Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/39932
Title: Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine
Authors: Daher, André
Aljayyoussi, Ghait
Pereira, Dhelio Batista
Lacerda, Marcus V. G.
Alexandre, Márcia A. A.
Nascimento, Cristiana T.
Alves, Júlio Castro
Fonseca, Laís Bastos da
Silva, Diego Medeiros Dias da
Pinto, Douglas Pereira
Rodrigues, Danielle Fonseca
Silvino, Ana Carolina Rios
Sousa, Taís Nóbrega de
Brito, Cristiana Ferreira Alves de
Kuile, Feiko O. ter
Lalloo, David G.
Affilliation: Fundação Oswaldo Cruz. Instituto de Tecnologia de Medicamentos (Farmanguinhos). Rio de Janeiro, RJ, Brasil/Fundação Oswaldo Cruz. Vice-Presidência de Pesquisa e Coleções Biológicas. Rio de Janeiro, RJ, Brasil/Liver-pool School of Tropical Medicine, Liverpool, UK.
Liver-pool School of Tropical Medicine, Liverpool, UK.
Tropical Medicine Research Center of Rondonia (CEPEM), Porto Velho, Rondonia, Brazil/Universidade Federal de Rondonia. Porto Velho, RO, Brazil
Fundação Oswaldo Cruz. Instituto Leônidas & Maria Deane. Manaus, AM, Brazil/Fundação de Medicina Tropical Medicine Dr. Heitor Vieira Dourado. Manaus, AM, Brazil.
Fundação de Medicina Tropical Medicine Dr. Heitor Vieira Dourado. Manaus, AM, Brazil.
Fundação de Medicina Tropical Medicine Dr. Heitor Vieira Dourado. Manaus, AM, Brazil.
Fundação Oswaldo Cruz. Instituto Nacional de Doenças Infecciosas. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Laboratório de Farmacocinética. Rio de Janeiro, RJ, Brazil.
Fundação Oswaldo Cruz. Laboratório de Farmacocinética. Rio de Janeiro, RJ, Brazil.
Fundação Oswaldo Cruz. Laboratório de Farmacocinética. Rio de Janeiro, RJ, Brazil.
Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou, Belo Horizonte, MG, Brazil
Liver-pool School of Tropical Medicine, Liverpool, UK.
Liver-pool School of Tropical Medicine, Liverpool, UK.
Abstract: Background: Activation of hypnozoites of vivax malaria causes multiple clinical relapses, which contribute to the Plasmodium vivax burden and continuing transmission. Artemisinin-based combination therapy (ACT) is effective against blood-stage P. vivax but requires co-administration with primaquine to achieve radical cure. The therapeutic efficacy of primaquine depends on the generation of a therapeutically active metabolite via cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 metabolism has been associated with primaquine treatment failure. This study investigated the association between impaired CYP2D6 genotypes, drug-exposure to the long-acting ACT component (schizonticidal drugs) and tolerance and efficacy. Methods: Adult patients with acute vivax malaria were enrolled in a recently completed trial and treated with artesunate–mefloquine, chloroquine or artemether–lumefantrine. All received concomitant primaquine (0.5 mg/kg/day for 7–9 days). The association between efficacy and safety and drug exposure was explored using area-under-the-curve (AUC) and half-life (t1/2) estimates obtained by non-compartmental analysis of the long half-life drugs. Parasite recurrences by day 63 were categorized as related relapses or re-infections/unrelated hypnozoite activation by genotyping three microsatellite loci and two polymorphic loci of merozoite surface antigen-1. The CYP2D6 genotype was identified with Taqman assays by real-time PCR to 9 polymorphisms (8 SNPs and one deletion). Impaired CYP2D6 activity was inferred using the Activity Score System. Results: Most recurrences in the ASMQ (67%), CQ (80%) and AL (85%) groups were considered related relapses. Eight of nine (88.9%) of the patients with impaired CYP2D6 activity relapsed with related parasite compared to 18/25 (72%) with normal activity (RR = 1.23, 0.88; 1.72, p = 0.40). There were no associations between the measured PK parameters and recurrence. Patients with longer chloroquine half-lives had more pruritus (RR = 1.09, 1.03; 1.14, p = 0.001). Higher CQ AUCs were associated with reduced falls in haemoglobin by day 14 (Coef − 0.02, − 0.005; − 0.03, p = 0.01). All regimens were well tolerated. Conclusion: Genotyping of P. vivax showed that activation of related (homologous) hypnozoites was the most frequent cause of recurrence. The high proportion of the impaired CYP2D6 activity among patients with recurrent infections suggests that slow primaquine metabolism might influence related relapse rates in Brazil among patients receiving primaquine for radical cure, although confirmatory studies are needed. There was no association between drug exposure of the long-acting ACT component (schizonticidal drugs) and risk of related relapse. ACT was well tolerated. These results provide further re-assuranceabout the safety and efficacy of ACT when combined with short course primaquine to treat uncomplicated malaria vivax in Brazil.
Keywords: Malaria
Plasmodium vivax
Anti-malarial treatment
Chloroquine
Mefloquine
Lumefantrine
Primaquine
Artemisinin-based combination therapy
ACT
Pharmacokinetics
Clinical trial
Issue Date: 2019
Publisher: BMC (part of Springer Nature)
Citation: DAHER, Andre et al. Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine. Malar J, v. 18, 325, 2019
DOI: 10.1186/s12936-019-2950-4
ISSN: 1475-2875
Copyright: restricted access
Appears in Collections:MG - IRR - Artigos de Periódicos

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