Population Pharmacokinetics of Nifurtimox in Adult and Pediatric Patients With Chagas Disease

Abstract

Nifurtimox (LAMPIT) has been used for decades for the treatment of Chagas disease, a chronic and potentially life‐threatening disease caused by the parasite Trypanosoma cruzi. The pharmacokinetic (PK) information on nifurtimox in humans derived from controlled clinical studies is very limited. The objective was to investigate and compare the population PK of nifurtimox in adult and pediatric patients with Chagas disease to confirm the clinical dosing regimen in children, which was based on allometric approaches using the concept that a dose‐equivalent exposure would reach equivalent antiparasitic efficacy as in adults. The resulting adult model adequately described the PK in adults. Significant predictors of the availability in PK were food intake, tablet formulation (fast‐ vs slow‐dissolution tablet), study, and body weight. As the resulting adult model could not adequately predict the sparse sampled pediatric patient data, these data were analyzed separately to derive exposure estimates for comparison with adult exposure. In the population PK model for pediatric patients, significant covariates were body weight and age. As compared to adults, children aged >2 years were estimated to have 50.6% higher apparent clearance. No hints of dose nonlinearity were observed in a dose range of 30 to 240 mg single dose in adults and 15 to 300 mg 3 times daily (8‐20 mg/kg) in children. Altogether, this study retroactively showed that the current mg/kg dosing regimen in children reached similar exposure as in adults receiving an 8 mg/kg total daily dose.

Nifurtimox for Treatment of Chagas Disease in Pediatric Patients: the Challenges of Applying Pharmacokinetic-Pharmacodynamic Principles to Dose Finding

“…NONMEM-run execution, bootstrap, and visual predictive check (VPC) were performed using Perl-speaks-NONMEM (PsN), version 4.8.1. Methodological details of the development of the popPK model have been reported (7). Modeling used PK data from phase 1 studies of nifurtimox in adults with Chagas disease (9,10) and the phase 3 CHICO study in pediatric patients with Chagas disease (8).…”

“…Modeling used PK data from phase 1 studies of nifurtimox in adults with Chagas disease (9,10) and the phase 3 CHICO study in pediatric patients with Chagas disease (8). An adult popPK model described the data in adults but could not adequately predict the sparse-sampled pediatric data; therefore, the pediatric data were modeled separately to obtain exposure estimates for comparison with adult data (7).…”

“…The reference ranges used here are the 5th-95th percentiles of the scaled exposure and C max values; exposure modeled at the individual level in the target pediatric population is assessed against the reference exposure range. Exposure-response relationships were explored in participants with PK data using the individual predicted exposure of plasma nifurtimox concentration versus time at steady state (AUC ss ), AUC within the dosing interval (0-8 h), and maximum concentration at steady state (C max;ss ) based on dosing records (7), with observed effects on efficacy (e.g., seroreduction measured by conventional ELISAs) and safety parameters (TEAE occurrence and severity). We used R version 3.5.1 (13) to create forest plots and then diagnosed any correlation between PK and efficacy or between PK and safety parameters by visual inspection.…”

“…Dose determination for nifurtimox in Chagas disease was conducted according to standards applicable at the time (6), and did not include phase 1 clinical development studies now routinely performed for new chemical entities. A recent population pharmacokinetic (popPK) model (7), which used pharmacokinetic (PK) data from a phase 3 study (CHICO) in patients with Chagas disease aged < 18 years (including newborns) (8), determined that both body weight and age can affect apparent oral clearance and apparent volume of distribution of nifurtimox in pediatric patients. This pediatric model also found that the PK characteristics of nifurtimox are unaffected by sex and that there was no indication of deviation from dose linearity across the pediatric dose range (7).…”

“…A recent population pharmacokinetic (popPK) model (7), which used pharmacokinetic (PK) data from a phase 3 study (CHICO) in patients with Chagas disease aged < 18 years (including newborns) (8), determined that both body weight and age can affect apparent oral clearance and apparent volume of distribution of nifurtimox in pediatric patients. This pediatric model also found that the PK characteristics of nifurtimox are unaffected by sex and that there was no indication of deviation from dose linearity across the pediatric dose range (7). The efficacy of nifurtimox was demonstrated in CHICO based on body weight-adjusted dosing stratified by age (participants aged < 12 years and weighing < 40 kg received a total daily dose in the range 10-20 mg/kg/day, and participants aged ≥ 12 years and weighing ≥ 40 kg received 8-10 mg/kg/day), determined at the judgement of the treating physician (8).…”