Pharmacokinetic and Safety of GSK573719 and GW642444 Administered Individually and Concurrently, With Verapamilin in Healthy Subjects

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT01128634

Collaborator

(none)

Enrollment

Location

Arms

1.7

Actual Duration (Months)

18.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to see if the Pharmacokinetics and the Safety Profile of GSK573719 and GSK573719/GW642444 are effected by concurrent dosing with the PGP inhibitor verapamil.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: GSK573719 Drug: GW573719/GW573719	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

32 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

A Single-Centre, Randomised, Open-label Study to Evaluate the Effects of Steady-State Verapamil, a Moderate P-Glycoprotein and CYP3A4 Inhibitor, on the Pharmacokinetics of GSK573719 and GSK573719 in Combination With GW642444

Actual Study Start Date :

Mar 4, 2010

Actual Primary Completion Date :

Apr 26, 2010

Actual Study Completion Date :

Apr 26, 2010

Arms and Interventions

Arm	Intervention/Treatment
Other: GSK573719 GSK573719	Drug: GSK573719 13 days dosing with GSK573719, once daily dosing from day 1 to 13, concurrent dosing with verapamil from day 9 to 13.
Other: GSK573719/GW642444 GSK573719/GW642444	Drug: GW573719/GW573719 13 days dosing with GSK573719/GW573719, once daily dosing from day 1 to 13, concurrent dosing with verapamil from day 9 to 13.

Arm

Intervention/Treatment

Other: GSK573719

GSK573719

Drug: GSK573719

13 days dosing with GSK573719, once daily dosing from day 1 to 13, concurrent dosing with verapamil from day 9 to 13.

Other: GSK573719/GW642444

GSK573719/GW642444

Drug: GW573719/GW573719

13 days dosing with GSK573719/GW573719, once daily dosing from day 1 to 13, concurrent dosing with verapamil from day 9 to 13.

Outcome Measures

Primary Outcome Measures

Pharmacokinetic parameters of plasma and urine [15 days]

Secondary Outcome Measures

General safety and tolerability endpoints: adverse events, heart rate, systolic and diastolic blood pressure, 12- lead ECG (QTc(B), QTc(F)) and clinical laboratory safety tests. 24hr Holter monitoring [From first dose on day 1 through to Follow Up visit]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

AST, ALT, alkaline phosphatase and bilirubin < 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
A female subject is eligible to participate if she is of: non childbearing potential including pre-menopausal females with documented (medical report verification) hysterectomy, double oophorectomy or bilateral salpingectomy., or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 40 pg/ml (<140 pmol/L) or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until completion of the follow up visit.
Body weight > 45 kg and BMI within the range 18 - 28 kg/m2 (inclusive).
Capable of giving written informed consent and a signed and dated written informed consent is obtained, which includes compliance with the requirements and restrictions listed in the consent form.
Normal spirometry (FEV1 ≥ 80% of predicted, FEV1/FVC ≥ 70%).
Non-smokers (never smoked or not smoking for >6 months with <10 pack years history (Pack years = (cigarettes per day smoked/20) x number of years smoked))
Available to complete the study

Exclusion Criteria:

Any clinically important abnormality identified at the screening medical assessment (physical examination/medical history), clinical laboratory tests, ECG (12-lead) or from 24hr Holter monitoring. If the Investigator and the GSK Medical Monitor agree that a finding is unlikely to introduce additional risk factors and will not interfere with the study procedures a subject can be included.
A mean QTc(B) value at screening >450msec, or an ECG that is not suitable for QT measurements (e.g. LBBB or poorly defined termination of the T wave).
A history of elevated resting blood pressure or a mean blood pressure higher than 140/90 mmHg at screening.
A mean heart rate outside the range 40-90 bpm at screening.
The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates and benzodiazepines. The detection of drugs with a legitimate medical use would not necessarily be an exclusion to study participation. The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study.
A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome).
A positive test for HIV antibody (if testing required by local SOP's).
History of regular alcohol consumption within 3months of the study defined as:

an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males), or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). One unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine.

The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
History of sensitivity to any of the study medications, verapamil or components thereof, known allergy or hypersensitivity to milk protein or the excipients lactose monohydrate and MgSt, or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
Unwillingness or inability to follow the procedures outlined in the protocol.
The subject is unable to use the novel dry powder inhaler correctly.
The subject has a known allergy or hypersensitivity to ipratropium bromide, tiotropium, atropine and any of its derivatives.
Any adverse reaction including immediate or delayed hypersensitivity to any β2 agonist or sympathomimetic drug,.
Subject is kept under regulatory of judicial order in an institution.
Subject is mentally or legally incapacitated.