Impact of Polymorphisms of OCT2 and OCTN1 on the Kinetic Disposition of Gabapentin in Patients Undergoing Chronic Use

Impact of Genetic Polymorphisms of OCT2 and OCTN1 on the Kinetic Disposition of Gabapentin in Patients Undergoing Chronic Use of the Drug

This study aims to evaluate the influence of genetic polymorphisms of OCTN1 and OCT2 and other possible covariates on the kinetic disposition of GAB in patients undergoing GAB chronic treatment. Thus, patients treated with GAB, for at least one week, are being investigated.

Study Overview

• Status: Completed
• Conditions: Epilepsy; Chronic Pain
• Intervention / Treatment: Procedure: Sparse blood sampling; Procedure: Urine sampling; Procedure: DNA extraction; Drug: Gabapentin

Detailed Description

Gabapentin (GAB), an anticonvulsant used for the treatment of epilepsy and chronic pain, has nonlinear kinetics, it is not metabolized and it is mainly eliminated by renal excretion. Studies suggest that the renal excretion of GAB is dependent on active secretion by organic cation transporter 2 (OCT2) and organic cation/ergothioneine transporter 1 (OCTN1). These transporters are expressed at the membrane of the renal proximal tubules and they are involved in the elimination of endogenous compounds and many drugs. The genetic polymorphism of drug transporters has been studied to explain the kinetic disposition variability of their substrates. The objective of this study is to investigate the influence of genetic polymorphisms of OCTN1 and OCT2 and other possible covariates (e.g., sex, age, creatinine clearance, body mass index) on the kinetic disposition of GAB in patients undergoing GAB chronic treatment. Patients treated with GAB, for at least one week, are being investigated. Blood and urine samples are being collected to GAB pharmacokinetic analysis, serum creatinine analysis and for genotyping. The plasma concentration of GAB will be assessed using liquid chromatography with UV detection (LC-UV).

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • São Paulo
    • Araraquara, São Paulo, Brazil, 14800903
      • Universidade Estadual Paulista Julio de Mesquita Filho

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with 18 years old or older, both gender.
• Patients undergoing chronic use of gabapentin (at least one week).

Exclusion Criteria:

• Pregnant and lactating patients.
• Patients who were in use of OCT2 and OCTN1 inhibitors.
• Patients who disagree to continue the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Homozygous for the wild type allele; Patients with 18 years old or older with epilepsy, neuropathic pain or any chronic pain undergoing chronic treatment with gabapentin are being recruited. Sparse blood sampling are being collected up to 4 h after administration of the drug for pharmacokinetic study. Urine sampling are being collected during the dosing interval, only in patients hospitalized at the Hospital Estadual de Américo Brasiliense (HEAB). Blood sample are being collected for DNA extraction. DNA are being extracted from the whole blood of all patients for genotyping of the SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms.	Procedure: Sparse blood sampling; Blood samples are being collected at times 0, 90 and 240 minutes after gabapentin administration.; Procedure: Urine sampling; Urine samples are being collected during the dosing interval, only in patients hospitalized at Hospital Estadual de Américo Brasiliense (HEAB).; Procedure: DNA extraction; Blood sample are being collected for DNA extraction. DNA are being extracted from the whole blood of all patients for genotyping of the SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms; Drug: Gabapentin; All patients undergoing chronic treatment with gabapentin are being recruited.; Other Names: GAB
Active Comparator: Homo- or heterozygous for rare alleles; Patients with 18 years old or older with epilepsy, neuropathic pain or any chronic pain undergoing chronic treatment with gabapentin are being recruited. Sparse blood sampling are being collected up to 4 h after administration of the drug for pharmacokinetic study. Urine sampling are being collected during the dosing interval, only in patients hospitalized at the Hospital Estadual de Américo Brasiliense (HEAB). Blood sample are being collected for DNA extraction. DNA are being extracted from the whole blood of all patients for genotyping of the SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms.	Procedure: Sparse blood sampling; Blood samples are being collected at times 0, 90 and 240 minutes after gabapentin administration.; Procedure: Urine sampling; Urine samples are being collected during the dosing interval, only in patients hospitalized at Hospital Estadual de Américo Brasiliense (HEAB).; Procedure: DNA extraction; Blood sample are being collected for DNA extraction. DNA are being extracted from the whole blood of all patients for genotyping of the SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms; Drug: Gabapentin; All patients undergoing chronic treatment with gabapentin are being recruited.; Other Names: GAB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gabapentin plasma concentration.	Blood samples will be collected at 0, 90 and 240 minutes after gabapentin administration. The gabapentin plasma concentration will be assessed using liquid chromatography with UV detection (LC-UV).	Up to 240 minutes after gabapentin administration.
OCT2 and OCTN1 genotyping	The single nucleotide polymorphisms of SLC22A2 gene (c.808G>T) and SLC22A4 (c.1507C>T) are being evaluated in all included patients.	Up to 5 minutes before gabapentin administration

Collaborators and Investigators

• Sponsor: São Paulo State University
• Collaborators: University of Sao Paulo
• Investigators: Principal Investigator: Fabíola D. Eckeli, Prof., University of Sao Paulo; Principal Investigator: Edgar Ianhez Júnior, Hospital Estadual de Américo Brasiliense; Study Chair: Natália V. de Moraes, Prof., Universidade Estadual Paulista Julio de Mesquita Filho

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (Actual): February 1, 2018
• Study Completion (Actual): February 1, 2018

Study Registration Dates

• First Submitted: November 18, 2016
• First Submitted That Met QC Criteria: November 25, 2016
• First Posted (Estimate): November 30, 2016

Study Record Updates

• Last Update Posted (Actual): April 18, 2018
• Last Update Submitted That Met QC Criteria: April 16, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Gabapentin; Pharmacogenetics; OCT2; OCTN1; Polymorphisms
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Chronic Pain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Anti-Anxiety Agents; Anticonvulsants; Antimanic Agents; Gabapentin
• Other Study ID Numbers: OCTGab

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No