PMID- 21366361
OWN - NLM
STAT- MEDLINE
DCOM- 20110602
LR  - 20211203
IS  - 1173-2563 (Print)
IS  - 1173-2563 (Linking)
VI  - 31
IP  - 5
DP  - 2011
TI  - Safety, tolerability and pharmacokinetics of dalcetrapib following single and 
      multiple ascending doses in healthy subjects: a randomized, double-blind, 
      placebo-controlled, phase I study.
PG  - 325-35
AB  - BACKGROUND: Dalcetrapib is a modulator of cholesteryl ester transfer protein 
      (CETP) activity developed to raise levels of high-density lipoprotein cholesterol 
      (HDL-C) with the goal of further reduction of cardiovascular events additive to 
      standard of care alone. In clinical studies, dalcetrapib has been shown to 
      effectively increase levels of HDL-C with no significant safety concerns. 
      OBJECTIVE: The primary objective was to investigate the safety of single 
      ascending and multiple ascending doses of dalcetrapib at doses markedly greater 
      than that intended therapeutically (600 mg/day). Secondary objectives were to 
      investigate the pharmacokinetics/pharmacodynamics and dose proportionality of 
      dalcetrapib. STUDY DESIGN: Randomized, double-blind, placebo-controlled, combined 
      single and multiple ascending dose phase I study. Healthy males (age 18-65 years, 
      body mass index 18-32 kg/m2) were randomized to four of five dalcetrapib doses 
      (2100, 2700, 3300, 3900 or 4500 mg) or placebo, with >/=10 days washout between 
      doses (n = 15, single ascending doses) or to dalcetrapib (1800, 2100, 3000 or 
      3900 mg once daily) or placebo for 7 days (four cohorts, each n = 10, 
      randomization 8 : 2, multiple ascending doses). MAIN OUTCOME MEASURE: 
      Tolerability and safety were assessed by monitoring adverse events (AEs), 
      laboratory parameters, vital signs and 12-lead ECG recordings. Primary 
      pharmacokinetic assessments were area under the plasma concentration-time curve 
      (AUC) from time zero to infinity (AUC(infinity)) and maximum observed plasma 
      concentration (C(max)) [single doses] and AUC from time zero to 24 hours 
      (AUC(24)) and C(max) (multiple doses). Pharmacodynamic assessments included CETP 
      activity and lipids (multiple dosing only). RESULTS: Exposure increased with dose 
      but was less than proportional to increasing dose after single dosing, although 
      deviation from dose proportionality could not be demonstrated for C(max). Dose 
      proportionality was consistent following multiple doses. Steady state was 
      modelled to have been reached by approximately 4 days, with little to no 
      accumulation. CETP activity reduction was dose dependent (maximum -55% after 
      3900 mg; placebo -2.6%) at 6 hours post-dose on day 1, while HDL-C increased by 
      12-19% (placebo -13%) on day 8 following treatment with 1800-3900 mg/day for 7 
      days. All AEs were mild or moderate in intensity and there were no serious AEs, 
      deaths or withdrawals due to AEs. No clinically relevant effects on laboratory 
      parameters, cardiac parameters or vital signs were noted. CONCLUSION: Single-dose 
      dalcetrapib up to 4500 mg and multiple doses up to 3900 mg were generally safe 
      and well tolerated.
FAU - Derks, Michael
AU  - Derks M
AD  - F. Hoffmann-La Roche Ltd, Basel, Switzerland. michael.derks@roche.com
FAU - Anzures-Cabrera, Judith
AU  - Anzures-Cabrera J
FAU - Turnbull, Lynn
AU  - Turnbull L
FAU - Phelan, Mary
AU  - Phelan M
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - New Zealand
TA  - Clin Drug Investig
JT  - Clinical drug investigation
JID - 9504817
RN  - 0 (Amides)
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (Cholesterol Ester Transfer Proteins)
RN  - 0 (Esters)
RN  - 0 (Sulfhydryl Compounds)
RN  - 3D050LIQ3H (dalcetrapib)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Amides
MH  - Anticholesteremic Agents/*administration & dosage/adverse 
      effects/pharmacokinetics
MH  - Area Under Curve
MH  - Cholesterol Ester Transfer Proteins/*antagonists & inhibitors
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Electrocardiography
MH  - Esters
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
MH  - Sulfhydryl Compounds/*administration & dosage/adverse effects/pharmacokinetics
MH  - Time Factors
MH  - Young Adult
EDAT- 2011/03/04 06:00
MHDA- 2011/06/03 06:00
CRDT- 2011/03/04 06:00
PHST- 2011/03/04 06:00 [entrez]
PHST- 2011/03/04 06:00 [pubmed]
PHST- 2011/06/03 06:00 [medline]
AID - 10.1007/BF03256931 [doi]
PST - ppublish
SO  - Clin Drug Investig. 2011;31(5):325-35. doi: 10.1007/BF03256931.