Bridget E. Barber, Azrin N. Abd-Rahman, Rebecca Webster, A. Potter, S. Llewellyn, L. Marquart, Nischal Sahai, Indika Leelasena, G. Birrell, M. Edstein, G. Shanks, D. Wesche, Joerg J. Moehrle, J. McCarthy
{"title":"他非诺喹对感染恶性疟原虫的健康志愿者血期抗疟活性的研究","authors":"Bridget E. Barber, Azrin N. Abd-Rahman, Rebecca Webster, A. Potter, S. Llewellyn, L. Marquart, Nischal Sahai, Indika Leelasena, G. Birrell, M. Edstein, G. Shanks, D. Wesche, Joerg J. Moehrle, J. McCarthy","doi":"10.1101/2022.11.21.22282610","DOIUrl":null,"url":null,"abstract":"Background The long acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. Methods Healthy G6PD-normal adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia, and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48+/-2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Results Twelve participants were inoculated and administered 200 mg (n=3), 300 mg (n=4), 400 mg (n=2), or 600 mg (n=3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 h and 4.2 h respectively) was faster than with 200 mg or 300 mg (11.8 h and 9.6 h respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants), but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 10^6 and 10^9, respectively, in a 60 kg adult. Conclusions Although a single dose or tafenoquine exhibits potent P. falciparum blood stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":"2 1","pages":"1919 - 1927"},"PeriodicalIF":0.0000,"publicationDate":"2022-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"3","resultStr":"{\"title\":\"Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum\",\"authors\":\"Bridget E. Barber, Azrin N. Abd-Rahman, Rebecca Webster, A. Potter, S. Llewellyn, L. Marquart, Nischal Sahai, Indika Leelasena, G. Birrell, M. Edstein, G. Shanks, D. Wesche, Joerg J. Moehrle, J. McCarthy\",\"doi\":\"10.1101/2022.11.21.22282610\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Background The long acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. Methods Healthy G6PD-normal adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia, and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48+/-2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Results Twelve participants were inoculated and administered 200 mg (n=3), 300 mg (n=4), 400 mg (n=2), or 600 mg (n=3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 h and 4.2 h respectively) was faster than with 200 mg or 300 mg (11.8 h and 9.6 h respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants), but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 10^6 and 10^9, respectively, in a 60 kg adult. Conclusions Although a single dose or tafenoquine exhibits potent P. falciparum blood stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency.\",\"PeriodicalId\":10421,\"journal\":{\"name\":\"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America\",\"volume\":\"2 1\",\"pages\":\"1919 - 1927\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-11-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"3\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2022.11.21.22282610\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2022.11.21.22282610","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum
Background The long acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. Methods Healthy G6PD-normal adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia, and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48+/-2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Results Twelve participants were inoculated and administered 200 mg (n=3), 300 mg (n=4), 400 mg (n=2), or 600 mg (n=3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 h and 4.2 h respectively) was faster than with 200 mg or 300 mg (11.8 h and 9.6 h respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants), but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 10^6 and 10^9, respectively, in a 60 kg adult. Conclusions Although a single dose or tafenoquine exhibits potent P. falciparum blood stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency.