RESUMO
The combination piperaquine and dihydroartemisinin is emerging as first line treatment of uncomplicated falciparum malaria in Southeast Asia. The aim of this study was to determine the influence of a standard Vietnamese meal on the single-dose pharmacokinetics of piperaquine when administered in combination with dihydroartemisinin, and to gain extended data on the terminal half-life of piperaquine in healthy Vietnamese volunteers. Subjects were randomly assigned to take a single oral dose of piperaquine phosphate (640 mg)+dihydroartemisinin (80 mg) together with a standardized Vietnamese meal (n=16) or to remain fasting for 4h following drug intake (n=16). Frequent blood sampling was conducted during 36 h, followed by weekly samples for 7 weeks. The pharmacokinetic parameters of piperaquine were determined by noncompartmental analysis. The median (80% central range) AUC(0-last) was 11.5 (6.9-17.3)h mg/L in fed and 13.9 (2.8-19.3)h mg/L in fasting subjects, indicating a considerable variability in exposure in both groups. The estimated overall oral clearance was 0.27 (0.12-1.49)L/(h kg), the volume of distribution during the terminal elimination phase was 230 (102-419)L/kg and estimated terminal half-life was 18 (5-93) days. This study did not demonstrate a significant impact of a standardized Vietnamese meal on the oral absorption of piperaquine.
Assuntos
Antimaláricos/farmacocinética , Interações Alimento-Droga , Carne , Óvulo , Quinolinas/farmacocinética , Verduras , Administração Oral , Adulto , Antimaláricos/administração & dosagem , Área Sob a Curva , Artemisininas/administração & dosagem , Disponibilidade Biológica , Quimioterapia Combinada , Jejum , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quinolinas/administração & dosagem , Vietnã , VoluntáriosRESUMO
OBJECTIVE: To investigate whether the antimalarial drug artemisinin affects CYP2A6 activity in healthy subjects and to compare the utility of coumarin and nicotine as in vivo probe compounds for CYP2A6. METHODS: Twelve healthy male Vietnamese subjects were given coumarin or nicotine in randomized sequence before and after 5 days of a repeated oral administration of artemisinin during two different treatment periods 1 month apart. Sequential blood samples were drawn at baseline 7 days prior to artemisinin treatment and on the first and fifth day of artemisinin treatment during both treatment periods. Plasma concentrations of 7-hydroxycoumarin glucuronide (7-OHCG), nicotine, cotinine and artemisinin were analysed by high-performance liquid chromatography and those of coumarin and 7-hydroxycoumarin (7-OHC) were determined by liquid chromatography-tandem mass spectrometry. Urine, collected in two time intervals on the days of coumarin intake, was treated with beta-glucuronidase and analysed for 7-OHC levels. RESULTS: Artemisinin AUC(0-infinity) values decreased significantly to 23% [95% confidence interval (CI) 18%-28%] on the fifth day of artemisinin administration as compared with the first. The sum of renally excreted 7-OHC and 7-OHCG increased by 1.55-fold (adjusted 95% CI 1.08-2.23) in the 3- to 8-h interval compared to baseline 7 days before. The 7-OHCG/7-OHC plasma AUC(0-infinity) ratio increased by 1.72-fold (adjusted 95% CI 1.16-2.54) following 5 days of artemisinin intake. There was no significant change in the cotinine/nicotine AUC(0-11 hr) ratio between study days. CONCLUSION: Artemisinin significantly increased the sum of renally excreted 7-OHC and 7-OHCG in one of the two collection intervals, suggesting an induction of CYP2A6. A significant increase in the 7-OHCG to 7-OHC AUC(0-infinity) ratio indicates artemisinin to be an inducer of glucuronidation.
Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Oxigenases de Função Mista/efeitos dos fármacos , Adulto , Antimaláricos/farmacocinética , Área Sob a Curva , Artemisininas/farmacocinética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Cumarínicos/administração & dosagem , Cumarínicos/farmacocinética , Estudos Cross-Over , Citocromo P-450 CYP2A6 , Humanos , Masculino , Oxigenases de Função Mista/metabolismo , Nicotina/administração & dosagem , Nicotina/farmacocinética , Espectrometria de Massas em Tandem , Umbeliferonas/sangue , VietnãRESUMO
OBJECTIVE: To investigate the pharmacokinetic properties of piperaquine after repeated oral administration of the antimalarial combination CV8 in healthy subjects. METHODS: Twelve healthy fasted Vietnamese males were administered four tablets CV8 (320 mg piperaquine phosphate, 32 mg dihydroartemisinin, 5 mg primaquine phosphate, 90 mg trimethoprim) on day 1, followed by two tablets every 24th hour, for a total of 3 days. Blood samples were frequently drawn on days 1 and 3 and sparsely drawn until day 29. Samples were analyzed for piperaquine using solid phase extraction followed by high-performance liquid chromatography. Population pharmacokinetic parameter estimates were obtained by nonlinear mixed effects modeling of the observed data using NONMEM. RESULTS: A two-compartment disposition model with an absorption lag time described the observed piperaquine concentrations. Absorption profiles were found to be irregular with double or multiple peaks. A dual pathway first-order absorption model improved the goodness of fit. Piperaquine pharmacokinetics were characterized by a large volume of distribution and a terminal half-life of several days. Estimates [95% confidence interval (CI)] of CL/F, V(ss)/F and t(1/2)(z) were found to be 56.4 (29-84) l/h, 6,000 (3,500-8,500) l and 11.7 (8.3-15.7) days, respectively. CONCLUSION: Piperaquine pharmacokinetics after repeated oral doses were characterized by multiple concentration peaks and multiphasic disposition, resulting in a long terminal half-life. Sustained exposure to the drug after treatment should be taken into account when designing future clinical studies, e.g. duration of follow-up, and may also drive resistance development in areas of high malaria transmission.