Population pharmacokinetics of oral baclofen at steady‐state in alcoholic‐dependent adult patients |
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| Authors: | Lucie Chevillard Naomi Sabo Michel Tod Laurence Labat Céline Chasport Céline Chevaleyre Florence Thibaut Jérôme Barré Julien Azuar Franck Questel Florence Vorspan Vanessa Bloch Frank Bellivier Bernard Granger Camille Barrault Xavier Declèves |
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| Affiliation: | 1. Inserm, UMR‐S 1144, Université Paris Descartes ‐ Paris Diderot, Variabilité de Réponse Aux Psychotropes, Paris, France;2. Biologie du Médicament et Toxicologie, H?pital Cochin, Assistance Publique‐H?pitaux de Paris, Paris, France;3. EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Ma?eutique Lyon‐Sud, Université Lyon 1, Oullins, France;4. Pharmacie, H?pital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France;5. Service de Psychiatrie et Médecine Addictologique, H?pital Lariboisière, Assistance Publique‐H?pitaux de Paris, Paris, France;6. Centre Hospitalier Intercommunal de Créteil, Service Centre de Ressources Biologiques, Créteil, France;7. Service de Psychiatrie, H?pital Tarnier, Assistance Publique‐H?pitaux de Paris, Paris, France;8. Centre Hospitalier Intercommunal de Créteil, Service d'addictologie et hépato‐gastro‐entérologie, Créteil, France |
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| Abstract: | Baclofen has been proposed for few years to help treating alcohol dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol‐dependent patients treated with steady‐state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One hundred and forty‐nine baclofen concentrations were sampled 30 min to 15 h after the last dose, and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m2, respectively, was composed of two‐thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one‐compartment model with first‐order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F) and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h?1, respectively. Inter‐individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter‐individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg/day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter‐individual variability of baclofen exposure that could not be explained by demographic and biological data. |
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| Keywords: | alcohol dependence baclofen inter‐individual variability population pharmacokinetics |
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