Influence of Diabetes on Tramadol Pharmacokinetics

NCT02246712 | Completed Phase 4

• 1 other identifier: DIABETRA
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This study aimed to investigate the influence of uncontrolled type 1 and type 2 diabetes mellitus (DM) on the kinetic disposition, metabolism and pharmacokinetics-pharmacodynamics of tramadol enantiomers in patients with neuropathic pain. Thus, nondiabetic patients (control group, n = 12), patients with type 1 DM (n = 9), and patients with type 2 DM (n = 9), all with neuropathic pain and phenotyped as extensive metabolizers of cytochrome P450 2D6 (CYP2D6) who were treated with a single oral dose of 100 mg racemic tramadol were investigated.

Conditions

Neuropathic Pain; Type 1 Diabetes Mellitus; Type 2 Diabetes Mellitus

Keywords

tramadol; pharmacokinetics; enantiomers; metabolism; diabetes

Outcome Measures

Primary Outcomes (1)

• Kinetic parameters (AUC, Cmax, Tmax, apparent total clearance, and apparent volume of distribution) of tramadol enantiomers were estimated.

  Up to 24h after a single oral dose of tramadol (100 mg)

Secondary Outcomes (3)

• Urinary concentration ratio (metoprolol/alfa-hydroxymetoprolol) as an in vivo measure of CYP2D6 activity

  Up to 8h after metoprolol administration

• Clearance of midazolam as a measure of CYP3A in vivo activity

  Up to 6h after midazolam administration

• Pain scores on the visual analog scale

  Up to 24h after a single oral dose of tramadol (100 mg)

Study Arms (3)

Control group

ACTIVE COMPARATOR

Patients received a single oral dose of 100 mg racemic tramadol. Serial blood samples were collected up to 24 h after administration of the drug for pharmacokinetic study and for the analysis of noradrenaline in plasma. Pain was rated on a visual analog pain scale at the same time as blood sampling. CYP2D6 phenotype was evaluated using metoprolol as probe drug. CYP3A phenotype was evaluated using midazolam. Patients were genotyped for the single nucleotide polymorphism (SNP) 516G\>T in CYP2B6 gene (CYP2B6 genotype).

Drug: Single oral dose of 100 mg racemic tramadol; Other: CYP2D6 phenotype; Other: CYP3A phenotype; Genetic: CYP2B6 genotype

T2DM group

EXPERIMENTAL

Patients received a single oral dose of 100 mg racemic tramadol. Serial blood samples were collected up to 24 h after administration of the drug for pharmacokinetic study and for the analysis of noradrenaline in plasma. Pain was rated on a visual analog pain scale at the same time as blood sampling. CYP2D6 phenotype was evaluated using metoprolol as probe drug. CYP3A phenotype was evaluated using midazolam. Patients were genotyped for SNP 516G\>T in CYP2B6 gene (CYP2B6 genotype). The diagnosis of type 2 DM was performed according to the American Diabetes Association (2010).

Drug: Single oral dose of 100 mg racemic tramadol; Other: CYP2D6 phenotype; Other: CYP3A phenotype; Genetic: CYP2B6 genotype

T1DM group

EXPERIMENTAL

Patients received a single oral dose of 100 mg racemic tramadol. Serial blood samples were collected up to 24 h after administration of the drug for pharmacokinetic study and for the analysis of noradrenaline in plasma. Pain was rated on a visual analog pain scale at the same time as blood sampling. CYP2D6 phenotype was evaluated using metoprolol as probe drug. CYP3A phenotype was evaluated using midazolam. Patients were genotyped for SNP 516G\>T in CYP2B6 gene (CYP2B6 genotype). The diagnosis of type 1 DM was performed according to the American Diabetes Association (2010).

Drug: Single oral dose of 100 mg racemic tramadol; Other: CYP2D6 phenotype; Other: CYP3A phenotype; Genetic: CYP2B6 genotype

Interventions

Single oral dose of 100 mg racemic tramadol DRUG

Serial blood samples were collected up to 24 h after drug administration; Pain was evaluated at the same time of blood sampling using visual analog scale

Also known as: Tramadol treament, Blood sampling, Tramadol pharmacokinetics

Control group; T1DM group; T2DM group

CYP2D6 phenotype OTHER

Patients were phenotyped using metoprolol (100 mg, single oral dose). Urine was collected up to 8 hours after metoprolol administration. Urinary concentrations of metoprolol and alfa-hydroxymetoprolol were determined by high performance liquid chromatography (HPLC), using fluorescence detector. CYP2D6 phenotyped was determined by alfa-hydroxymetoprolol/metoprolol urinary rato

Also known as: CYP2D6 phenotyping, CYP2D6 in vivo activity

Control group; T1DM group; T2DM group

CYP3A phenotype OTHER

A single oral dose of midazolam (15 mg) was administered to all patients. Serial blood samples were collected up to 6 hours after the administration of midazolam. The concentration of midazolam was determined in plasma in order to calculate midazolam clearance. The in vivo activity of CYP3A was evaluated by midazolam oral clearance.

Also known as: CYP3A phenotyping, CYP3A in vivo activity

Control group; T1DM group; T2DM group

CYP2B6 genotype GENETIC

The single nucleotide polymorphism 516G\>T in CYP2B6 gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Also known as: Genotype of SNP 516G>T in CYP2B6

Control group; T1DM group; T2DM group

Eligibility Criteria

• Age: 18 Years - 59 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Adult patients, both gender
• Patients with self-reported neuropathic pain (score \>4 in a 0-10 visual analog scale)
• Patients with normal renal function (creatinine clearance \>60 mL/min)

You may not qualify if:

• Patients with nociceptive somatic pain, visceral or autonomic associated during the study period;
• Patients with morbid obesity (BMI\> 40), congestive heart failure, severe hypertension
• Patients who have had acute myocardial infarction or accident stroke less than 6 months of the period of investigation.
• Patients with chronic obstructive pulmonary disease
• Patients who were in use of analgesics, CYP2D6 inhibitors or CYP3A4 inducers or inhibitors were excluded.
• Pregnant and lactating patients were excluded.

Sponsors & Collaborators

• Universidade Estadual Paulista Júlio de Mesquita Filho: lead
• University of Sao Paulo: collaborator

Study Sites (1)

Universidade Estadual Paulista Julio de Mesquita Filho

Araraquara, São Paulo, 14801902, Brazil

Location

Related Publications (2)

• de Moraes NV, Lauretti GR, Lanchote VL. Effects of type 1 and type 2 diabetes on the pharmacokinetics of tramadol enantiomers in patients with neuropathic pain phenotyped as cytochrome P450 2D6 extensive metabolizers. J Pharm Pharmacol. 2014 Sep;66(9):1222-30. doi: 10.1111/jphp.12255. Epub 2014 Apr 10.

  PMID: 24717054 RESULT

• de Moraes NV, Lauretti GR, Napolitano MN, Santos NR, Godoy AL, Lanchote VL. Enantioselective analysis of unbound tramadol, O-desmethyltramadol and N-desmethyltramadol in plasma by ultrafiltration and LC-MS/MS: application to clinical pharmacokinetics. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Jan 1;880(1):140-7. doi: 10.1016/j.jchromb.2011.11.033. Epub 2011 Nov 28.

  PMID: 22173007 RESULT

MeSH Terms

Conditions

Neuralgia; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes Mellitus

Interventions

Blood Specimen Collection; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP2B6

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 Enzyme System; Cytochromes; Enzymes and Coenzymes; Cytochrome P450 Family 2; Mixed Function Oxygenases; Oxygenases; Oxidoreductases; Enzymes; Hemeproteins; Proteins; Amino Acids, Peptides, and Proteins; Cytochrome P450 Family 3; Oxidoreductases, N-Demethylating; Oxidoreductases Acting on CH-NH Group Donors

Study Officials

• Natalia V de Moraes, PhD

  Universidade Estadual Paulista Julio de Mesquita Filho

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: September 16, 2014
• First Posted: September 23, 2014
• Study Start: June 1, 2008
• Primary Completion: May 1, 2010
• Study Completion: December 1, 2011
• Last Updated: September 23, 2014

Record last verified: 2014-09

Locations

BR (1)