Onderzoek naar, de farmacologie, de effecten van voedsel en geneesmiddel interactie met meervoudige oplopende doseringen van LY2562175 in gezonde vrijwilligers

The drug to be given, LY2562175, is a new, investigational compound that may
eventually be used in the treatment of high cholesterol (too high percentage of
fat in the blood). High cholesterol is associated with a higher risk of
developing Coronary Heart Disease (CHD).

Cholesterol can build up in the walls of your arteries. This buildup of
cholesterol is called plaque. Over time, plaque can cause narrowing of the
arteries. This is called atherosclerosis, or hardening of the arteries.
Narrowing of your coronary arteries due to plaque can stop or slow down the
flow of blood to your heart. When the arteries narrow, the amount of
oxygen-rich blood is decreased. This is called coronary heart disease (CHD). By
lowering the percentage of fat in the blood, LY2562175 reduces the risk of high
cholesterol and subsequently the risk of CHD.

The purpose of the study is to investigate how safe the compound is and how
well the compound is tolerated. The study will also investigate how quickly and
to what extent the drug is absorbed, metabolised and eliminated from the body.
The influence of other drugs on the compound and the effect of food will also
be investigated. This study is not intended to improve your health, but is
necessary for the further development of the drug.

Design:
This is a 2-part, single center study in healthy male and/or female subjects.
Part 1 will be a randomized, double-blind, placebo-controlled, multiple
ascending dose study with 4 groups of 12 healthy subjects (males and/or females
of non-child bearing potential [NCBP]). In each group, 9 subjects will receive
LY2562175 and 3 subjects will receive placebo orally once daily for a period of
14 days in the fasted state. Each subject will participate in one 14-day
multiple dose treatment period. A Mixed Meal Tolerance Test (MMTT) will be
performed at breakfast and lunch on Days -2 and 10.
Part 2 will be an open-label study with 9 healthy male and/or NCBP female
subjects. Subjects will receive LY2562175 orally once daily for a period of 14
days in the fed state. Midazolam (intravenous [iv] injection) and pravastatin
(oral) will be administered as single doses on Day -2 and Day 12.
All subjects of both study parts will return for a follow-up visit on Days 21
and 28.
Procedures and assessments
Screening and follow-up:
Demographics, medical history, clinical laboratory (clinical chemistry,
hematology, urinalysis and coagulation), urine drug and alcohol screen,
pharmacodynamic (PD) assessments (fasting lipid panel: triglycerides [TG],
low-density lipoprotein-bound cholesterol [LDL-C], very low-density
lipoprotein-bound cholesterol [VLDL C], high-density lipoprotein-bound
cholesterol [HDL C] and total cholesterol [TC]), antiviral serology (HBsAg,
anti HCV, anti HIV 1/2), pregnancy test (females only), vital signs (blood
pressure, pulse rate, oral body temperature and respiratory rate), 12 lead
electrocardiogram (ECG) (triplicate), complete physical examination including
body height and weight, previous and concomitant medication recording, and
adverse events (AEs).
Follow-up Day 21: Clinical laboratory (clinical chemistry, hematology,
urinalysis and coagulation), PD assessments (bile acid panel:
glycochenodeoxycholic acid [GCDCA], glycocholic acid [GCA],
taurochenodeoxycholic acid [TCDCA], taurocholic acid [TCA], cholic acid [CA],
chenodeoxycholic acid [CDCA], taurodeoxycholic acid [TDCA] and glycodeoxycholic
acid [GDCA]; fasting lipid panel: TG, LDL-C, VLDL C, HDL-C and TC; fasting
glucose and insulin) and directed physical examination.
Follow-up Day 28:Clinical laboratory (only if clinically significant on Day 21
[clinical chemistry, hematology, urinalysis and coagulation]), PD assessments
(bile acid panel: GCDCA, GCA, TCDCA, TCA, CA, CDCA, TDCA and GDCA; fasting
lipid panel: TG, LDL-C, VLDL C, HDL-C and TC; fasting glucose and insulin),
vital signs (blood pressure and pulse rate), ECG (single) and complete physical
examination.
Observation period :
Part 1:1 period in clinic from Day -4 up to Day 16, and an ambulant visit on
Day 18.
Part 2: 1 period in clinic from Day -3 up to Day 16, and an ambulant visit on
Day 18.

Blood sampling:
Part 1:
For pharmacokinetics (PK) of LY2562175: at pre-dose and at 0.5, 1, 2, 4, 6, 8,
12 and 24 hours post-dose on Day 1, at pre-dose on Days 3, 5 and 10, and at
pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 24, 48 and 96 hours post-dose on Day 14.
For PD (bile acid panel: GCDCA, GCA, TCDCA, TCA, CA, CDCA, TDCA and GDCA;
fasting lipid panel: LDL-C, VLDL C, HDL-C and TC): at pre-dose on Days 1, 2, 4,
7, 10 and 14.
For PD (TG): at pre-dose on Days 1, 2, 4, 7 and 14.
For PD (MMTT: TG): Day 10: before starting breakfast (pre-dose), at 1, 2, 3, 4
and 5 hours (pre lunch) after starting breakfast, and at 1, 2, 3, 4 and 5 hours
(pre-dinner) after starting lunch.
Blood sampling for this PD parameter will also be done on Day -2 at the same
time points as on Day 10.
For PD (MMTT: nuclear magnetic resonance [NMR] lipoprofile): Day 10: before
starting breakfast (pre-dose), at 1, 2, 3, 4 and 5 hours (pre-lunch) after
starting breakfast and at 1, 2, 3, 4 and 5 hours (pre dinner) after starting
lunch.
Blood sampling for this PD parameter will also be done on Day -2 at the same
time points as on Day 10.
For PD (MMTT: apolipoprotein B-48 [ApoB48] and apolipoprotein B-100 [ApoB100]):
Day 10: before starting breakfast (pre-dose), at 3, 4 and 5 hours (pre-lunch)
after starting breakfast and at 3, 4 and 5 hours (pre-dinner) after starting
lunch.
Blood sampling for these PD parameters will also be done on Day -2 at the same
time points as on Day 10.
For PD (fasting glucose and insulin): before starting breakfast (pre-dose) on
Days 1, 2, 4, 7, 10 and 14.
Part 2:
For PK of LY2562175: at pre-dose and at 0.5, 1, 2, 4, 6, 8, 12 and 24 hours
post-dose on Day 1, at pre-dose on Days 3, 5 and 10, and at pre-dose and at
0.5, 1, 2, 4, 6, 8, 12, 24, 48 and 96 hours post-dose on Day 14.
For PK of midazolam, midazolam metabolites, and pravastatin: at pre-dose and at
0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose on Day 12.
Blood sampling for PK of midazolam, midazolam metabolites, and pravastatin will
also be done on Day -2 at the same time points as on Day 12.
For PD (bile acid panel: GCDCA, GCA, TCDCA, TCA, CA, CDCA, TDCA and GDCA;
fasting lipid panel: TG, LDL-C, VLDL C, HDL-C and TC): at pre-dose on Days 1,
2, 4, 7, 10 and 14.
For PD (NMR lipoprofile): Day 10: before starting breakfast, at 2.5, 3.5, 4.5
and 5.5 hours (pre-lunch) after starting breakfast and at 1, 2, 3, 4 and 5
hours (pre dinner) after starting lunch.
Blood sampling for NMR lipoprofile will also be done on Day -2 at the same time
points as on Day 10.
For PD (palmitoleic acid [C-16-1]): Day 10: before starting breakfast, at 2.5
and 3.5 hours after starting breakfast and at 2 and 3 hours after starting
lunch.
Blood sampling for palmitoleic acid [C-16-1] will also be done on Day -2 at the
same time points as on Day 10.
MMTT:
on Days -2 and 10 (Part A only)
Safety assessments :
AEs and concomitant medication: recorded from the time the Informed Consent
Form is signed until completion of the follow up visit; physical examination
(directed): on Day 7; vital signs (blood pressure and pulse rate): at pre-dose
and at 3 hours post-dose on Days 1, 7 and 14; ECG (triplicate): at pre dose and
at 2, 4 and 24 hours post dose on Days 1 and 14; clinical laboratory (clinical
chemistry, hematology, urinalysis and coagulation): at pre-dose on Day 7 and at
48 hours post-dose on Day 14.

Study Medication Active substance: LY2562175 midazolam pravastatin Activity : potent farnesoid x receptor agonist sedative HMG-CoA reductase Inhibitors Indication : dyslipidemia anesthesia prevention of strokes/heart attacks Strength : 5, 25 and 100 mg 200 µg 40 mg Dosage form: capsules iv injection tablet

Procedures: pain, light bleeding, heamatoma, possibly an infection.