A PHASE 1, OPEN-LABEL, CROSS-OVER, FIXED SEQUENCE STUDY TO EVALUATE THE EFFECT OF MULTIPLE DOSES OF DS-1971A ON THE SINGLE DOSE PHARMACOKINETICS OF PROBE SUBSTRATES FOR CYP2B6, CYP2C8, CYP2C9, CYP2C19 AND CYP3A4 ENZYMES IN HEALTHY MALE AND FEMALE SUBJECTS

NCT02473627 | Completed Phase 1

• 1 other identifier: DS1971-A-E105
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, cross-over, fixed-sequence study. All subjects will receive the same treatment in two study periods. The study is designed to test whether DS-1971a has any effect on the activity of various enzymes involved in the metabolism of medicines, using test medications. These will be given without and then with DS-1971a to see if DS-1971a has any effect on the blood levels of the test medicines.

Conditions

Healthy

Keywords

Pharmacokinetics

Outcome Measures

Primary Outcomes (5)

• Pharmacokinetic profile for bupropion

  Pharmacokinetic parameters (Cmax, tmax , AUC) for bupropion when administered without or with DS-1971a

  Days 2-6 of Period 1 and Day 9-13 of Period 2

• Pharmacokinetic profile for pioglitazone

  Pharmacokinetic parameters (Cmax, tmax , AUC) for pioglitazone when administered without or with DS-1971a

  Days 2-4 of Period 1 and Days 9-11 of Period 2

• Pharmacokinetic profile for tolbutamide

  Pharmacokinetic parameters (Cmax, tmax , AUC) for tolbutamide when administered without or with DS-1971a

  Days 2-4 of Period 1 and Days 9-11 of Period 2

• Pharmacokinetic profile for omeprazole

  Pharmacokinetic parameters (Cmax, tmax , AUC) for omeprazole when administered without or with DS-1971a

  Day 2 of Period 1 and Day 9 of Period 2

• Pharmacokinetic profile for midazolam

  Pharmacokinetic parameters (Cmax, tmax , AUC) for midazolam when administered without or with DS-1971a

  Day 1 of Period 1 and Day 8 of Period 2

Secondary Outcomes (3)

• Pharmacokinetic profile of DS-1971a

  Day 1, 3, 6, 8, 9, and 12

• Pharmacokinetic profile of metabolites of substrates

  Days 1-6 of Period 1 and Days 8-13 of Period 2

• number and severity of Adverse Events

  Day 0 - Week 9

Study Arms (2)

Period 1

EXPERIMENTAL

Period 1 Day 1: single oral dose of 2.5 mg midazolam hydrochloride Day 2: single oral cocktail dose of 20 mg omeprazole, 15 mg pioglitazone hydrochloride, 500 mg tolbutamide and 150 mg bupropion

Drug: midazolam hydrochloride; Drug: Omeprazole; Drug: Pioglitazone hydrochloride; Drug: Buproprion; Drug: Tolbutamide

Period 2

EXPERIMENTAL

Period 2 Days 1 through 12 repeated doses of 400 mg DS-1971a administered orally bid . On the days listed below, each probe substrate(s) will be coadministered with the morning dose of DS 1971a: Day 8: single oral dose of 2.5 mg midazolam hydrochloride Day 9: single oral cocktail dose of 20 mg omeprazole, 15 mg pioglitazone hydrochloride, 500 mg tolbutamide and 150 mg bupropion

Drug: DS-1971a; Drug: midazolam hydrochloride; Drug: Omeprazole; Drug: Pioglitazone hydrochloride; Drug: Buproprion; Drug: Tolbutamide

Interventions

DS-1971a DRUG

200mg tablet

Period 2

midazolam hydrochloride DRUG

2.5mg oromucosal liquid

Period 1; Period 2

Omeprazole DRUG

20mg gastro-resistant capsule

Period 1; Period 2

Pioglitazone hydrochloride DRUG

15mg tablet

Period 1; Period 2

Buproprion DRUG

150mg Prolonged release tablet

Period 1; Period 2

Tolbutamide DRUG

500mg tablet

Period 1; Period 2

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female aged 18 to 65 years, inclusive.
• Be in good general health as determined by medical history, physical examination and Screening investigations, and be taking no regular medication.
• A body mass index (BMI) in the range 18 to 30 kg/m2, inclusive, and weighing between 50 and 100 kg, inclusive. BMI is calculated as weight \[kg\]/(height \[m\])\*2.
• Female subjects must be of nonchildbearing potential as follows:
• Must be postmenopausal (the last menstrual period was at least 12 months before Screening, and a follicle stimulating hormone \[FSH\] test at Screening confirms postmenopausal status); or Must be surgically sterile having undergone hysterectomy, bilateral oophorectomy, bilateral salpingectomy and/or bilateral tubal ligation.
• Willing to comply with all study restrictions, including the use of contraception, concomitant medication and dietary and lifestyle restrictions.
• Possessing sufficient intelligence to understand the nature of the study and any hazards of participating in it, and the ability to communicate satisfactorily with the Investigator and to participate in, and comply with the requirements of, the entire study.
• Have given written consent to participate after reading the ICF, and after having the opportunity to discuss the study with the Investigator or his/her delegate.
• Have given written consent to have his/her data entered into The Overvolunteering Prevention System.

You may not qualify if:

• Clinically relevant abnormal history, physical findings, ECG findings or laboratory values that could interfere with the objectives of the study or the safety of the subject.
• Presence of history of acute or chronic illness, including (but not limited to) liver or kidney disease, hypertension, seizures, or any known impairment of endocrine, or other specific body-organ dysfunction.
• Presence or history of severe adverse reaction to any medicine.
• Presence or history of malignant disease.
• Acute or chronic infectious disease, including human immunodeficiency virus (HIV), hepatitis B virus or C virus (HCV) infection.
• Surgery (eg, stomach bypass) or medical condition that might affect absorption of medicines.
• Significant illness within 4 weeks before the dose of study medication.
• Participation in another clinical trial of a new chemical entity or a prescription medicine within the previous 3 months, or unwilling to abstain from participating in other clinical trials during the study and for 3 months after receipt of study medication.
• Participation in another clinical study with DS-1971a.
• Blood pressure (BP) and heart rate in semisupine position at the Screening examination outside the ranges 90 to 140 mmHg systolic, 40 to 90 mmHg diastolic; heart rate 40 to 100 beats/min. Subjects with Stage 1 hypertension (systolic 140 to 160 mmHg; diastolic 90 to 100 mmHg) may be enrolled provided they do not have evidence of end-organ damage, diabetes or a 10 year cardiovascular risk \> 20%.
• Abnormal ECG waveform morphology at Screening that would preclude accurate measurement of the uncorrected QT interval (QT) duration.
• QT interval for heart rate corrected using Fridericia's formula (QTcF) interval duration \> 430 msec for men or \> 450 msec for women, obtained as an average from the measurements on duplicate Screening ECGs.
• Estimated glomerular filtration rate (eGFR) \< 80 mL/min/1.73 m\*2 or an absolute creatinine value above the upper limit of the normal range. eGFR will be estimated at Screening using the Modification of Diet in Renal Disease (MDRD) equation.
• Use of any prescription medicine, over the counter (OTC) medications, herbal remedies (such as St John's Wort), or food known to be strong inhibitors or strong inducers of CYP enzymes (also known as CYP450 enzymes) during the 30 days before the dose of study medication; use of any other prescription or OTC medicine, including dietary supplements or herbal remedies, during the 7 days before the first dose of study medication.
• Consumption of certain foods or beverages before the dose and throughout the study period.

Sponsors & Collaborators

• Daiichi Sankyo: lead

Study Sites (1)

Unknown Facility

London, NW10 7EW, United Kingdom

Location

MeSH Terms

Interventions

DS-1971a; Midazolam; Omeprazole; Pioglitazone; Tolbutamide

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Benzimidazoles; Thiazolidinediones; Thiazoles; Azoles; Benzenesulfonamides; Sulfonamides; Amides; Sulfonylurea Compounds; Urea; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 12, 2015
• First Posted: June 16, 2015
• Study Start: May 1, 2015
• Primary Completion: July 1, 2015
• Study Completion: July 1, 2015
• Last Updated: November 5, 2015

Record last verified: 2015-11

Locations

GB (1)