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

The aim of the work presented here was a retrospective exploration to find a PK/PD correlation based on the PK and PD data of the CHICO study in pediatric patients aged from birth to 17 years (8). In CHICO, the efficacy and safety of nifurtimox administered using the treatment regimens described herein were confirmed in pediatric subjects with Chagas disease by the primary efficacy parameter (i.e., at least 20% reduction in optical density or reversion of serological response to negative measured by two conventional ELISA tests) (8). However, post-treatment follow-up in CHICO was limited to 12 months. In chronic Chagas disease, conversion of serological response to negative occurs several years or even decades after antiparasitic treatment in most individuals. Given the limitations resulting from the time of post-treatment follow-up, we refrained from defining a target exposure range based on these study results. Instead, we decided to build our assessment on phase 1 studies in adults. In the absence of data from controlled clinical studies in a corresponding patient population, we derived a reference exposure range for which antitrypanosomal efficacy can be assumed based on the experience from decades of clinical application. We explicitly defined this as the reference rather than the target range to account for the limitations of this approach.

Our investigations included a subgroup of patients enrolled in the phase 3 CHICO study who had consented to participate in the popPK part of the trial and for whom exposure data were collected. In terms of efficacy, we found no relationship between level of exposure to nifurtimox and serological measures associated with parasite clearance. In terms of safety, neither the overall level of exposure to nifurtimox nor peak plasma nifurtimox concentration was associated with the occurrence or severity of specific TEAEs. Modeling exposure in response to different treatment regimens supported the body weight–adjusted, age-stratified dosing regimen used in CHICO and demonstrated the limitations of using simpler dosing regimens in pediatric patients with Chagas disease. Comparison of demographic characteristics demonstrated that the subgroup of patients analyzed was representative of the overall CHICO population; therefore, findings within the subgroup can reasonably be extrapolated to the wider pediatric patient population.

To contextualize the efficacy and safety findings in pediatric patients reported here, we benchmarked the modeled levels of exposure in our analysis population against a 5th–95th percentile reference range derived from non-compartmental PK analysis of adult plasma nifurtimox data. This range was scaled from levels of exposure seen in subtherapeutic, single-dose, phase 1 studies of nifurtimox in adults with Chagas disease to provide an indication of the exposure range that would be expected in adults receiving nifurtimox at the approved therapeutic dose. Owing to a lack of adult clinical data (and of specific immunological or clinical markers) to validate the range as the therapeutic window of drug exposure, it is not intended to define fixed boundaries below which the antiparasitic efficacy of nifurtimox is compromised or above which TEAEs become more frequent or severe. The observation that median exposure and median maximum plasma nifurtimox concentration were similar in individuals who responded to treatment and in those who did not (Fig. 1) supports the assertion that the reference range does not define the efficacy limits of nifurtimox. In addition, Fig. 2b shows that individuals with mild TEAEs were exposed to nifurtimox across the breadth of the adult reference range and often at levels below the 5th percentile, so the upper limit of the adult reference range certainly does not define a threshold beyond which TEAEs become more frequent. Thus, the degree to which the range can be used to interpret pediatric exposure data has limitations, but it does provide a bracket in which there is some precedent for the efficacy and safety performance of nifurtimox, and outside of which the risk of safety and efficacy issues are unknown.

Despite the absence of a clear relationship between nifurtimox exposure and efficacy parameters measured, both parasite susceptibility in vitro and clinical study data confirm that nifurtimox is an effective treatment for Chagas disease. However, the findings do show that the relationship between exposure and available PD measures of clinical efficacy is not straightforward. Having a reference range for exposure is helpful because of the challenge of demonstrating parasitological cure in Chagas disease and, therefore, of characterizing efficacious dosing levels in pediatric patients based on what is effective in adults. Treatment success in Chagas disease is difficult to quantify based on negative seroconversion measured by conventional serologic tests, because T. cruzi elicits a strong antibody response which persists even after successful treatment and parasitic clearance. Indeed, it can take 10 to 20 years for chronically infected adults to become seronegative following treatment. In a recent study in children aged 2–14 years at the time of antitrypanosomal treatment initiation, the average (SD) time to negative seroconversion by conventional serology was 15.7 (8.7) years post-treatment (18). Thus, the lack of any direct relationship between efficacy endpoints and nifurtimox exposure in our analysis may be attributable to the limited duration of follow-up post-treatment in CHICO (12 months).

The qPCR test also has limitations; a positive result can confirm treatment failure by detecting parasites in blood, but a negative result is not a reliable indicator of parasitological cure. Further complications include the fact that different strains of T. cruzi have been shown to have variable levels of susceptibility to antiparasitic therapy (19, 20). It is also unknown whether children experience any drug concentration–dependent sensitivity to nifurtimox that is not observed in adult patients.

The TEAEs that were observed were representative of those known to be associated with nifurtimox. In CHICO, all but one of the TEAEs were classified as mild or moderate severity (8), and the few individuals studied here who had moderate TEAEs were generally below the median level of nifurtimox exposure in adults. Both the number of individuals who experienced a TEAE and the overall number of TEAEs experienced were relatively small, but we found no evidence of an association between safety outcomes and the levels of nifurtimox to which these patients were exposed. Drug-induced delay in cardiac repolarization is of particular interest in safety terms, but our analysis provided no evidence that nifurtimox caused QTc prolongation of particular concern (Fig. 3). In accordance with findings elsewhere (21), we found no evidence that nifurtimox delays cardiac repolarization. It cannot be concluded that no relationship exists between TEAEs and nifurtimox exposure, but it is unlikely that such a relationship would be seen among individuals receiving the age- and body weight–adjusted dosing used in CHICO.

A fixed-dose simulation (data not shown) was performed to better understand the relationship between physiological development of the child and exposure to nifurtimox. The PK data modeled and reported here demonstrate the limitations of using flat dosing regimens compared to established body weight–adjusted regimens in pediatric patients with Chagas disease. Furthermore, a flat-dose nifurtimox regimen seems to be ill-suited for the whole pediatric population owing to the very broad range of body weights seen from newborns to 18-year-olds. Thus, any flat-dose strategy would lead to extremes of exposure somewhere in the pediatric age range. Abrupt changes in exposure can also be seen on transition between different dose levels. This would not necessarily preclude the approach, but the maximum dose level at which body weight–adjusted dosing is applied would have to be considered carefully. The dose limit in humans is not well characterized; dose-limiting toxicity was reported in patients with neuroblastoma aged less than 21 years, receiving nifurtimox at more than 30 mg/kg/day (22). Toxic effects have also been reported in animal studies of nifurtimox at high doses (up to 150 mg/kg/day in rodents and up to 120 mg/kg/day in dogs for 28 days) (23).

Moving to a body weight–adjusted dosing regimen at a fixed level (for example, 8 mg/kg/day) with no defined body weight threshold at which the dose level changes (e.g., 40 kg) was also associated with exposure to nifurtimox outside of the adult reference range (Fig. 5). Selecting a low dose may prioritize safety in terms of reducing the risk of TEAEs, but this must be balanced against possible impact on effectiveness. As shown in Fig. 4, population norms indicate that children aged 12 years have a median body weight of approximately 40 kg (16, 17). Most of the pediatric population had a level of exposure below the adult reference range when modeled at 8 mg/kg/day, but nearly all children aged less than 12 years were below the range at this dosing level. It is hard to justify such a strategy when a higher dose would have no safety implications. Similarly, prioritizing efficacy by using the higher dose of 20 mg/kg/day subjected most children aged over 12 years to a level of exposure that may put them at increased risk of TEAEs (Fig. 5).

Modeling of the two standard dose ranges used in pediatric patients (Fig. 6) showed how younger children are generally best served using a dose range that is different to that used in older patients in terms of balancing efficacy and safety by smoothing changes in exposure as body weight increases. However, there was also a noticeable inflexion in the data modeled at the 10–20 mg/kg/day dose that coincides with the threshold of body weight of 40 kg and age 12 years. Comparison with modeled data in which pediatric patients switch from the higher to the lower dose range at age 12 years shows that such a regimen reduces the likelihood of excessive nifurtimox exposure in adolescents. The regimen could be refined even further by introducing another threshold and more than two dose ranges, but this would increase the complexity of administration. Figure 6 also shows that modeled levels of exposure based on the dosing used in CHICO were generally below the median exposure level in adults. Thus, the efficacy of nifurtimox in CHICO was not attributable to drug overexposure, and in safety terms, levels of exposure were conservative.

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