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Transporters for Organic Cations and Glycemic Control in Patients With Neuropathic Pain.

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ClinicalTrials.gov Identifier: NCT03047278
Recruitment Status : Completed
First Posted : February 8, 2017
Last Update Posted : July 3, 2019
Sponsor:
Collaborator:
University of Sao Paulo
Information provided by (Responsible Party):
Natalia Valadares de Moraes, Universidade Estadual Paulista Júlio de Mesquita Filho

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Neuropathic Pain Type 2 Diabetes Mellitus Diabetic Neuropathy, Painful Procedure: Serial Blood Samples Procedure: Serial Urine Samples Drug: Gabapentin 300 mg Drug: Cetirizine Hydrochloride 10 mg Phase 4

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 29 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Gabapentin Kinetic Disposition and Renal Excretion: Role of Transporters for Organic Cations and the Effect of Glycemic Control in Patients With Neuropathic Pain.
Actual Study Start Date : November 1, 2015
Actual Primary Completion Date : May 1, 2018
Actual Study Completion Date : July 1, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 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.
Procedure: Serial Blood Samples
Serial blood samples were collected at times 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 36 hours after gabapentin administration, for all patients.

Procedure: Serial Urine Samples
Serial urine samples were collected at intervals 0-8 hours, 8-16 hours, 16-24 hours and 24-36 hours after gabapentin administration, for all patients.

Drug: Gabapentin 300 mg
All patients were treated with oral single dose of gabapentin 300 mg.

Drug: Cetirizine Hydrochloride 10 mg
Patients of control group were treated with cetirizine hydrochloride, 10 mg, twice as day, orally, for five days.

Experimental: 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).
Procedure: Serial Blood Samples
Serial blood samples were collected at times 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 36 hours after gabapentin administration, for all patients.

Procedure: Serial Urine Samples
Serial urine samples were collected at intervals 0-8 hours, 8-16 hours, 16-24 hours and 24-36 hours after gabapentin administration, for all patients.

Drug: Gabapentin 300 mg
All patients were treated with oral single dose of gabapentin 300 mg.

Experimental: 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).
Procedure: Serial Blood Samples
Serial blood samples were collected at times 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 36 hours after gabapentin administration, for all patients.

Procedure: Serial Urine Samples
Serial urine samples were collected at intervals 0-8 hours, 8-16 hours, 16-24 hours and 24-36 hours after gabapentin administration, for all patients.

Drug: Gabapentin 300 mg
All patients were treated with oral single dose of gabapentin 300 mg.




Primary Outcome Measures :
  1. Pharmacokinetic parameter (AUC) [ Time Frame: Up to 36 hours after gabapentin (300 mg) administration ]
    Area under the plasma concentration versus time (AUC)


Secondary Outcome Measures :
  1. Pharmacokinetic parameter (Total clearance) [ Time Frame: Up to 36 hours after gabapentin (300 mg) administration ]
    Total clearance

  2. Pharmacokinetic parameter (Renal clearance) [ Time Frame: Up to 36 hours after gabapentin (300 mg) administration ]
    Renal clearance

  3. Pharmacokinetic parameter (Vd) [ Time Frame: Up to 36 hours after gabapentin (300 mg) administration ]
    Volume of distribution (Vd)

  4. Pharmacokinetic parameter (Elimination half-life) [ Time Frame: Up to 36 hours after gabapentin (300 mg) administration ]
    Elimination half-life



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Ages Eligible for Study:   18 Years to 59 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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)

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Responsible Party: Natalia Valadares de Moraes, Assistant Professor, Universidade Estadual Paulista Júlio de Mesquita Filho
ClinicalTrials.gov Identifier: NCT03047278     History of Changes
Other Study ID Numbers: GBPDIABETCET
First Posted: February 8, 2017    Key Record Dates
Last Update Posted: July 3, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Neuralgia
Diabetic Neuropathies
Diabetes Mellitus
Endocrine System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Pain
Neurologic Manifestations
Signs and Symptoms
Diabetes Complications
Cetirizine
Gabapentin
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anticonvulsants
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antimanic Agents
Anti-Allergic Agents
Histamine H1 Antagonists, Non-Sedating
Histamine H1 Antagonists