Open Label Pharmacokinetic-Pharmacogenetic Study on Polymorphisms in the Organic Cation Transporter OCT1

NCT02054299 | Completed Phase 1

• 2 other identifiers: PG-OCT2012-003546-33
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine the effect of the organic cation transporter OCT1 polymorphisms on the pharmacokinetics of several drugs in order to explain efficacy and adverse effects.

Conditions

Drug Metabolism; Membrane Transport

Outcome Measures

Primary Outcomes (1)

• Area under the plasma concentration-time curve (AUC) of the investigational drugs

  up to 60 hours

Secondary Outcomes (5)

• Total clearance, Cmax, Tmax, Mean AbsorptionTime, Alpha and Beta half-lives, Mean Residence Time (MRT) and Volume of distribution of the investigated drugs and their metabolites

  up to 60 hours

• Dry mouth, fatigue, nausea, headache, vertigo, tinnitus, chills, anxiety and difficulties to read on Visual Analog Scales.

  up to 60 hours

• Sedation on Stanford sedation scale

  up to 60 hours

• Pupil diameter, latency, diameter at maximal constriction, amplitude and time for 33% recovery of initial pupil diameter measured by pupillometrie

  up to 60 hours

• Genetic variants in OCT1, CYP2C19, CYP2D6 and MAO A

  Baseline

Study Arms (1)

Drug application

EXPERIMENTAL

6 treatment periods. On each period one of the following interventions

Drug: Drug application Amitriptyline; Drug: Drug application Desvenlafaxine; Drug: Drug application Sumatriptan; Drug: Drug application Proguanil; Drug: Drug application Fenoterol; Drug: Drug application Thiamine

Interventions

Drug application Amitriptyline DRUG

Amitriptyline: 25 mg, single oral application

Drug application

Drug application Desvenlafaxine DRUG

Desvenlafaxine: 50 mg, single oral application

Drug application

Drug application Sumatriptan DRUG

Sumatriptan: 50 mg, single oral application

Drug application

Drug application Proguanil DRUG

Proguanil: 200mg, single oral application

Drug application

Drug application Fenoterol DRUG

Fenoterol: 180 mcg, single intravenous application

Drug application

Drug application Thiamine DRUG

Thiamine: 200mg, single oral application

Drug application

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Written informed consent obtained prior to study entry including informed consent for molecular genetic analysis concerning candidate genes relevant for pharmacokinetics and pharmacodynamics of the study medication.
• Both genders (male and female), as far as feasible, in each of the 3 OCT1 genotype groups, an equal proportion of males and females will be included.
• Healthy adults aged ≥18 to \< 50 years
• Body weight not less than 48 kg and body mass index (BMI) not less than 17 kg/m² and not greater than 32 kg/m².
• Willingness to meet the study instructions and to co-operate with the study personal
• No clinically relevant pathological findings in any of the investigations at the screening visit. Minor deviations of laboratory values from the normal range may be accepted, if judged by the investigator to have no clinical relevance
• Systolic blood pressure ≤ 140 mmHg and ≥ 100 mmHg, diastolic blood pressure ≤ 90 mmHg and ≥ 60 mmHg and heart rate ≤ 90 bpm and ≥ 50 bpm at screening visit
• Female subjects will only be included if they express their willingness not to become pregnant during the entire study period by practicing abstinence or reliable methods of contraception as specified in the respective protocol section.

You may not qualify if:

• Unwillingness or inability to give informed consent
• Involvement in the planning and conduct of the study (applies to staff directly employed at the study site / department)
• Participation in a clinical study or use of any other investigational or non-registered drug or vaccine during the study period or within 30 days preceding the first dose of study drugs.
• Blood, plasma or thrombocyte donation during the last 15 days prior to application of the test drugs.
• Any planned surgical treatment during the last 14 days prior and 14 days after the application of the test drugs.
• Known pregnancy or lactation period
• Any relevant pathological findings in any of the investigations at the screening visit including significant abnormalities as result of the medical-screening-laboratory-analysis, especially of the liver and kidney related parameters unless judged as medically irrelevant.
• QTcF \> 450 ms in screening ECG
• Systolic blood pressure \> 140 mmHg and \< 100 mmHg, diastolic blood pressure \> 90 mmHg and \< 60 mmHg and heart rate \> 90 bpm and \< 50 bpm pre-dose at treatment period 4 (Amitriptyline)
• Any disease affecting liver or kidney or impairment of the liver or kidney-function
• Any cardiovascular disease
• Moderate to severe hypertension requiring medication therapy
• Bronchogenic asthma requiring constant drug treatment (stages 2 to 4 asthma)
• Diabetes mellitus, hyperthyroidism, hypothyroidism
• Glaucoma

Sponsors & Collaborators

• University Medical Center Goettingen: lead

Study Sites (1)

Department of Clinical Pharmacology, University Medical Center Goettingen

Göttingen, 37075, Germany

Location

Related Publications (1)

• Tzvetkov MV, Matthaei J, Pojar S, Faltraco F, Vogler S, Prukop T, Seitz T, Brockmoller J. Increased Systemic Exposure and Stronger Cardiovascular and Metabolic Adverse Reactions to Fenoterol in Individuals with Heritable OCT1 Deficiency. Clin Pharmacol Ther. 2018 May;103(5):868-878. doi: 10.1002/cpt.812. Epub 2017 Dec 8.

  PMID: 28791698 DERIVED

Study Officials

• Juergen Brockmoeller, Prof.

  University Medical Center Goettingen

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Sub-investigator, Principal investigator is Prof. Juergen Brockmoeller

Study Record Dates

• First Submitted: January 30, 2014
• First Posted: February 4, 2014
• Study Start: April 1, 2013
• Primary Completion: February 1, 2016
• Study Completion: February 1, 2016
• Last Updated: May 12, 2016

Record last verified: 2016-05

Locations

DE (1)