlo experiments to identify the oral doses of linezolid, moxifloxacin, and faropenem that would achieve optimal target exposures associated with optimal efficacy in children with disseminated tuberculosis. The linezolid and moxifloxacin exposure targets were AUC 0–24 /MIC ratios of 62 and 122, and a faropenem percentage of time above MIC >60%, in combination therapy. A linezolid AUC 0–24 of 93.4 mg × hour/L was target for toxicity. Population pharmacokinetic parameters of each drug and between-child variability, as well as MIC distribution, were used, and the cumulative fraction of response (CFR) was calculated. We also considered drug penetration indices into meninges, bone, and peritoneum.

Results: The linezolid dose of 15 mg/kg in full-term neonates and infants aged up to 3 months and 10 mg/kg in toddlers, administered once daily, achieved CFR = 90%, with <10% achieving linezolid AUC 0–24 associated with toxicity. The moxifloxacin dose of 25 mg/kg/day achieved a CFR > 90% in infants, but the optimal dose was 20 mg/kg/day in older children. The faropenem medoxomil optimal dosage was 30 mg/kg 3–4 times daily.

Conclusions: The regimen and doses of linezolid, moxifloxacin, and faropenem identified are proposed to be adequate for all disseminated tuberculosis syndromes, whether drug-resistant or -susceptible.  

Keywords: Monte Carlo experiments; pharmacokinetic variability; dosage design; combination regimen; target setting.

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