Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas 77030, USA.
J Neurosurg Spine. 2012 Sep;17(1 Suppl):129-40. doi: 10.3171/2012.5.AOSPINE12112.
The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18-70 years old with acute spinal cord injury (SCI).
Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A-C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (C(max)), trough concentration (C(min)), systemic exposure (AUC(0-12)), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F).
The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (C(max), C(min), AUC(0-12), CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that C(max), C(min), and AUC(0-12) (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng × hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng × hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed.
This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.
本文旨在描述在一项关于利鲁唑作为成人急性脊髓损伤（SCI）神经保护剂的 1 期临床试验中，口服利鲁唑的个体和群体药代动力学特征。
35 名符合条件的急性 SCI 患者（美国脊髓损伤协会损伤分级 A-C 级，神经损伤水平 C-4 至 T-12）参与了由北美治疗脊髓损伤临床试验网络赞助的 1 期临床试验，接受 50mg 利鲁唑，每日 2 次，共 28 剂。首剂在损伤后平均 8.7±2.2 小时给予。治疗第 3 天和第 14 天，在给药前 1 小时内采集谷底血样，给药后 2 小时采集峰血样。采用高效液相色谱法测定利鲁唑浓度。采用基本结构和协变量模型对个体和群体药代动力学进行分析。研究的药代动力学参数包括峰浓度（C(max)）、谷浓度（C(min)）、系统暴露（AUC(0-12)）、清除率（CL/F）和分布容积（V_F）归一化生物利用度（F）。
由于清除率较高和分布容积较大，SCI 患者的 C(max)和 AUC(0-12)在相同剂量基础上低于 ALS 患者。利鲁唑的药代动力学（C(max)、C(min)、AUC(0-12)、CL 和 V）在 14 天的治疗期间，在 SCI 的急性和亚急性期发生变化。在所有临床地点的患者中，均观察到 C(max)、C(min)和 AUC(0-12)（分别为 128.9ng/ml、45.6ng/ml 和 982.0ng×hr/ml）在第 3 天明显高于第 14 天（分别为 76.5ng/ml、19.1ng/ml 和 521.0ng×hr/ml）。这些变化是由于第 3 天的 CL（49.5 比 106.2L/小时）和 V（557.1 比 1297.9/L）较低所致。在治疗过程中，没有发现由于伴随药物使用导致的液体失衡或细胞色素 P 1A2 诱导，以解释 V 和 CL 的这种增加。讨论了这些变化的可能机制。
这是 SCI 患者利鲁唑临床药代动力学的首次报告。由于 SCI 患者的清除率较高和分布容积较大，因此在相同剂量基础上，SCI 患者的 C(max)和 AUC(0-12)低于 ALS 患者。在 SCI 后第 3 天至第 14 天期间，利鲁唑的清除率和分布增加，而第 14 天的利鲁唑血浆浓度较低，这一发现强调了在解释临床试验中用于 SCI 的治疗药物的安全性和疗效时，监测 SCI 后药物代谢变化的重要性。临床试验注册号：NCT00876889。
