Pharmacokinetics of Ganaplacide and Lumefantrine in Adults, Adolescents, and Children with Plasmodium falciparum Malaria Treated with Ganaplacide Plus Lumefantrine Solid Dispersion Formulation: Analysis of Data from a Multinational Phase 2 Study.

Autor: Sangana R; PK Sciences, Biomedical Research, Novartis, Cambridge, MA, USA., Ogutu B; Centre for Clinical Research, Kenya Medical Research Institute, Kisumu, Kenya and CREATES, Strathmore University, Nairobi, Kenya., Yeka A; Infectious Diseases Research Collaboration, Kampala, Uganda., Kusemererwa S; Medical Research Council/Uganda Virus Resea, rch Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda., Tinto H; Institut de Recherche en Science de la Santé - Unité de Recherche Clinique de Nanoro (IRSS-URCN), Nanoro, Burkina Faso., Toure AO; Department of Parasitology-Mycology, Institut Pasteur de Côte d'Ivoire, Abidjan, Côte d'Ivoire., Kibuuka A; Infectious Diseases Research Collaboration (IDRC), Kampala, Uganda., Lingani M; Institut de Recherche en Science de la Santé - Unité de Recherche Clinique de Nanoro (IRSS-URCN), Nanoro, Burkina Faso., Lourenço C; Chókwè Health Research and Training Center/Centro de Investigação e Treino em Saúde de Chókwè (CITSC), National Institute of Health, Mozambique., Mombo-Ngoma G; Centre de Recherches Médicales de Lambaréné (CERMEL), Lambaréné, Gabon.; Department of Implementation Research, Bernhard Nocht Institute for Tropical Medicine and Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany., Nduba V; Kenya Medical Research Institute-Centre for Respiratory Diseases Research (KEMRI-CRDR), Nairobi, Kenya., Landry N'Guessan T; Department of Parasitology-Mycology, Institut Pasteur de Côte d'Ivoire, Abidjan, Côte d'Ivoire., Nassa GJW; Institut de Recherche en Science de la Santé - Unité de Recherche Clinique de Nanoro (IRSS-URCN), Nanoro, Burkina Faso., Nyantaro M; Medical Research Council/Uganda Virus Resea, rch Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda., Tina LO; Centre for Clinical Research, Kenya Medical Research Institute/US Army Medical Research Directorate, Kisumu, Kenya., Anvikar A; ICMR-National Institute of Malaria Research, New Delhi, India., Sinha A; ICMR-National Institute of Malaria Research, New Delhi, India., Kaguthi G; Kenya Medical Research Institute-Centre for Respiratory Diseases Research (KEMRI-CRDR), Nairobi, Kenya., Fofana B; Malaria Research and Training Center, Bamako, Mali., Grobusch MP; Centre de Recherches Médicales de Lambaréné (CERMEL), Lambaréné, Gabon.; Department of Infectious Diseases, Center of Tropical Medicine and Travel Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.; Institute of Tropical Medicine, University of Tubingen, Tubingen, Germany., Gaaloul ME; Medicines for Malaria Venture, Geneva, Switzerland., Marrast AC; Medicines for Malaria Venture, Geneva, Switzerland., Pathan R; Novartis Healthcare Pvt. Ltd., Hyderabad, India., Chikoto H; Novartis Healthcare Pvt. Ltd., Hyderabad, India., Csermak K; Novartis Healthcare Pvt. Ltd., Hyderabad, India., Risterucci C; Novartis Healthcare Pvt. Ltd., Hyderabad, India., Su G; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA., Winnips C; Novartis Pharma AG, Basel, Switzerland., Zhang J; PK Sciences, Biomedical Research, Novartis, East Hanover, NJ, USA., Zack J; PK Sciences, Biomedical Research, Novartis, East Hanover, NJ, USA.
Jazyk: angličtina
Zdroj: Journal of clinical pharmacology [J Clin Pharmacol] 2024 Sep 29. Date of Electronic Publication: 2024 Sep 29.
DOI: 10.1002/jcph.6138
Abstrakt: The novel antimalarial ganaplacide combined with lumefantrine solid dispersion formulation (LUM-SDF) was effective and well tolerated in the treatment of uncomplicated falciparum malaria in adults, adolescents, and children in a multinational, prospective, randomized, active-controlled Phase II study conducted between August 2017 and June 2021 (EudraCT 2020-003284-25, Clinicaltrials.gov NCT03167242). Pharmacokinetic data from that study are reported here. The trial comprised three parts: a run-in part in 12 adult/adolescent patients treated with a single dose of ganaplacide 200 mg plus LUM-SDF 960 mg assessed potential pharmacokinetic (PK) interactions between ganaplacide and lumefantrine; in Part A, adult/adolescent patients received one of the six ganaplacide-LUM-SDF regimens or artemether-lumefantrine; and in Part B, three dose regimens identified in Part A, and artemether-lumefantrine, were assessed in children aged 2 to <12 years, with body weight ≥10 kg. A rich blood sampling schedule was used for all 12 patients in the PK run-in part and a subset of patients (N = 32) in Part A, with sparse sampling for remaining patients in Parts A (N = 275) and B (N = 159). Drug concentrations were determined by a validated protein precipitation and reverse phase liquid chromatography with tandem mass spectrometry detection method. Parameters including AUC inf , AUC last , AUC 0-t , C max, and t max were reported where possible, using non-compartmental analysis. In the PK run-in part, there was no notable increase in ganaplacide or lumefantrine exposure when co-administered. In Parts A and B, ganaplacide exposures increased with dose, but lumefantrine exposure was numerically under dose-proportional. Lumefantrine exposure was higher with ganaplacide-LUM-SDF than with artemether-lumefantrine, although high variability was observed. Ganaplacide and lumefantrine exposures (C max and AUC 0-24 h ) were comparable across age and body weight groups. Drug exposures needed for efficacy were achieved using the dose regimen 400 mg ganaplacide plus lumefantrine 960 mg once daily for 3 days under fasted conditions.
(© 2024 Novartis. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
Databáze: MEDLINE
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