The alpha(α)2 -agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two-compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: -160) and methadone (OFV: -132) submodels. Second, a detomidine concentration-dependent reduction of distributional Cls of each drug further improved detomidine (OFV: -60) and methadone (OFV: -52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output).

中文翻译：

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用α2-肾上腺素能受体激动剂对消除和分布清除进行非线性建模的可能解决方案：镇静马匹中静脉注射的托咪啶和美沙酮组合的实例。

α（α）2-激动剂脱托咪定用于与阿片类药物（如美沙酮）进行马镇静作用。我们从两项随机，交叉研究中检索到了数据，其中分别单独或以静脉注射地托米定和美沙酮静脉注射（研究1）（Gozalo-Marcilla等人，2017;兽医麻醉和镇痛，2017,44,1116）或作为2小时恒定速率输注（研究2）（Gozalo-Marcilla等，2019，马兽医杂志，51，530）。用经过验证的串联质谱分析法测量血浆药物浓度。我们使用了非线性混合效应模型，并从两项研究中获取了药代动力学（PK）数据，以同时拟合两种药物并探索其非线性动力学。确定了对经典的乳腺两室模型的两个重大改进。第一，包括地托米定血浆浓度对两种药物的消除清除率（Cls）的影响，都改善了地托米定（目标功能值[OFV]：-160）和美沙酮（OFV：-132）子模型的适应性。其次，每种药物的托托咪定浓度依赖性的分布Cls减少进一步改善了托托咪定（OFV：-60）和美沙酮（OFV：-52）子模型拟合。利用两项研究的PK数据（a）有助于探索关于消除和分布Cls的非线性的假设，以及（b）允许在模型中纳入与模型的药理学相符的血管舒美定血浆浓度的动态影响（血管收缩和减少）心输出量）。-160）和美沙酮（OFV：-132）子模型。其次，每种药物的托托咪定浓度依赖性的分布Cls减少进一步改善了托托咪定（OFV：-60）和美沙酮（OFV：-52）子模型拟合。利用两项研究的PK数据（a）有助于探索关于消除和分布Cls的非线性的假设，以及（b）允许在模型中纳入与模型的药理学相符的血管舒美定血浆浓度的动态影响（血管收缩和减少）心输出量）。-160）和美沙酮（OFV：-132）子模型。其次，每种药物的托托咪定浓度依赖性的分布Cls减少进一步改善了托托咪定（OFV：-60）和美沙酮（OFV：-52）子模型拟合。利用两项研究的PK数据（a）有助于探索关于消除和分布Cls的非线性的假设，以及（b）允许在模型中纳入与模型的药理学相符的血管舒美定血浆浓度的动态影响（血管收缩和减少）心输出量）。