Department of Clinical Pharmacology, Konkuk University Medical Center, Seoul, Republic of Korea.
Center for Clinical Pharmacology and Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea.
Clin Ther. 2018 Dec;40(12):2112-2124. doi: 10.1016/j.clinthera.2018.10.017. Epub 2018 Nov 27.
Pregabalin is a widely used drug for the management of neuropathic pain. This study compared the pharmacokinetics of the GLA5PR GLARS-NF1 tablet, a 150-mg controlled-release formulation of pregabalin taken once daily, with those of a 75-mg immediate-release (IR) capsule formulation of pregabalin taken twice daily with a 12-h interval between doses.
Two separate studies, single dose and multiple dose, were conducted with a sequence-randomized, open-label crossover design. In the single-dose study, 30 participants each received 3 treatments: two 75-mg IR capsules taken 12 h apart, each after a high-fat meal (SRF treatment); a single 150-mg GLA5PR GLARS-NF1 tablet taken after a high-fat meal (STF treatment); and a single 150-mg GLAR5PR GLARS-NF1 tablet taken in an overnight-fasted state (ST treatment). In the multiple-dose study, 24 participants each received 2 treatments, both of which occurred over 3 days: one 75-mg IR capsule in the evening after a standardized meal and a second 75-mg IR capsule the following morning after a standardized meal, for 3 days (MRF treatment); and a single 150-mg GLA5PR GLARS-NF1 tablet in the evening after a standardized meal, for 3 days (MTF treatment). Blood samples for pharmacokinetic assessments were collected over the 36 h following drug administration in each treatment period.
In the single-dose study, the geometric mean ratios (GMRs) of the Cmax and the AUC values of the GLA5PR GLARS-NF1 tablet to those of the IR capsules (STF/SRF) were 1.047 (90% CI, 0.971-1.129) and 0.757 (90% CI, 0.694-0.826), respectively. In the multiple-dose study, the GMRs (MTF/MRF) of the Cmax and the AUC values over the dosing interval were 1.277 (90% CI, 1.210-1.348) and 0.974 (90% CI, 0.933-1.017), respectively. The systemic pregabalin exposure from the GLA5PR GLARS-NF1 tablet was higher in the fed state than in the fasted state; GMRs (STF/ST): C, 1.458 (90% CI, 1.353-1.573) and AUC, 1.655 (90% CI, 1.518-1.804).
The overall pregabalin exposure after multiple administrations of GLA5PR GLARS-NF1 tablets was comparable to that after multiple administrations of the IR capsules. A single administration of the GLA5PR GLARS-NF1 tablet produced lower overall pregabalin exposure than that of the same dose administered in 2 IR capsules taken every 12 h. A high-fat diet significantly increased the bioavailability of the GLA5PR GLARS-NF1 tablet. ClinicalTrials.gov identifiers: NCT01638273 and NCT02326987.
普瑞巴林是一种广泛用于治疗神经病理性疼痛的药物。本研究比较了 GLA5PR GLARS-NF1 片剂（每日一次给予的 150 毫克控释制剂）与每日两次给予的 75 毫克普通释放（IR）胶囊制剂（两次剂量间隔 12 小时）的药代动力学。
两项单独的研究，即单次剂量和多次剂量研究，采用序列随机、开放标签交叉设计进行。在单次剂量研究中，30 名参与者每人接受 3 种治疗：两种 75 毫克 IR 胶囊，相隔 12 小时，每次均在高脂肪餐后给予（SRF 治疗）；单次给予 150 毫克 GLA5PR GLARS-NF1 片剂，在高脂肪餐后给予（STF 治疗）；以及单次给予 150 毫克 GLAR5PR GLARS-NF1 片剂，在禁食状态下给予（ST 治疗）。在多次剂量研究中，24 名参与者每人接受两种治疗，共 3 天：一种是在标准化餐后给予的 75 毫克 IR 胶囊，另一种是在标准化餐后第二天早上给予的另一种 75 毫克 IR 胶囊，连续 3 天（MRF 治疗）；以及在标准化餐后给予单次 150 毫克 GLA5PR GLARS-NF1 片剂，连续 3 天（MTF 治疗）。在每个治疗期给药后 36 小时内采集用于药代动力学评估的血样。
在单次剂量研究中，GLA5PR GLARS-NF1 片剂与 IR 胶囊（STF/SRF）的 Cmax 和 AUC 值的几何均数比值（GMR）分别为 1.047（90%CI，0.971-1.129）和 0.757（90%CI，0.694-0.826）。在多次剂量研究中，Cmax 和 AUC 值的 24 小时内 GMR（MTF/MRF）分别为 1.277（90%CI，1.210-1.348）和 0.974（90%CI，0.933-1.017）。与禁食状态相比，高脂肪饮食状态下 GLA5PR GLARS-NF1 片剂的全身性普瑞巴林暴露量更高；GMR（STF/ST）：C 值为 1.458（90%CI，1.353-1.573），AUC 值为 1.655（90%CI，1.518-1.804）。
多次给予 GLA5PR GLARS-NF1 片剂后的普瑞巴林总体暴露量与多次给予 IR 胶囊后的暴露量相当。单次给予 GLA5PR GLARS-NF1 片剂的普瑞巴林总体暴露量低于每日两次给予相同剂量的 12 小时间隔给予的 2 粒 IR 胶囊。高脂肪饮食显著增加了 GLA5PR GLARS-NF1 片剂的生物利用度。临床试验标识符：NCT01638273 和 NCT02326987。
