RESUMO
Dose selection during antiparasitic drug development in animal models and humans traditionally has relied on correlations between plasma concentrations obtained at or below maximally tolerated doses that are efficacious. The objective of this study was to improve the understanding of the relationship between dose and plasma/tissue exposure of the model antiparasitic agent, pafuramidine, using a semiphysiologically based pharmacokinetic (semi-PBPK) modeling approach. Preclinical and clinical data generated during the development of pafuramidine, a prodrug of the active metabolite, furamidine, were used. A whole-body semi-PBPK model for rats was developed based on a whole-liver PBPK model using rat isolated perfused liver data. A whole-body semi-PBPK model for humans was developed on the basis of the whole-body rat model. Scaling factors were calculated using metabolic and transport clearance data generated from rat and human sandwich-cultured hepatocytes. Both whole-body models described pafuramidine and furamidine disposition in plasma and predicted furamidine tissue (liver and kidney) exposure and excretion profiles (biliary and renal). The whole-body models predicted that the intestine contributes significantly (30-40%) to presystemic furamidine formation in both rats and humans. The predicted terminal elimination half-life of furamidine in plasma was 3- to 4-fold longer than that of pafuramidine in rats (170 versus 47 h) and humans (64 versus 19 h). The dose-plasma/tissue exposure relationship for the prodrug/active metabolite pair was determined using the whole-body models. The human model proposed a dose regimen of pafuramidine (40 mg once daily) based on a predefined efficacy-safety index. A similar approach could be used to guide dose-ranging studies in humans for next-in-class compounds.
Assuntos
Antiparasitários/farmacologia , Antiparasitários/farmacocinética , Modelos Biológicos , Pró-Fármacos/farmacologia , Pró-Fármacos/farmacocinética , Animais , Relação Dose-Resposta a Droga , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologiaRESUMO
BACKGROUND: Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT. METHODS: The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent. FINDINGS/CONCLUSION: Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.
Assuntos
Antiprotozoários/administração & dosagem , Antiprotozoários/efeitos adversos , Benzamidinas/administração & dosagem , Benzamidinas/efeitos adversos , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Angola , República Democrática do Congo/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pentamidina/administração & dosagem , Pentamidina/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently require parenteral administration. In previous studies, orally administered pafuramidine was well tolerated in healthy patients (for up to 21 days) and stage 1 HAT patients (for up to 10 days), and demonstrated efficacy comparable to pentamidine. METHODS: This was a Phase 3, multi-center, randomized, open-label, parallel-group, active control study where 273 male and female patients with first stage Trypanosoma brucei gambiense HAT were treated at six sites: one trypanosomiasis reference center in Angola, one hospital in South Sudan, and four hospitals in the Democratic Republic of the Congo between August 2005 and September 2009 to support the registration of pafuramidine for treatment of first stage HAT in collaboration with the United States Food and Drug Administration. Patients were treated with either 100 mg of pafuramidine orally twice a day for 10 days or 4 mg/kg pentamidine intramuscularly once daily for 7 days to assess the efficacy and safety of pafuramidine versus pentamidine. Pregnant and lactating women as well as adolescents were included. The primary efficacy endpoint was the combined rate of clinical and parasitological cure at 12 months. The primary safety outcome was the frequency and severity of adverse events. The study was registered on the International Clinical Trials Registry Platform at www.clinicaltrials.gov with the number ISRCTN85534673. FINDINGS/CONCLUSIONS: The overall cure rate at 12 months was 89% in the pafuramidine group and 95% in the pentamidine group; pafuramidine was non-inferior to pentamidine as the upper bound of the 95% confidence interval did not exceed 15%. The safety profile of pafuramidine was superior to pentamidine; however, 3 patients in the pafuramidine group had glomerulonephritis or nephropathy approximately 8 weeks post-treatment. Two of these events were judged as possibly related to pafuramidine. Despite good tolerability observed in preceding studies, the development program for pafuramidine was discontinued due to delayed post-treatment toxicity.
Assuntos
Benzamidinas/administração & dosagem , Benzamidinas/efeitos adversos , Pentamidina/administração & dosagem , Pentamidina/efeitos adversos , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Angola , Criança , República Democrática do Congo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Injeções Intramusculares , Nefropatias/induzido quimicamente , Nefropatias/patologia , Masculino , Pessoa de Meia-Idade , Gravidez , Sudão , Resultado do Tratamento , Trypanosoma brucei gambiense , Adulto JovemRESUMO
Aromatic diamidines are potent trypanocides. Pentamidine, a diamidine, has been used for more than 60 years to treat human African trypanosomiasis (HAT); however, the drug must be administered parenterally and is active against first-stage HAT only, prior to the parasites causing neurological deterioration through invasion of the CNS. A major research effort to design novel diamidines has led to the development of orally active prodrugs and, remarkably, a new generation of compounds that can penetrate the CNS. In this review, progress in the development of diamidines for the treatment of HAT is discussed.