Gabapentin Kinetic Disposition and Renal Excretion: Role of Transporters for Organic Cations and the Effect of Glycemic Control in Patients With Neuropathic Pain.
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 29
- 主要终点
- Pharmacokinetic parameter (AUC)
研究概览
简要总结
This study aimed to investigate the influence of the glycemic control of type 2 diabetes (DM2) and of cetirizine (OCTs inhibitor) on gabapentin kinetics disposition and pharmacodynamics (PK-PD) in patients with neuropathic pain. Thus, non-diabetic patients (Control Group, n=10), patients with controlled diabetes (n=9) and patients with uncontrolled diabetes (n=10), all with neuropathic pain of intensity ≥ 4 in pain visual analog scale (0-10) were investigated.
详细描述
Gabapentin (GBP), anticonvulsant used to neuropathic pain treatment, is mainly eliminated unchanged in urine. Renal active tubular secretion has been suggested to contribute on GBP excretion by renal excretion. Studies performed on rats with experimental diabetes suggest that hyperglycemia reduces the activity of organic cation transporters (Oct). Thus, the aim of the study was to investigate the role of OCTs on kinetic disposition and pharmacodynamics of GBP in patients with neuropathic pain and to verify the regulation of these transporters' activity by glycemic control in diabetes. A cross-over clinical study was performed in patients with neuropathic pain (n=10, Control) to evaluate the influence of CTZ on GBP kinetic disposition. To evaluate the effect of glycemic control, patients with controlled DM2 (DC, n=9) and uncontrolled DM2 (DNC, n=10) were investigated. All participants investigated had neuropathic pain of intensity ≥ 4 evaluated by analogue visual scale (EVA) and were treated with oral single-dose of 300 mg of GBP (Phase 1) or cetirizine (20 mg/day) for 5 days and single-dose of GBP on the last day (Phase 2). Only participants of Control group participated of Phase 2. Serial blood and urine samples were collected up to 36 hours after GBP administration. The intensity of pain was evaluated at the same time of blood sampling, using the visual analog scale. GBP concentration in plasma and urine was validated by JPLC-UV. All participants were genotyped for polymorphisms SLC22A2 808G>T and SLC22A4 1507C>T. The pharmacokinetic parameters were estimated by non-compartmental analysis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 59 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult patients, both gender
- •Patients with neuropathic pain with score ≥ 4 in visual analog scale
- •Patients with controlled type 2 diabetes (glycated hemoglobin ≤ 8.0%) and diabetic neuropathy with score ≥ 4 in visual analog scale
- •Patients with uncontrolled type 2 diabetes (glycated hemoglobin ≥ 8.0%) and diabetic neuropathy with score ≥ 4 in visual analog scale
- •Patients that suspend the use of analgesics for 10 times half-life before starting the protocol
排除标准
- •Patients with acute or chronicle severe renal failure (creatinine clearance ≤ 30 mL/min)
- •Patients with gastrointestinal diseases
- •Patients with history of alcohol and drug abuse
- •Patients with acute myocardial insufficiency
- •Patients with another kind of chronicle pain as severe as neuropathic pain
- •Patients in chronicle use of drugs that interact with gabapentin (antacids and cimetidine)
研究组 & 干预措施
Control Group
Adult patients (18 - 59 years old) with neuropathic pain of score ≥ 4 that do not use gabapentin were recruited. All patients received oral single dose of gabapentin (300 mg) as capsules after 12 hour-fasting (phase I). To investigate GBP pharmacokinetics, blood samples were collected in heparinized tubes up to 36 hours after GBP administration. The urine of the patients was collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling through the visual analog scale (0-10). In phase II, after 15 days (wash-out) from phase I, cetirizine hydrochloride (10 mg) was administered orally, twice a day, as pills, for five days. On the last day of cetirizine treatment, an oral single dose of gabapentin (300 mg), as capsule, was administered. Serial blood and urine samples were collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling.
干预措施: Serial Blood Samples (Procedure)
Control Group
Adult patients (18 - 59 years old) with neuropathic pain of score ≥ 4 that do not use gabapentin were recruited. All patients received oral single dose of gabapentin (300 mg) as capsules after 12 hour-fasting (phase I). To investigate GBP pharmacokinetics, blood samples were collected in heparinized tubes up to 36 hours after GBP administration. The urine of the patients was collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling through the visual analog scale (0-10). In phase II, after 15 days (wash-out) from phase I, cetirizine hydrochloride (10 mg) was administered orally, twice a day, as pills, for five days. On the last day of cetirizine treatment, an oral single dose of gabapentin (300 mg), as capsule, was administered. Serial blood and urine samples were collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling.
干预措施: Serial Urine Samples (Procedure)
Control Group
Adult patients (18 - 59 years old) with neuropathic pain of score ≥ 4 that do not use gabapentin were recruited. All patients received oral single dose of gabapentin (300 mg) as capsules after 12 hour-fasting (phase I). To investigate GBP pharmacokinetics, blood samples were collected in heparinized tubes up to 36 hours after GBP administration. The urine of the patients was collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling through the visual analog scale (0-10). In phase II, after 15 days (wash-out) from phase I, cetirizine hydrochloride (10 mg) was administered orally, twice a day, as pills, for five days. On the last day of cetirizine treatment, an oral single dose of gabapentin (300 mg), as capsule, was administered. Serial blood and urine samples were collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling.
干预措施: Gabapentin 300 mg (Drug)
Uncontrolled Diabetes Group
Adult patients (18 - 59 years old) with uncontrolled type 2 diabetes (glycated hemoglobin ≥ 8.0%) and diabetic neuropathy of score ≥ 4 that do not use gabapentin were recruited. All patients received oral single dose of gabapentin (300 mg) as capsules after 12 hour-fasting. To investigate GBP pharmacokinetics, blood samples were collected in heparinized tubes up to 36 hours after GBP administration. The urine of the patients was collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling through the visual analog scale (0-10).
干预措施: Gabapentin 300 mg (Drug)
Control Group
Adult patients (18 - 59 years old) with neuropathic pain of score ≥ 4 that do not use gabapentin were recruited. All patients received oral single dose of gabapentin (300 mg) as capsules after 12 hour-fasting (phase I). To investigate GBP pharmacokinetics, blood samples were collected in heparinized tubes up to 36 hours after GBP administration. The urine of the patients was collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling through the visual analog scale (0-10). In phase II, after 15 days (wash-out) from phase I, cetirizine hydrochloride (10 mg) was administered orally, twice a day, as pills, for five days. On the last day of cetirizine treatment, an oral single dose of gabapentin (300 mg), as capsule, was administered. Serial blood and urine samples were collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling.
干预措施: Cetirizine Hydrochloride 10 mg (Drug)
Controlled Diabetes Group
Adult patients (18 - 59 years old) with controlled type 2 diabetes (glycated hemoglobin ≤ 8.0%) and diabetic neuropathy of score ≥ 4 that do not use gabapentin were recruited. All patients received oral single dose of gabapentin (300 mg) as capsules after 12 hour-fasting. To investigate GBP pharmacokinetics, blood samples were collected in heparinized tubes up to 36 hours after GBP administration. The urine of the patients was collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling through the visual analog scale (0-10).
干预措施: Serial Blood Samples (Procedure)
Controlled Diabetes Group
Adult patients (18 - 59 years old) with controlled type 2 diabetes (glycated hemoglobin ≤ 8.0%) and diabetic neuropathy of score ≥ 4 that do not use gabapentin were recruited. All patients received oral single dose of gabapentin (300 mg) as capsules after 12 hour-fasting. To investigate GBP pharmacokinetics, blood samples were collected in heparinized tubes up to 36 hours after GBP administration. The urine of the patients was collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling through the visual analog scale (0-10).
干预措施: Serial Urine Samples (Procedure)
Controlled Diabetes Group
Adult patients (18 - 59 years old) with controlled type 2 diabetes (glycated hemoglobin ≤ 8.0%) and diabetic neuropathy of score ≥ 4 that do not use gabapentin were recruited. All patients received oral single dose of gabapentin (300 mg) as capsules after 12 hour-fasting. To investigate GBP pharmacokinetics, blood samples were collected in heparinized tubes up to 36 hours after GBP administration. The urine of the patients was collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling through the visual analog scale (0-10).
干预措施: Gabapentin 300 mg (Drug)
Uncontrolled Diabetes Group
Adult patients (18 - 59 years old) with uncontrolled type 2 diabetes (glycated hemoglobin ≥ 8.0%) and diabetic neuropathy of score ≥ 4 that do not use gabapentin were recruited. All patients received oral single dose of gabapentin (300 mg) as capsules after 12 hour-fasting. To investigate GBP pharmacokinetics, blood samples were collected in heparinized tubes up to 36 hours after GBP administration. The urine of the patients was collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling through the visual analog scale (0-10).
干预措施: Serial Blood Samples (Procedure)
Uncontrolled Diabetes Group
Adult patients (18 - 59 years old) with uncontrolled type 2 diabetes (glycated hemoglobin ≥ 8.0%) and diabetic neuropathy of score ≥ 4 that do not use gabapentin were recruited. All patients received oral single dose of gabapentin (300 mg) as capsules after 12 hour-fasting. To investigate GBP pharmacokinetics, blood samples were collected in heparinized tubes up to 36 hours after GBP administration. The urine of the patients was collected up to 36 hours after GBP administration. The intensity of pain was evaluated in each time of blood sampling through the visual analog scale (0-10).
干预措施: Serial Urine Samples (Procedure)
结局指标
主要结局
Pharmacokinetic parameter (AUC)
时间窗: Up to 36 hours after gabapentin (300 mg) administration
Area under the plasma concentration versus time (AUC)
次要结局
- Pharmacokinetic parameter (Total clearance)(Up to 36 hours after gabapentin (300 mg) administration)
- Pharmacokinetic parameter (Elimination half-life)(Up to 36 hours after gabapentin (300 mg) administration)
- Pharmacokinetic parameter (Renal clearance)(Up to 36 hours after gabapentin (300 mg) administration)
- Pharmacokinetic parameter (Vd)(Up to 36 hours after gabapentin (300 mg) administration)
研究者
Natalia Valadares de Moraes
Assistant Professor
Universidade Estadual Paulista Júlio de Mesquita Filho