Clinical trial NCT01128634: Pharmacokinetic and Safety of GSK573719 and GW642444 Administered Individually and Concurrently, With Verapamilin in Healthy Subjects
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Verapamil
Anticholinergic, β2 agonist
P-GP
LABA
Muscarinic Receptor Antagonist
LAMA
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2010-05-24
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Pharmacokinetic parameters of plasma and urine
timeFrame: 15 days
Secondary outcomes:
measure: 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
timeFrame: From first dose on day 1 through to Follow Up visit
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Mehta R, Kelleher D, Preece A, Hughes S, Crater G. Effect of verapamil on systemic exposure and safety of umeclidinium and vilanterol: a randomized and open-label study. Int J Chron Obstruct Pulmon Dis. 2013;8:159-67. doi: 10.2147/COPD.S40859. Epub 2013 Mar 27.