From the Menninger Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine, Houston, TX.
Almatica Pharma, Department of Clinical Research and Development, Morristown, NJ.
J Clin Psychopharmacol. 2023;43(4):350-360. doi: 10.1097/JCP.0000000000001715. Epub 2023 Jun 19.
PURPOSE/BACKGROUND: Once-daily extended-release (ER) lorazepam was developed to reduce fluctuations in plasma levels compared with lorazepam immediate-release (IR) for short-term anxiety relief. Here we report a series of phase 1 randomized, open-label, multiperiod crossover studies characterizing ER lorazepam pharmacokinetics and safety in healthy adults.
METHODS/PROCEDURES: These phase 1 studies assessed the pharmacokinetics of ER lorazepam administered: (study 1) 3 mg once daily versus IR lorazepam 1 mg 3 times a day (TID; every 8 hours), (study 2) with or without food, and (study 3) intact versus sprinkled onto food. Study 3 further evaluated the proportionality of 1 × 4- versus 4 × 1-mg doses. Safety was also monitored.
FINDINGS/RESULTS: There were 43, 27, and 29 subjects who completed studies 1, 2, and 3, respectively. The 90% confidence intervals for Cmax,SS , Cmin , and AUC TAU,SS of once-daily ER lorazepam compared with IR given TID were within 80% to 125% limits establishing steady-state bioequivalence. Maximum mean lorazepam concentrations were achieved at 11 hours compared with 1 hour after dosing for ER versus IR lorazepam, respectively. Pharmacokinetic parameters ( Cmax , AUC last or AUC 0- t , AUC inf or AUC 0-inf ) of ER lorazepam were bioequivalent whether taken with or without food, administered intact or sprinkled onto food, or administered as intact 1 × 4- versus 4 × 1-mg capsules. No serious safety concerns were found.
IMPLICATIONS/CONCLUSIONS: Once-daily ER lorazepam provided a pharmacokinetic profile bioequivalent to IR lorazepam given TID and was well tolerated in healthy adults across all phase 1 studies. These data suggest that ER lorazepam could be an alternative for patients currently treated with IR lorazepam.
目的/背景：与劳拉西泮即时释放（IR）相比，每日一次的延长释放（ER）劳拉西泮可减少血浆水平波动，从而短期缓解焦虑。在此，我们报告了一系列 I 期随机、开放标签、多周期交叉研究，以描述健康成年人中 ER 劳拉西泮的药代动力学和安全性。
方法/程序：这些 I 期研究评估了 ER 劳拉西泮的药代动力学：（研究 1）每日一次 3 毫克与 IR 劳拉西泮 1 毫克每日 3 次（TID；每 8 小时一次），（研究 2）与或不与食物一起服用，以及（研究 3）完整与撒在食物上。研究 3 进一步评估了 1×4-与 4×1-mg 剂量的比例。还监测了安全性。
结果/发现：分别有 43、27 和 29 名受试者完成了研究 1、2 和 3。每日一次 ER 劳拉西泮与 TID 相比，IR 的 Cmax，SS ， Cmin ，和 AUC TAU，SS 的 90%置信区间在 80%至 125%范围内，证明达到稳态生物等效性。与 ER 劳拉西泮相比，IR 劳拉西泮的最大平均劳拉西泮浓度分别在给药后 11 小时和 1 小时达到。ER 劳拉西泮的药代动力学参数（ Cmax ， AUC last 或 AUC 0-t ， AUC inf 或 AUC 0-inf ）无论是否与食物一起服用，是否完整服用或撒在食物上服用，或作为完整的 1×4-与 4×1-mg 胶囊服用，均具有生物等效性。未发现严重的安全性问题。
意义/结论：每日一次 ER 劳拉西泮提供了与 TID 给予的 IR 劳拉西泮生物等效的药代动力学特征，在所有 I 期研究中，在健康成年人中均具有良好的耐受性。这些数据表明，ER 劳拉西泮可能是目前接受 IR 劳拉西泮治疗的患者的替代选择。
