title: Effect of food on the bioavailability of palbociclib.
abstract: This phase I study estimated the effect of food on bioavailability of palbociclib (IBRANCE®), and a selective inhibitor of cyclin-dependent kinase 4/6 approved for oncology indications has pH-dependent solubility and high permeability.
  
  
  
  In this randomized, four-sequence, four-period crossover study, 28 healthy volunteers received a single 125-mg dose of palbociclib (free-base capsule) following an overnight fast or (1) after a high-fat/-calorie meal, (2) after a low-fat/-calorie meal, and (3) between two moderate-fat/standard-calorie meals. Pharmacokinetic samples were collected predose and serially ≤144 h postdose; palbociclib concentrations were measured using validated high-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic data were analyzed using a noncompartmental approach based on a mixed-effects model.
  
  
  
  Median time to maximum concentration was 8 h for all conditions. Exposure (AUCinfand Cmax) increased slightly in the fed versus fasted conditions; ratios (90% CIs) of the adjusted geometric mean relative to the fasted condition ranged from 111.8 (104.3-119.9%) to 120.6% (112.6-129.1%) for AUCinfand from 124.0 (108.4-141.9%) to 137.8% (120.6-157.5%) for Cmaxdue mainly to three subjects with significantly lower exposure (low liers) in the fasted condition. Pharmacokinetic variability was reduced in the fed (AUCinf, 23-27%; Cmax, 21-24%) versus fasted (AUCinf, 39%; Cmax, 73%) conditions. In a supplemental analysis excluding the three low liers, food intake did not affect palbociclib exposure.
  
  
  
  Food intake modestly increased palbociclib exposure while greatly reducing pharmacokinetic variability. For subjects with normal absorption, food intake did not affect palbociclib exposure. Thus, palbociclib should be administered with food.
  
  
  
  ClinicalTrials.gov: NCT01904747.
authors.affiliation: Pfizer Inc, 10646 Science Center Dr, San Diego, CA, 92121, USA. Ana.Ruiz@pfizer.com.
authors.forename: Ana
authors.identifier: 0000-0002-5462-3110
authors.initials: A
authors.lastname: Ruiz-Garcia
authors.affiliation: Pfizer Inc, Collegeville, PA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Plotka
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: O'Gorman
authors.affiliation: Pfizer Inc, 10646 Science Center Dr, San Diego, CA, 92121, USA.
authors.forename: Diane D
authors.initials: DD
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000009:adverse effects / Q000493:pharmacokinetics*; D002149:Energy Intake; D005215:Fasting / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D062407:Meals; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D010879:Piperazines; D011725:Pyridines; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib
keywords: Bioavailability; CDK4/6 inhibitor; Food effect; Palbociclib; Pharmacokinetics; Phase I