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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >A Population Pharmacokinetic Model of (R)- and (S-) Oxybutynin and Its Active Metabolites After Oral and Intravesical Administration to Healthy Volunteers
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A Population Pharmacokinetic Model of (R)- and (S-) Oxybutynin and Its Active Metabolites After Oral and Intravesical Administration to Healthy Volunteers

机译：（r） - （r） - 和（s-）oxybutynin及其活性代谢物的人口药代动力学模型及其在口腔和膀胱内施用后的健康志愿者

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Oxybutynin is a racemic anticholinergic drug used for the symptomatic treatment of detrusor overactivity. The formation of active metabolites related to tolerability problems depends on the route of administration. The objective of this evaluation was to develop a pharmacokinetic model for oral/intravesical administration as the basis for simulations with different dosages. Data from a published changeover clinical study with 18 healthy adults receiving a single oral dose of 5 mg immediate-release oxybutynin and single and multiple intravesical doses of 10 mg oxybutynin solution was evaluated. Enantioselective plasma concentrations of oxybutynin and N-desethyloxybutynin (NDO) were used to establish a population pharmacokinetic model using nonlinear mixed-effects modeling with NONMEM 7.4.1. For both enantiomers, the data were described well by a 2-compartment model for oxybutynin with an additional compartment for NDO. Oxybutynin absorption was modeled by transit compartments for oral and first-order absorption for intravesical application. Bioavailability of the more active (R)-enantiomer was 7% for oral and 10%-22% for intravesical administration. In simulations, intravesical doses of 5 to 15 mg (R)-oxybutynin administered 2 to 3 times daily decreased peak-trough fluctuations of NDO to 8% compared with 24% after oral administration. The NDO/oxybutynin ratio was reduced from 17 after oral administration to unity. Chronic intravesical versus oral administration of (R)-oxybutynin generates distinctly lower and less variable concentrations of (R)-NDO. Pharmacokinetic simulations suggest that exposure for 12.5 mg (R)-oxybutynin administered twice daily might not compromise efficacy and tolerability compared with exposure for standard thrice-daily administrations. This assumption needs to be assessed in clinical studies.
机译：奥昔布宁是一种外消旋抗胆碱能药物，用于逼尿肌过度活动的症状治疗。与耐受性问题相关的活性代谢物的形成取决于给药途径。本次评估的目的是建立口服/膀胱内给药的药代动力学模型，作为不同剂量模拟的基础。评估了18名健康成年人单次口服5 mg速释奥昔布宁和单次及多次膀胱内注射10 mg奥昔布宁溶液的已发表转换临床研究数据。使用NONMEM 7.4.1的非线性混合效应模型，使用奥昔布宁和N-去乙基氧代布宁（NDO）的对映选择性血浆浓度建立群体药代动力学模型。对于这两种对映体，数据均由氧丁宁的二室模型和NDO的附加室进行了很好的描述。奥昔布宁的吸收由转运室模拟，用于口服和膀胱内应用的一级吸收。更具活性的（R）-对映体口服的生物利用度为7%，膀胱内给药的生物利用度为10%-22%。在模拟实验中，每天给药2至3次5至15 mg（R）-奥昔布宁的膀胱内剂量将NDO的峰谷波动降低至8%，而口服给药后为24%。口服给药后，NDO/Oxybutonin比值从17降至unity。慢性膀胱内注射与口服（R）-奥昔布宁相比，产生的（R）-NDO浓度明显较低且变化较小。药代动力学模拟表明，与标准每日三次给药相比，每天两次给药12.5 mg（R）-奥昔布宁的暴露可能不会影响疗效和耐受性。这一假设需要在临床研究中进行评估。

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