Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations

Abstract

Optimal doses for antituberculosis (anti-TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosage ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods. Nonlinear mixed-effects models were applied to describe the population PK of those drugs using MonolixSuite2016R1 (Lixoft, France). Bayesian estimation was performed, the correlation coefficient, bias, and precision between the observed and predicted areas under the concentration-time curve (AUCs) were calculated, and Bland-Altman plots were analyzed. The population PK of RIF and PZA was described by a one-compartment model and that for INH and EMB by a two-compartment model. Plasma maximum concentration () and AUC targets were based on published results for children from India. The lowest target values for pediatric TB patients were attainable at the WHO-recommended dosage schedule for RIF and INH, except for -acetyltransferase 2 non-slow acetylators (rapid and intermediate acetylators) in the lower-weight bands. However, higher published adult targets were not attainable for RIF and INH. The targets were not achieved for PZA and EMB. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.).

Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?

“…When a model-based approach is used to interpret the concentrations of anti-TB drugs, as in previous analyses by Chirehwa et al and Rockwood et al and the present analysis, the lower exposure in lower-weight patients has been explained as a direct consequence of allometric scaling. According to this well-established concept, corroborated by both empirical evidence and physiological/biological theory, the relationship between body size and drug clearance is nonlinear (18,19). This means that weightnormalized clearance (liters per hour per kilogram of body weight) is higher in smaller individuals, who then need a larger milligram-per-kilogram dose to achieve concentrations comparable to those in larger individuals.…”

In vitro Pharmacokinetic Cell Culture System that Simulates Physiologic Drug and Nanoparticle Exposure to Macrophages

“…The PK elimination profile of RIF in vivo is best described by a one-compartment model with a half-life of 3 h (24,25). Therefore, we designed the in vitro PK cell culture system to mimic a one compartment model (first-order model) in comparison to a traditional static cell culture system that is described by a zero-order model.…”

“…Therefore, an in vitro dynamic pharmacokinetic (PK) cell culture system that more precisely simulates physiologic cell drug exposure based on dosing and elimination pharmacokinetic parameters was developed. We used rifampin (RIF), a model antibiotic with a short half-life used for the treatment of tuberculosis (TB) (24, 25), to explore the advantages of a dynamic PK cell culture system to study intracellular drug concentrations for nanoparticle and free drug compared to standard cell culture approaches.…”

Current research toward optimizing dosing of first-line antituberculosis treatment

“…Dosing guidelines for antituberculosis drugs typically advocate a uniform milligram per kilogram of body weight (mg/kg) dose, and the drugs are typically dosed by weight band to achieve a narrow mg/kg range using the available formulations [40,41]. A consistent finding of pharmacokinetic studies in adults and children dosed in this way is that lower weight patients have lower drug exposures [5,10,13,18,33,37,[42][43][44]. This can be attributed to the nonlinear relationship between clearance and size whereby smaller people need higher maintenance doses per kilogram of body weight [45].…”

“…The doses of have been increased by 50% for rifampin to 15 (10-20) mg/kg and by 100% for isoniazid to 10 (7-15) mg/kg, while 35 (30-40) mg/kg doses of pyrazinamide are recommended. Emerging studies evaluating the revised doses show that while the higher pediatric weight bands achieve average rifampin and pyrazinamide exposures similar to adults, in children under 12 kg exposures fall short of those in adults [42][43][44]55].…”