RESUMO
The effects of loading doses and probenecid coadministration on oseltamivir pharmacokinetics at four increasing dose levels in groups of eight healthy adult Thai volunteers (125 individual series) were evaluated. Doses of up to 675 mg were well-tolerated. The pharmacokinetics were dose linear. Oseltamivir phosphate (OS) was rapidly and completely absorbed and converted (median conversion level, 93%) to the active carboxylate metabolite. Median elimination half-lives (and 95% confidence intervals [CI]) were 1.0 h (0.9 to 1.1 h) for OS and 5.1 h (4.7 to 5.7 h) for oseltamivir carboxylate (OC). One subject repeatedly showed markedly reduced OS-to-OC conversion, indicating constitutionally impaired carboxylesterase activity. The coadministration of probenecid resulted in a mean contraction in the apparent volume of distribution of OC of 40% (95% CI, 37 to 44%) and a reduction in the renal elimination of OC of 61% (95% CI, 58 to 62%), thereby increasing the median area under the concentration-time curve (AUC) for OC by 154% (range, 71 to 278%). The AUC increase for OC in saliva was approximately three times less than the AUC increase for OC in plasma. A loading dose 1.25 times the maintenance dose should be given for severe influenza pneumonia. Probenecid coadministration may allow considerable dose saving for oseltamivir, but more information on OC penetration into respiratory secretions is needed to devise appropriate dose regimens.
Assuntos
Antivirais/farmacocinética , Oseltamivir/farmacocinética , Administração Oral , Adulto , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Área Sob a Curva , Povo Asiático/genética , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Meia-Vida , Humanos , Virus da Influenza A Subtipo H5N1/metabolismo , Influenza Humana/tratamento farmacológico , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Náusea/induzido quimicamente , Oseltamivir/administração & dosagem , Oseltamivir/efeitos adversos , Oseltamivir/sangue , Probenecid/administração & dosagem , Probenecid/farmacocinética , Saliva , Tailândia , Urinálise , Vômito/induzido quimicamenteRESUMO
Antimalarial drug resistance emerges de novo predominantly in areas of low malaria transmission. Because of the logarithmic distribution of parasite numbers in human malaria infections, inadequately treated high biomass infections are a major source of de novo antimalarial resistance, whereas use of antimalarial prophylaxis provides a low resistance selection risk. Slowly eliminated antimalarials encourage resistance largely by providing a selective filter for resistant parasites acquired from others, and not by selecting resistance de novo. The de novo emergence of resistance can be prevented by use of antimalarial combinations. Artemisinin derivative combinations are particularly effective. Ensuring adequate treatment of the relatively few heavily infected patients would slow the emergence of resistance.