The study is designed to estimate the bioavailability of amlodipine and enalapril maleate
fixed dose combination (FDC) relative to co-administration of amlodipine and enalapril
maleate tablets. The rational for this study is to provide a more convenient dosing regimen
for patients. This is an open-label, randomized, single dose, two-way crossover study, in
which 16 healthy adult male and female subjects will be enrolled and dosed under fasting
conditions. Each subject will participate in two treatment periods of 7 days each. There
will be at least 14 days of wash out period between the two dosing periods and a follow-up
period of up to 21 days after treatment period 2. The total duration of study will be
approximately 35 days from the start of the first treatment.
Inclusion Criteria
- Male or female aged between 18 and 65 years of age inclusive, at the time of signing
the informed consent.
- Healthy as determined by a responsible and experienced physician, based on a medical
evaluation including medical history, physical examination, laboratory tests and
cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s)
which is/are not specifically listed in the inclusion or exclusion criteria, outside
the reference range for the population being studied may be included only if the
Investigator, in consultation with the GlaxoSmithKline (GSK) Medical Monitor if
required, agree and document that the finding is unlikely to introduce additional
risk factors and will not interfere with the study procedures.
- Body weight >=50 kilograms (kg) and Body Mass Index within the range 19 to 32
kg/meter squared (m^2) (inclusive).
- A female subject is eligible to participate if she is of non-childbearing potential
defined as pre-menopausal females with a documented tubal ligation or hysterectomy
[for this definition, "documented" refers to the outcome of the
investigator's/designee's review of the subject's medical history for study
eligibility, as obtained via a verbal interview with the subject or from the
subject's medical records]; or postmenopausal defined as 12 months of spontaneous
amenorrhea [in questionable cases a blood sample with simultaneous follicle
stimulating hormone > 40 milli international unit (MlU)/ milliliter (mL) and
estradiol < 40 picogram/mL (<147 picomoles/liter) is confirmatory]. OR Child-bearing
potential with negative pregnancy test as determined by serum human chorionic
gonadotropin test at screening or prior to dosing. Agrees to use one of the
contraception methods for an appropriate period of time (as determined by the product
label or investigator) prior to the start of dosing to sufficiently minimize the risk
of pregnancy at that point. Female subjects must agree to use contraception until the
follow-up contact visit. OR has only same-sex partners, when this is her preferred
and usual lifestyle.
- Male subjects with female partners of child-bearing potential must agree to use one
of the contraception methods This criterion must be followed from the time of the
first dose of study medication until the follow-up contact visit.
- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
- Alanine aminotransferase, alkaline phosphatase and bilirubin <=1. 5 x upper limit of
normal (ULN) (isolated bilirubin >1. 5xULN is acceptable if bilirubin is fractionated
and direct bilirubin <35 percent).
- Based on single or averaged QT duration corrected for heart rate (QTc) values of
triplicate electrocardiograms (ECGs)obtained over a brief recording period: QTc by
Fridericia's formula <450 millisecond (msec).
Exclusion Criteria Based Upon Medical Histories
- Current or chronic history of liver disease, or known hepatic or biliary
abnormalities (With the exception of Gilbert's syndrome or asymptomatic gallstones).
- History of regular alcohol consumption within 6 months of the study defined as An
average weekly intake of >21 units for males or >14 units for females. In Australia
one unit (=standard drink) is equivalent to 10 grams of alcohol: 270 mL of full
strength beer (4. 8 percent), 375 mL of mid strength beer (3. 5 percent), 470mL of
light beer (2. 7 percent), 250 mL pre-mix full strength spirit (5 percent), 100 mL of
wine (13. 5 percent) and 30 mL of spirit (40 percent).
- History of sensitivity to any of the study medications, or components thereof or a
history of drug or other allergy that, in the opinion of the investigator or GSK
Medical Monitor, contraindicates their participation.
Exclusion Criteria Based Upon Diagnostic Assessments
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening.
- Urinary cotinine levels indicative of smoking or history or regular use of tobacco-
or nicotine-containing products within 6 months prior to screening.
- A positive pre-study drug/alcohol screen.
- A positive test for human immuno virus antibody.
- Pregnant females as determined by positive serum hCG test at screening or at any
other time points.
- Any subject with a systolic blood pressure <95 millimeter of mercury (mmHg) or with a
recent history of postural symptoms.
- Orthostatic event at screening, defined as a symptomatic event (i. e. dizziness or any
pre syncope or syncope) and a reduction in systolic blood pressure of 20mmHg or more
and/or a reduction in diastolic blood pressure of 10 mmHg or more for standing versus
supine measurement.
Other Exclusion Criteria
- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within a 56 day period.
- Lactating females.
- 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.
- Unable to refrain from the 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.
- Subject is mentally or legally incapacitated.
- Positive carbon monoxide on admission to the Unit.
- Unable to refrain from consumption of red wine, seville oranges, grapefruit or
grapefruit juice (and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit
juices) from 7 days prior to the first dose of study medication.
