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Assessing the relative potency of (S)- and (R)-warfarin with a new PK-PD model, in relation to VKORC1 genotypes.
Ferrari, Myriam; Pengo, Vittorio; Barolo, Massimiliano; Bezzo, Fabrizio; Padrini, Roberto.
Afiliación
  • Ferrari M; Computer-Aided Process Engineering Laboratory (CAPE-lab), Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131, Padua, Italy.
  • Pengo V; Department of Cardiological, Thoracic and Vascular Sciences, University of Padova Medical School, Via Giustiniani 2, 35128, Padua, Italy.
  • Barolo M; Computer-Aided Process Engineering Laboratory (CAPE-lab), Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131, Padua, Italy.
  • Bezzo F; Computer-Aided Process Engineering Laboratory (CAPE-lab), Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131, Padua, Italy.
  • Padrini R; Department of Medicine (DIMED), University of Padova Medical School, Via Giustiniani 2, 35128, Padua, Italy. roberto.padrini@unipd.it.
Eur J Clin Pharmacol ; 73(6): 699-707, 2017 Jun.
Article en En | MEDLINE | ID: mdl-28382498
PURPOSE: The purpose of this study is to develop a new pharmacokinetic-pharmacodynamic (PK-PD) model to characterise the contribution of (S)- and (R)-warfarin to the anticoagulant effect on patients in treatment with rac-warfarin. METHODS: Fifty-seven patients starting warfarin (W) therapy were studied, from the first dose and during chronic treatment at INR stabilization. Plasma concentrations of (S)- and (R)-W and INRs were measured 12, 36 and 60 h after the first dose and at steady state 12-14 h after dosing. Patients were also genotyped for the G>A VKORC1 polymorphism. The PK-PD model assumed a linear relationship between W enantiomer concentration and INR and included a scaling factor k to account for a different potency of (R)-W. Two parallel compartment chains with different transit times (MTT1 and MTT2) were used to model the delay in the W effect. PD parameters were estimated with the maximum likelihood approach. RESULTS: The model satisfactorily described the mean time-course of INR, both after the initial dose and during long-term treatment. (R)-W contributed to the rac-W anticoagulant effect with a potency of about 27% that of (S)-W. This effect was independent of VKORC1 genotype. As expected, the slope of the PK/PD linear correlation increased stepwise from GG to GA and from GA to AA VKORC1 genotype (0.71, 0.90 and 1.49, respectively). CONCLUSIONS: Our PK-PD linear model can quantify the partial pharmacodynamic activity of (R)-W in patients contemporaneously exposed to therapeutic (S)-W plasma levels. This concept may be useful in improving the performance of future algorithms aiming at identifying the most appropriate W maintenance dose.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Warfarina / Vitamina K Epóxido Reductasas / Modelos Biológicos / Anticoagulantes Tipo de estudio: Prognostic_studies Límite: Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Eur J Clin Pharmacol Año: 2017 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Warfarina / Vitamina K Epóxido Reductasas / Modelos Biológicos / Anticoagulantes Tipo de estudio: Prognostic_studies Límite: Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Eur J Clin Pharmacol Año: 2017 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Alemania