This is an open-label, single-centre, randomized, single dose, three-way crossover, six
sequence study to evaluate the comparative bioavailability of two Fixed Dose Combination
(FDC) tablet formulations of amlodipine and rosuvastatin relative to innovator samples under
fasting conditions, in healthy adult subjects. Subjects will be 12 Chinese and 12 Caucasian
subjects living in Singapore. The randomisation will be stratified by ethnicity to ensure an
equal number of subjects will be assigned to each dosing sequence. Subjects will receive
each of the following three treatments administered in a randomized three-way crossover
design: a reference treatment consisting of a single 10mg amlodipine tablet and 20mg
rosuvastatin tablet ; a single fixed dose combination tablet consisting of 10mg amlodipine
and 20mg rosuvastatin (Test Formulation - FDC 1); and another single fixed dose combination
tablet consisting of 10mg amlodipine and 20mg rosuvastatin (Test Formulation - FDC 2). Two
test formulations have same active pharmaceutical ingredients (amlodipine and rosuvastatin),
same doses and different inactive ingredients. Each subject will participate in three
treatment periods. The study consists of a screening phase, three treatment periods and a
follow-up visit. The three treatment periods will be separated by a washout period of 12-17
days.
Minimum age: 21 Years.
Maximum age: 65 Years.
Gender(s): Both.
Inclusion Criteria:
- Male or female between 21 and 65 years of age inclusive, at the time of signing the
informed consent.
- Alanine transaminase, alkaline phosphatase and total bilirubin <=1. 5x upper limit of
normal (ULN) (isolated bilirubin >1. 5xULN is acceptable if bilirubin is fractionated
and direct bilirubin <35%).
- Normal electrocardiogram (ECG) morphology and measurements. Single corrected QT
interval (QTc) <450 milliseconds (msec). In particular QTc <450 msec or QT <480 msec
in subjects with Bundle Branch Block based on an average from three ECGs obtained
over a brief recording period.
- 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 parameters
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 and the GSK Medical Monitor agree that the finding is unlikely to
introduce additional risk factors and will not interfere with the study procedures.
- 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 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 (FSH) >40 milli-international units
per milliliter (MIU/mL) and estradiol <40 picograms per milliliter (pg/mL) (<147
picomole per liter) is confirmatory]; On hormone replacement therapy (HRT) and whose
menopausal status is in doubt will be required to use a protocol approved
contraception method if they wish to continue their HRT during the study. Otherwise,
they must discontinue HRT to allow confirmation of post-menopausal status prior to
study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the
cessation of therapy and the blood draw; this interval depends on the type and dosage
of HRT. Following confirmation of their post-menopausal status, they can resume use
of HRT during the study without use of a contraceptive method; Child-bearing
potential with negative pregnancy test as determined by serum or urine human
chorionic gonadotropin (hCG) test at the screening or prior to dosing and agrees to
use one of the contraception methods for an appropriate period of time (as determined
by the product label or the 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 14 days after last dose of amlodipine/rosuvastatin, i. e.
after single dose of treatment period 3.
- Male subjects with female partners of child-bearing potential must agree to use one
of the contraceptive methods and not to donate sperm. These criteria must be followed
from the time of the first dose of study medication until the follow-up contact
visit.
- Body weight >=50 kilogram (kg) and body mass index (BMI) within the range 18. 5 - 29. 9
kilogram per square meter (kg/m^2) (inclusive).
- Chinese or Caucasian self-reported by the subjects for both parents and all 4
grandparents. The ethnic group is as defined by National Registration Identity Cards
provided additional confirmation of ethnicity.
- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
Exclusion Criteria:
- 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. More than 2
standard drinks a day for a woman, and more than 3 drinks a day (about 30 gram [g] of
alcohol) for a man, and more than 4 days per week. One standard drink contains 10g of
pure alcohol and is equivalent to a can of beer (220 milliliter [mL]), 1 glass of
wine (100mL), or 1 nip (30mL) of spirits.
- History of sensitivity to heparin or heparin-induced thrombocytopenia.
- 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.
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening.
- A systolic blood pressure <95 millimeter of mercury (mmHg) or a recent history of
postural symptoms.
- 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 Immunodeficiency Virus (HIV) antibody.
- Pregnant females as determined by positive urine hCG test at Day -1 or serum hCG at
screening visit.
- Where participation in the study would result in donation of blood or blood products
in excess of 450mL 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.
- Unwillingness or inability to follow the procedures outlined in the protocol.
- Subject is mentally or legally incapacitated.
- 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.