Ana Ruiz-Garcia1, Anna Plotka2, Melissa O'Gorman3, Diane D Wang4. 1. Pfizer Inc, 10646 Science Center Dr, San Diego, CA, 92121, USA. Ana.Ruiz@pfizer.com. 2. Pfizer Inc, Collegeville, PA, USA. 3. Pfizer Inc, Groton, CT, USA. 4. Pfizer Inc, 10646 Science Center Dr, San Diego, CA, 92121, USA.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS:Median time to maximum concentration was 8 h for all conditions. Exposure (AUCinf and C max) 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 AUCinf and from 124.0 (108.4-141.9%) to 137.8% (120.6-157.5%) for C max due mainly to three subjects with significantly lower exposure (low liers) in the fasted condition. Pharmacokinetic variability was reduced in the fed (AUCinf, 23-27%; C max, 21-24%) versus fasted (AUCinf, 39%; C max, 73%) conditions. In a supplemental analysis excluding the three low liers, food intake did not affect palbociclib exposure. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01904747.
RCT Entities:
PURPOSE: 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. METHODS: 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. RESULTS: Median time to maximum concentration was 8 h for all conditions. Exposure (AUCinf and C max) 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 AUCinf and from 124.0 (108.4-141.9%) to 137.8% (120.6-157.5%) for C max due mainly to three subjects with significantly lower exposure (low liers) in the fasted condition. Pharmacokinetic variability was reduced in the fed (AUCinf, 23-27%; C max, 21-24%) versus fasted (AUCinf, 39%; C max, 73%) conditions. In a supplemental analysis excluding the three low liers, food intake did not affect palbociclib exposure. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01904747.
Entities:
Keywords:
Bioavailability; CDK4/6 inhibitor; Food effect; Palbociclib; Pharmacokinetics; Phase I
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