Efficacy and Safety of New Orodispersible Tablet Formulations of Praziquantel (Racemate and L-Praziquantel) in Schistosoma mansoni-Infected Preschool-Age Children and Infants: A Randomized Dose-Finding Phase 2 Study

Abstract

IntroductionTwo novel formulations of praziquantel (PZQ) and Levo-(L-)PZQ (arpraziquantel) have been developed for the treatment of schistosomiasis in preschool-age children and infants.MethodsThis open-label, dose-finding Phase 2 study assessed the efficacy and safety of PZQ formulations in children and infants infected with Schisostoma mansoni in Côte d’Ivoire. In Part 1, 420 children aged 2.1–6.9 years (weight 10.0–29.9 kg) were enrolled and randomized to one of 7 treatment arms (n=60 per arm): commercially available racemate (rac)-PZQ at 3x20 mg/kg or 40 mg/kg (treatment arms 1 and 2); rac-PZQ orodispersible tablet (ODT) at 40 mg/kg or 60 mg/kg (treatment arms 3 and 4); or L-PZQ ODT at 30 mg/kg, 45 mg/kg, or 60 mg/kg (treatment arms 5, 6, and 7). The optimal formulation and dose identified (L-PZQ ODT 50 mg/kg) was used in Part 2, which enrolled 24 infants aged 6–24 months (weight 7.5–14.8 kg). Infants were treated in an age-staggered approach: age 13–24 months (treatment arm 8, n=20) and age 6–12 months (treatment arm 9, n=4). The primary endpoint was clinical cure rate (CR) demonstrated by the Kato–Katz method 14–21 days post-treatment. Secondary endpoints included CR by point-of-care circulating cathodic antigen, egg reduction rate (ERR), and adverse events (AEs).ResultsIn Part 1, CRs ≥70% were achieved in all treatment arms and were highest with L-PZQ ODT 60 mg/kg (89.7%), rac-PZQ 3x20 mg/kg (89.5%), and L-PZQ ODT 45 mg/kg (86.0%). In Part 2, CRs were >90%. All treatment arms had ERRs >95%. Treatment-related AEs were reported by 71 participants (16.0%) and were similar across treatment arms; most were mild and transient. The most common treatment-emergent AEs were laboratory abnormalities. No deaths or discontinuation due to treatment-emergent AEs were reported and no new safety concerns were identified.ConclusionNew rac-PZQ and L-PZQ ODT formulations used as single-dose therapy against S. mansoni demonstrated acceptable overall efficacy and safety in preschool-age children and infants, warranting further studies in this population.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT02806232; Pan African Clinical Trials Registry, identifier PACTR201604001493593.

Prevalence and risk factors of schistosomiasis and hookworm infection in seasonal transmission settings in northern Côte d’Ivoire: A cross-sectional study

“…In fact, preschoolage children may be infected when accompanying their caregivers to water bodies that are likely to be infested with schistosome cercariae [34,35]. The new formulations of praziquantel for preschool-age children is a welcome addition to the armamentarium for reducing the burden of schistosomiasis in this age group, which has not been targeted for a long time by mass drug administration campaigns [36]. The somewhat higher prevalence of S. haematobium compared to S. mansoni was also observed in previous studies [16,37] [35,38,39].…”

Schistosomiasis in non-endemic areas: Italian consensus recommendations for screening, diagnosis and management by the Italian Society of Tropical Medicine and Global Health (SIMET), endorsed by the Committee for the Study of Parasitology of the Italian Association of Clinical Microbiologists (CoSP-AMCLI), the Italian Society of Parasitology (SoIPa), the Italian Society of Gastroenterology and Digestive Endoscopy (SIGE), the Italian Society of Gynaecology and Obstetrics (SIGO), the Italian Society of Colpo

“…At present, an orodispersible formulation (arpraziquantel) is under the European Medicines Agency review. A phase II clinical trial aimed at evaluating its efficacy and safety in children between 3 months and 6 years showed promising results [ 136 ].…”

Multi-step Flow Synthesis of the Anthelmintic Drug Praziquantel

“…existing synthetic routes to PZQ (1) (Figure 1) involve a series of chemical processes and the utilization of expensive, harmful, and toxic chemical intermediates in harsh to optimal conditions. 12 Based on the use of phenylethylamine (2) as starting material, chemical reagents such as 2,2′-(benzylazanediyl)diacetic acid, (2-isocyanoethyl)benzene, 2,2dimethoxyethan-1-amine, glycinoyl chloride HCl, 2-aminoethan-1-ol, 2- (1,3-dioxoisoindolin-2-yl)acetyl chloride and hydroxymethyl polystyrene as esters and intermediates (2)(3)(4)(5)(6)(7) are used for the production of PZQ. 13 Similarly, praziquinamine (8,9) and isoquinoline carbonitrile analogues (10, 11) under unique reaction conditions, also afforded PZQ.…”

“…5 The oral dispersible tablets of PZQ as paediatric dosage for parasite infected infants and children are undergoing phase II trials. 6 The first veterinary use of PZQ was reported by Merck KGaA and Bayer AG companies in 1970s and patented in 1973 for human use. 7 Chemically, PZQ is a class of tetrahydroisoquinolinone scaffold and is soluble in DMSO, ethyl alcohol, and chloroform.…”