Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA.
Drugs R D. 2012 Sep 1;12(3):127-39. doi: 10.2165/11634360-000000000-00000.
A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials.
Org 26576 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive allosteric modulator that acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. In preparation for phase II efficacy trials in major depressive disorder (MDD), two separate phase I trials were conducted to evaluate safety, tolerability, and pharmacokinetics in HVs and in the target patient population.
Both trials were randomized and placebo controlled, and included multiple rising-dose cohorts (HV range 100-400 mg bid; MDD range 100-600 mg bid). HVs (n = 36) and patients with MDD (n = 54) were dosed under similarly controlled conditions in an inpatient facility, HVs for up to 14 days and MDD patients for up to 28 days. Safety, tolerability, and pharmacokinetics were assessed frequently.
Despite comparable pharmacokinetic profiles, the maximum tolerated dose (MTD) in depressed patients was 450 mg bid, twice the MTD established in HVs. No clinically relevant safety issues associated with Org 26576 were noted.
This article presents safety, tolerability, and pharmacokinetic data from two different populations examined under similar dosing conditions. The important implications of such bridging work in phase II dose selection are discussed, as are study design and data interpretation challenges.
在早期中枢神经系统（CNS）药物开发中，剂量选择面临的一个关键挑战是，患者的耐受性特征通常与健康志愿者（HV）不同，然而 HV 是确定 II 期试验中要研究的剂量的主要人群。如果没有来自目标患者人群的明确耐受性数据，首次疗效试验可能包括过高或过低的剂量，从而给研究参与者和整个开发项目带来不必要的风险。桥接试验通过在全面的概念验证试验之前仔细研究目标人群的安全性和耐受性来应对这一挑战。
Org 26576 是一种α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）受体正变构调节剂，通过调节离子型 AMPA 型谷氨酸受体来增强谷氨酸能神经传递。为了在重度抑郁症（MDD）的 II 期疗效试验中做准备，进行了两项单独的 I 期试验，以评估 HV 和目标患者人群中的安全性、耐受性和药代动力学。
这两项试验均为随机、安慰剂对照试验，包括多个递增剂量队列（HV 范围 100-400mg bid；MDD 范围 100-600mg bid）。HV（n=36）和 MDD 患者（n=54）在住院设施中接受类似控制条件下的给药，HV 持续 14 天，MDD 患者持续 28 天。频繁评估安全性、耐受性和药代动力学。
尽管药代动力学特征相似，但 MDD 患者的最大耐受剂量（MTD）为 450mg bid，是 HV 中确定的 MTD 的两倍。未发现与 Org 26576 相关的临床相关安全性问题。
本文介绍了在类似给药条件下检查的两个不同人群的安全性、耐受性和药代动力学数据。讨论了此类桥接工作在 II 期剂量选择中的重要意义，以及研究设计和数据解释方面的挑战。
