Woodward Andrew P, Whittem Ted
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Werribee, Australia.
Melbourne Veterinary School, The University of Melbourne, Werribee, Australia.
J Vet Pharmacol Ther. 2019 Nov;42(6):693-706. doi: 10.1111/jvp.12812. Epub 2019 Sep 25.
Understanding the pharmacokinetics of intra-mammary antibiotics is important for the prediction of drug residues in milk and for the design of optimal dosage regimens. Unfortunately, compartmental pharmacokinetic models are not valid for this unique system. A minimal physiologically based pharmacokinetic model is presented incorporating the physiology of milk secretion, drug administration at the quarter level, drug absorption and dispersion, drug retention during the inter-milking interval and episodic drug elimination at milking. The primary objective of the study was the development and exploration of a model for major factors controlling drug concentration in milk, rather than generation of rigorously predictive pharmaco-statistical models for any particular drug. This model was implemented in a two-stage approach, using published concentration data for penicillin, cefuroxime, cephapirin and desacetyl-cephapirin in milk of healthy cows. Model simulations evaluated sensitivity and developed predictions of drug residues. The model successfully predicted both drug concentrations and drug residues in milk. The postmilking residual milk volume did not adequately explain antibiotic pharmacokinetics, requiring additional considerations for drug retention. Local sensitivity analysis indicated that increasing the number of quarters treated, the dosage, or the duration of the inter-milking interval prolonged both the persistence of drug residues and the duration that antibiotic concentration exceeded typical minimum inhibitory concentrations. The model was flexible across different beta-lactam drugs as a general description of intra-mammary pharmacokinetics. This model is suitable for the design and analysis of dosage regimens, and could be applied for the prediction of withholding periods when these antibiotic preparations are used off-label. The final model indicates that explicit consideration of the milking regimen is fundamental to the design and interpretation of pharmacokinetic studies of antibiotics in bovine milk.
了解乳房内抗生素的药代动力学对于预测牛奶中的药物残留以及设计最佳给药方案非常重要。不幸的是，房室药代动力学模型不适用于这个独特的系统。本文提出了一个基于生理的最小药代动力学模型，该模型纳入了乳汁分泌生理学、乳腺区给药、药物吸收与分布、挤奶间隔期药物滞留以及挤奶时的间歇性药物消除。本研究的主要目的是开发和探索一个控制牛奶中药物浓度的主要因素模型，而不是为任何特定药物生成严格预测性的药物统计学模型。该模型采用两阶段方法实现，使用了健康奶牛乳汁中青霉素、头孢呋辛、头孢匹林和去乙酰头孢匹林的已发表浓度数据。模型模拟评估了敏感性并预测了药物残留。该模型成功地预测了牛奶中的药物浓度和药物残留。挤奶后残留奶量不足以解释抗生素药代动力学，需要对药物滞留进行额外考虑。局部敏感性分析表明，增加治疗的乳腺区数量、剂量或挤奶间隔期会延长药物残留的持续时间以及抗生素浓度超过典型最低抑菌浓度的持续时间。作为乳房内药代动力学的一般描述，该模型对不同的β-内酰胺类药物具有灵活性。该模型适用于给药方案的设计和分析，并且可用于预测这些抗生素制剂超适应症使用时的停药期。最终模型表明，明确考虑挤奶方案对于牛乳中抗生素药代动力学研究的设计和解释至关重要。
