Single-dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.
OBJECTIVE
Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib.


METHODS
Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated.


RESULTS
Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure.


CONCLUSIONS
Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.
Krishna
Rajesh
R
Merck & Co., Inc., Whitehouse Station, NJ 07065-0900, USA. rajesh_krishna@merck.com
Garg
Amit
A
Panebianco
Deborah
D
Cote
Josee
J
Bergman
Arthur J
AJ
Van Hoydonck
Pascale
P
Laethem
Tine
T
Van Dyck
Kristien
K
Chen
Jingjing
J
Chavez-Eng
Cynthia
C
Archer
Laura
L
Lutz
Ryan
R
Hilliard
Deborah
D
Snyder
Karen
K
Jin
Bo
B
Van Bortel
Luc
L
Lasseter
Kenneth C
KC
Al-Huniti
Nidal
N
Dykstra
Kevin
K
Gottesdiener
Keith
K
Wagner
John A
JA
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D050171:Dyslipidemias / Q000188:drug therapy*; D005215:Fasting; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity; D023303:Oxazolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D012737:Sex Factors; D016896:Treatment Outcome; D055815:Young Adult
D053480:Cholesterol Ester Transfer Proteins; D023303:Oxazolidinones; C530884:anacetrapib