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首页> 外文期刊>Clinical drug investigation >Steady-state pharmacokinetics of gabapentin after administration of a novel gastroretentive extended-release formulation in postmenopausal women with vasomotor symptoms
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Steady-state pharmacokinetics of gabapentin after administration of a novel gastroretentive extended-release formulation in postmenopausal women with vasomotor symptoms

机译：加巴喷丁在患有血管舒缩症状的绝经后妇女中应用新型胃滞留缓释制剂后的稳态药代动力学

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Background and Objective: Approximately 75% of postmenopausal women experience vasomotor symptoms (hot flashes). Currently, hormone replacement therapy is the only approved treatment for hot flashes. However, its use has been associated with an increased risk of invasive breast cancer, coronary heart disease, stroke and venous thromboembolic disease. Gabapentin has also been demonstrated to be efficacious in the treatment of vasomotor symptoms in postmenopausal women when administered three times a day. A gastroretentive extended-release formulation of gabapentin (gabapentin-ER) has recently been demonstrated to be efficacious in the treatment of postmenopausal hot flashes. The objective of this paper is to report the steadystate pharmacokinetics and safety of gabapentin with different dosing regimens of gabapentin-ER in postmenopausal women with hot flashes. Methods: This was a multicentre, randomized, double-blind, dose-escalating, placebo-controlled, parallel group study in 124 postmenopausal women experiencing ≥7 moderate to severe hot flashes per day. The study consisted of two 5-week treatment periods, with each one preceded by a 1-week titration to the assigned dose. Groups A, B and C received gabapentin-ER 600mg evening (pm), 600 mg morning (am)/600mg pm and 1200 mg pm in the first period, and then 600mg am/1200mg pm, 600mg am/1800 mg pm and 1200mg am/1800 mg pm in the second period, respectively. The tablets were taken after a non-specified meal. Pharmacokinetic sampling was conducted over a 24-hour period at the end of each study period. Plasma samples were analysed by a validated liquid chromatography tandem mass spectrometry method. Non-compartmental pharmacokinetic analysis was performed on the concentration-time data to determine area under the plasma concentration versus time curve from time zero to 24 hours (AUC 24). Maximum (C max), minimum (C min) and average (C avg) drug concentration and time to reach Cmax (t max) were determined by inspection of the data. Tolerability was evaluated by physical examination, clinical laboratory measurements and adverse events monitoring. Results: Gabapentin exposure at steady state, as measured by AUC24, increased with doses from 600mg/day to 3000mg/day, although there was a slight decrease in gabapentin's relative bioavailability with increasing dose compared with the 600mg dose. The relative bioavailability compared with the 600mg dose was 86-88% for the 1200mg/day doses, 75% for the 1800mg/day dose, 84% for the 2400mg/day dose, and 73% for the 3000mg/day dose. C max generally increased with increasing dose as did C min and C avg for the various treatments in amanner thatwas consistent with the dosing regimen. The values of tmax were not different between the various doses, with the median tmax values relative to the most recent dose ranging from 6 to 8 hours for all dose levels. Gabapentin-ER was generally well tolerated at all doses studied. The most common AEs were headache, dizziness and somnolence, withmost being mild in intensity. Seven patients withdrew from the study due to AEs. Conclusion: The pharmacokinetic profile of gabapentin-ER may allow for once-or twice-daily dosing while maintaining bioavailability and thus efficacy. Gabapentin-ER was well tolerated.
机译：背景与目的：约75％的绝经后妇女会出现血管舒缩症状（潮热）。目前，激素替代疗法是唯一批准的潮热疗法。然而，其使用与浸润性乳腺癌，冠心病，中风和静脉血栓栓塞性疾病的风险增加有关。加巴喷丁每天3次，对绝经后妇女的血管舒缩症状有效。最近已证明加巴喷丁的胃滞留缓释制剂（加巴喷丁-ER）在绝经后潮热的治疗中有效。本文的目的是报道加巴喷丁-ER的不同给药方案对绝经后潮热妇女的稳态药代动力学和安全性。方法：这是一项多中心，随机，双盲，剂量递增，安慰剂对照，平行组研究，研究对象是124位绝经后妇女，每天经历≥7次中度至重度潮热。该研究包括两个为期5周的治疗期，每个治疗期之前均需进行1周滴定至指定剂量。 A，B和C组在第一时期分别接受600 mg夜间（pm），600 mg上午（am）/ 600mg pm和1200 mg pm的加巴喷丁-ER，然后分别接受600mg am / 1200mg pm，600mg am / 1800 mg pm和1200mg第二阶段分别为am / 1800 mg pm。非指定餐后服用片剂。在每个研究阶段结束后的24小时内进行药代动力学采样。通过验证的液相色谱串联质谱法分析血浆样品。对浓度-时间数据进行了非房室药代动力学分析，以确定从零到24小时（AUC 24）的血浆浓度-时间曲线下的面积。通过检查数据确定最大（C max），最小（C min）和平均（C avg）药物浓度以及达到Cmax的时间（t max）。通过体格检查，临床实验室测量和不良事件监测评估耐受性。结果：通过AUC24测定，稳态状态下的加巴喷丁暴露随剂量从600mg /天增加至3000mg /天，尽管与600mg剂量相比，加巴喷丁的相对生物利用度随剂量的增加而略有降低。相对于600mg剂量的相对生物利用度，对于1200mg /天的剂量为86-88％，对于1800mg /天的剂量为75％，对于2400mg /天的剂量为84％，对于3000mg /天的剂量为73％。 C max通常随着剂量的增加而增加，对于与剂量方案一致的各种处理方式而言，C min和C avg也会增加。在所有剂量水平下，tmax值均无差异，相对于最近剂量而言，tmax的中值在所有剂量水平下为6至8小时。在所有研究剂量下，加巴喷丁-ER的耐受性均良好。最常见的AE是头痛，头晕和嗜睡，强度最大。七名患者因不良事件退出研究。结论：加巴喷丁ER的药代动力学特征可以允许每天一次或两次给药，同时保持生物利用度并因此保持疗效。加巴喷丁-ER耐受性良好。

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