Efficacy, safety, and palatability of arpraziquantel (L-praziquantel) orodispersible tablets in children aged 3 months to 6 years infected with Schistosoma in Côte d'Ivoire and Kenya: an open-label, partly randomised, phase 3 trial

N’Goran, Eliézer K.; Odiere, Maurice R.; Aka, Ronald Assandé; Ouattara, Mamadou; Aka, Nda Angbeletchi David; Ogutu, Bernhards; Rawago, Fredrick; Bagchus, Wilhelmina; Bödding, Matthias; Kourany-Lefoll, Elly; Tappert, Aliona; Yin, Xiaoyan; Bezuidenhout, Deon; Badenhorst, Henk; Huber, Eric; Dälken, Benjamin; Saflo, Okba Haj-Ali

doi:10.1016/s1473-3099(23)00048-8

Cited by 13 publications

(6 citation statements)

References 26 publications

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“…While we did not investigate the in vivo metabolism of compounds 5 and 6 , one possible explanation for the better outcome of PZQ is the potential contribution of the metabolite 2 . This is relevant clinically as the main metabolite 2 has been up to 133‐fold more exposed than ( R )‐PZQ in healthy volunteers [20] …”

Section: Resultsmentioning

confidence: 99%

“…Activation of schistosome TRPM PZQ was measured using a Ca 2 + reporter assay, following transient transfection of codon-optimized (Genscript) constructs into HEK293 Table 3. (R)-PZQ (1) and its main metabolite (2) exposures from a Phase 3 study, [20] protein binding in relationship to Sm.TRPM PZQ and whole worm activities. [19,22] Compound [b] Relative contribution to activity 7 93 (C av,u /Sh.TRPM PZQ EC 50 ) [b] Relative contribution to activity 34 66 (C av,u /EC 50 ) [b] for S. mansoni Relative contribution to activity 25 75 (C av,u /EC 50 ) [b] for S. haematobium…”

Section: Discussionmentioning

confidence: 99%

“…This is relevant clinically as the main metabolite 2 has been up to 133-fold more exposed than (R)-PZQ in healthy volunteers. [20] Consequently, we embarked in assessing the potential contribution to the clinical activity of the main metabolite 2 despite an inherent weaker on-target activity. [12] Here we assumed that all activity was solely related to only the parent (R)-PZQ or its metabolite 2 (Table 3).…”

Section: Chemmedchemmentioning

confidence: 99%

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Metabolism of (R)‐Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel

Friedrich

Park

Ballard³

et al. 2023

ChemMedChem

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Praziquantel (PZQ) is an essential anthelmintic drug recently established to be an activator of a Transient Receptor Potential Melastatin (TRPMPZQ) ion channel in trematode worms. Bioinformatic, mutagenesis and drug metabolism work indicate that the cyclohexyl ring of PZQ is a key pharmacophore for activation of trematode TRPMPZQ, as well as serving as the primary site of oxidative metabolism which results in PZQ being a short‐lived drug. Based on our recent findings, the hydrophobic cleft in schistosome TRPMPZQ defined by three hydrophobic residues surrounding the cyclohexyl ring has little tolerance for polarity. Here we evaluate the in vitro and in vivo activities of PZQ analogues with improved metabolic stability relative to the challenge of maintaining activity on the channel. Finally, an estimation of the respective contribution to the overall activity of both the parent and the main metabolite of PZQ in humans is reported.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Chemmedchemmentioning

confidence: 99%

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Metabolism of (R)‐Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel

Friedrich

Park

Ballard³

et al. 2023

ChemMedChem

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“…However, opportunities for improvement certainly remain. These include optimization of formulations or derivatives that address the low oral bioavailability and rapid host metabolism of PZQ [ 7 , 8 ], as well as mitigation of other challenges (for example, bitter taste [ 9 ]) that result in poor compliance in the field [ 10 ]. Further opportunities relate to the lower efficacy of PZQ against certain parasites and life cycle stages—most clearly exemplified by the lack of PZQ activity against Fasciola species as well as the poor effectiveness of PZQ against juvenile schistosomes.…”

Section: Introductionmentioning

confidence: 99%

Progress interrogating TRPMPZQ as the target of praziquantel

Marchant

2024

PLoS Negl Trop Dis

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The drug praziquantel (PZQ) has served as the long-standing drug therapy for treatment of infections caused by parasitic flatworms. These encompass diseases caused by parasitic blood, lung, and liver flukes, as well as various tapeworm infections. Despite a history of clinical usage spanning over 4 decades, the parasite target of PZQ has long resisted identification. However, a flatworm transient receptor potential ion channel from the melastatin subfamily (TRPMPZQ) was recently identified as a target for PZQ action. Here, recent experimental progress interrogating TRPMPZQ is evaluated, encompassing biochemical, pharmacological, genetic, and comparative phylogenetic data that highlight the properties of this ion channel. Various lines of evidence that support TRPMPZQ being the therapeutic target of PZQ are presented, together with additional priorities for further research into the mechanism of action of this important clinical drug.

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“…Compared to the available praziquantel 600 mg tablets, the palatability of the new tablet has been improved [17] and it can be dissolved in liquid (2 ml per 150 mg tablet) thus facilitating more accurate and easier dosing for PSAC drug administration [18]. The drug has gone through clinical trials including Kenya, proved to be safe for use and will be rolled out in a pilot MDA [19].…”

Section: Introductionmentioning

confidence: 99%

Community preferred drug delivery approaches for pilot roll-out of a potential novel paediatric schistosomiasis treatment option in two endemic counties of Kenya: A mixed methods study

Masaku,

Gachohi,

Sinkeet

et al. 2024

PLOS Glob Public Health

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Treating preschool age children (PSAC) for schistosomiasis has remained a challenge due to lack of a pediatric formulation. In response to this unmet need, the Paediatric Praziquantel Consortium has developed a potential novel paediatric treatment option. In advance to its roll-out to follow regulatory response, we conducted a social science study to gather information on preferred drug delivery approaches to inform implementation. A cross-sectional study was conducted in eight villages in two purposively selected Kenyan counties. A questionnaire was administered on 690 parents/guardians of PSAC at household level. Preferred drug delivery approaches were analyzed using frequencies and proportions. We conducted key informant interviews with 17 opinion leaders and 28 healthcare workers, and 12 focus group discussions with parents/guardians of PSAC and 7 with community health volunteers (CHVs). Thematic analysis was performed on the qualitative data. Majority of the 690 respondents were women 594 (86.1%) with a mean age of 34.1 (SD = 11.3, min-max = 18–86). Community-based mass drug administration (cMDA) was the most preferred drug delivery method by 598 participants (86.7%), followed by health facility/fixed points by 398 participants (57.7%). Similarly, in the qualitative data participants indicated they prefer cMDA since the CHVs who would distribute the medication are familiar with households with PSAC and are trusted to explain the drug effects. Health facilities/fixed points were the second most preferred drug delivery approach, but some health workers we interviewed expressed concern about potential understaffing and overcrowding of facilities. Appropriate timing of the drug distribution, not to interfere with farming activities, was considered critical, irrespective of the approach used. All profiles of study participants preferred cMDA over the other delivery approaches due to the convenience of receiving drugs at home and providing explanations about the new drug. For positive outcomes, adequate planning, proper timings and community involvement are highly recommended.

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Efficacy, safety, and palatability of arpraziquantel (L-praziquantel) orodispersible tablets in children aged 3 months to 6 years infected with Schistosoma in Côte d'Ivoire and Kenya: an open-label, partly randomised, phase 3 trial

Cited by 13 publications

References 26 publications

Metabolism of (R)‐Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel

Metabolism of (R)‐Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel

Progress interrogating TRPMPZQ as the target of praziquantel

Community preferred drug delivery approaches for pilot roll-out of a potential novel paediatric schistosomiasis treatment option in two endemic counties of Kenya: A mixed methods study

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