Extrapolation of praziquantel pharmacokinetics to a pediatric population: a cautionary tale

Abstract

L-praziquantel (PZQ) pharmacokinetic data were analyzed from two relative bioavailability Phase 1 studies in adult, healthy subjects with two new oral dispersion tablet (ODT) formulations of L-PZQ administered under various combinations of co-administration with food, water, and/or crushing. Linear mixed effects models adequately characterized the noncompartmental estimates of the pharmacokinetic profiles in both studies. Dose, food, and formulation were found to significantly affect L-PZQ exposure in both studies. The model for AUC was then extrapolated to children 2–5 years old accounting for enzyme maturation and weight. The predicted exposures were compared to an external Phase 1 study conducted by the Swiss Tropical and Public Health Institute using a currently marketed formulation (Cesol 600 mg immediate-release tablets) and found to be substantially lower than observed. A root cause analysis was completed to identify the reason for failure of the models. Various scenarios were proposed and tested. Two possible reasons for the failure were identified. One reason was that the model did not account for the reduced hepatic clearance seen in patients compared to the healthy volunteer population used to build the model. The second possible reason was that PZQ absorption appears sensitive to meal composition and the model did not account for differences in meals between a standardized Phase 1 unit and clinical sites in Africa. Further studies are needed to confirm our hypotheses.Electronic supplementary materialThe online version of this article (10.1007/s10928-018-9601-1) contains supplementary material, which is available to authorized users.

Insights into Praziquantel Metabolism and Potential Enantiomeric Cytochrome P450–Mediated Drug-Drug Interaction

“…Racemic praziquantel (PZQ) is the World Health Organisation (WHO)'s drug of choice to treat Schistosomiasis (WHO, 2009), a neglected tropical disease affecting 207 million people worldwide (WHO, 2018). Given the prevalence of this disease in young children (3 months to 6 years) (Stothard et al, 2011), the Pediatric Praziquantel Consortium (http://www.pediatricpraziquantelconsortium.org) aims to develop a pediatric formulation for this population (Bonate et al, 2018). Considering the recommendations from Research and Training in Tropical Diseases on switching to an enantiomerically pure formulation of the active form R-PZQ (WHO, 2007), one goal of the Pediatric Praziquantel Consortium was to clinically compare racemic (rac-PZQ) vs pure R-PZQ formulations (WHO, 2010), with the expectation that an enantiomeric pure formulation will result in a smaller orally disintegrating tablet (ODT) with less bitter taste, as inactive S-PZQ mainly contributes to unpleasant taste (Meyer et al, 2009).…”

Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults

“…The selection of an empirical model based on statistical criteria may not lead to an accurate or acceptable model from a practical perspective. Cella et al [27], Santen et al [28], and Bonate et al [29] found that, despite statistical validation, a POPPK model may not predict PK parameters in a new population.…”

Relative Bioavailability of Orally Dispersible Tablet Formulations of Levo‐ and Racemic Praziquantel: Two Phase I Studies

“…The shapes of the individual concentration/time profiles were highly variable with early and late C max , broad and sharp peaks, and multiple peaks. Overall between‐subject variability was very high, which hindered the construction of reliable population PK models that would permit extrapolation of adult PK data to children . The lower bioavailability of L‐PZQ ODT, the high variability and the nondose linearity of the PK parameters indicated the need for a proper pediatric dose‐finding study.…”