title: Safety, tolerability and pharmacokinetics of dalcetrapib following single and multiple ascending doses in healthy subjects: a randomized, double-blind, placebo-controlled, phase I study.
abstract: 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.
  
  
  METHODS
  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).
  
  
  METHODS
  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(∞)) 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.
  
  
  CONCLUSIONS
  Single-dose dalcetrapib up to 4500 mg and multiple doses up to 3900 mg were generally safe and well tolerated.
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland. michael.derks@roche.com
authors.forename: Michael
authors.initials: M
authors.lastname: Derks
authors.forename: Judith
authors.initials: J
authors.lastname: Anzures-Cabrera
authors.forename: Lynn
authors.initials: L
authors.lastname: Turnbull
authors.forename: Mary
authors.initials: M
authors.lastname: Phelan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000577:Amides; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004562:Electrocardiography; D004952:Esters; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D013438:Sulfhydryl Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013997:Time Factors; D055815:Young Adult
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D004952:Esters; D013438:Sulfhydryl Compounds; C411602:dalcetrapib