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Characterising the blood-stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected with Plasmodium falciparum.
Barber, Bridget E; Webster, Rebecca; Potter, Adam J; Llewellyn, Stacey; Sahai, Nischal; Leelasena, Indika; Mathison, Susan; Kuritz, Karsten; Flynn, Julia; Chalon, Stephan; Marrast, Anne Claire; Gobeau, Nathalie; Moehrle, Joerg J.
Afiliación
  • Barber BE; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; University of the Sunshine Coast Clinical Trials, Morayfield, QLD, Australia; Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
  • Webster R; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Potter AJ; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Llewellyn S; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
  • Sahai N; University of the Sunshine Coast Clinical Trials, Morayfield, QLD, Australia.
  • Leelasena I; University of the Sunshine Coast Clinical Trials, Morayfield, QLD, Australia.
  • Mathison S; University of the Sunshine Coast Clinical Trials, Morayfield, QLD, Australia.
  • Kuritz K; IntiQuan GmbH, Basel, Switzerland.
  • Flynn J; Medicines for Malaria Venture, Geneva, Switzerland.
  • Chalon S; Medicines for Malaria Venture, Geneva, Switzerland.
  • Marrast AC; Medicines for Malaria Venture, Geneva, Switzerland.
  • Gobeau N; Medicines for Malaria Venture, Geneva, Switzerland.
  • Moehrle JJ; Medicines for Malaria Venture, Geneva, Switzerland. Electronic address: moehrlej@mmv.org.
Int J Antimicrob Agents ; 64(1): 107196, 2024 Jul.
Article en En | MEDLINE | ID: mdl-38734217
ABSTRACT
With the spread of artemisinin resistance throughout Southeast Asia and now in Africa, the antimalarial drug pyronaridine is likely to become an increasingly important component of new antimalarial drug regimens. However, the antimalarial activity of pyronaridine in humans has not been completely characterised. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in malaria naïve adults. Volunteers were inoculated with Plasmodium falciparum-infected erythrocytes on day 0 and administered different single oral doses of pyronaridine on day 8. Parasitaemia and concentrations of pyronaridine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47 ± 2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modelling. Ten participants were inoculated and administered 360 mg (n = 4), 540 mg (n = 4) or 720 mg (n = 1) pyronaridine. One participant was withdrawn without receiving pyronaridine. The time to maximum pyronaridine concentration was 1-2 h, the elimination half-life was 8-9 d, and the parasite clearance half-life was approximately 5 h. Parasite regrowth occurred with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters including the minimum inhibitory concentration (5.5 ng/mL) and minimum parasiticidal concentration leading to 90% of maximum effect (MPC90 8 ng/mL) were derived from the PK/PD model. Adverse events considered related to pyronaridine were predominantly mild to moderate gastrointestinal symptoms. There were no serious adverse events. Data obtained in this study will support the use of pyronaridine in new antimalarial combination therapies by informing partner drug selection and dosing considerations.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Malaria Falciparum / Parasitemia / Voluntarios Sanos / Naftiridinas / Antimaláricos Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Int J Antimicrob Agents Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Países Bajos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Malaria Falciparum / Parasitemia / Voluntarios Sanos / Naftiridinas / Antimaláricos Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Int J Antimicrob Agents Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Países Bajos