RESUMEN
AIM: To assess the translation of pharmacokinetic-pharmacodynamic (PK-PD) relationships for heart rate effects of PF-00821385 in dog and man. METHODS: Cardiovascular telemetric parameters and concentration data were available for animals receiving active doses (0.5-120 mg kg(-1), n= 4) or vehicle. PF-00821385 was administered to 24 volunteers and pharmacokinetic and vital signs data were collected. PK-PD models were fitted using nonlinear mixed effects. RESULTS: Compartmental models with linear absorption and clearance were used to describe pharmacokinetic disposition in animal and man. Diurnal variation in heart and pulse rate was best described with a single cosine function in both dog and man. Canine and human heart rate change were described by a linear model with free drug slope 1.76 bpm microM(-1)[95% confidence interval (CI) 1.17, 2.35] in the dog and 0.76 bpm microM(-1) (95% CI 0.54, 1.14) in man. CONCLUSIONS: The preclinical translational of concentration-response has been described and the potential for further interspecies extrapolation and optimization of clinical trial design is addressed.
Asunto(s)
Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/farmacocinética , Frecuencia Cardíaca/efectos de los fármacos , Piperazinas/farmacología , Piridinas/farmacología , Administración Oral , Adulto , Animales , Fármacos Anti-VIH/administración & dosificación , Estudios de Cohortes , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Infecciones por VIH/tratamiento farmacológico , Humanos , Modelos Lineales , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Adulto JovenRESUMEN
Recombinant alpha interferon (IFN-alpha) is used in the treatment of hepatitis C virus (HCV)-infected patients but is not optimal in terms of efficacy or tolerability. Toll-like 7 receptor (TLR-7) agonists stimulate the innate immune system to produce, among other cytokines, IFN-alpha and are being evaluated as alternative drugs to treat HCV infection. This paper describes the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling to understanding the behavior of a TLR-7 agonist [9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (BHMA)] in mice, using IFN-alpha as a biomarker. This is the first report of such a PK-PD model, and the conclusions may be of utility in the clinical development of TLR-7 agonists for HCV infection.
