463P - Effect of food on the bioavailability of palbociclib 125 mg capsules in healthy volunteers

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Drug Development
Pharmacology
Presenter Ana Ruiz-Garcia
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors A. Ruiz-Garcia1, A. Plotka2, S. Pawlak3, M. O’gorman4, M. Kosa5, S. Nidadavolu3, S. Phillips6, D.D. Wang7
  • 1Clinical Pharmacology, Pfizer Inc, 92121 - San Diego/US
  • 2Biostatistics, Pfizer Inc, Collegeville/US
  • 3Clinical Research And Precision Medicine, Pfizer Inc, New Haven/US
  • 4Global Clinical Pharmacology, Pfizer Inc, Groton/US
  • 5Clinical Assay Specialist Contracted Through Atrium Services, Pfizer Inc, San Diego/US
  • 6Development Operations, Pfizer Inc, Groton/US
  • 7Oncology Business Unit, Pfizer Inc, San Diego/US

Abstract

Aim

Palbociclib (P), a selective oral cyclin-dependent kinase 4/6 inhibitor that blocks G1/S cell cycle progression, is in phase 2 and 3 clinical trials across multiple oncology indications. P has low solubility and high permeability. This completed phase 1 study estimated the effect of food on P bioavailability.

Methods

This randomized, open-label, 4-sequence, 4-period crossover study (NCT01904747) in 28 healthy adult volunteers estimated the relative bioavailability of single-dose P 125 mg (free base capsule) administered 30 min after a high fat/calorie meal, 30 min after a low fat/calorie meal, or between 2 moderate fat/standard calorie meals (1 h after/2 h before) versus after fasting ≥10 h overnight (washout: ≥10 d between study periods). No food was allowed ≥4 h postdose (all conditions except moderate fat meal). Pharmacokinetic (PK) samples were collected predose and serially up to 144 h postdose; P concentrations were measured using validated high-performance liquid chromatography tandem mass spectrometry. PK data were analyzed using a non-compartmental approach based on a mixed effects model.

Results

Time to maximum P concentration (Tmax) and terminal plasma half-life (t1/2) values were similar across fed and fasted conditions (median Tmax: 8 h, all; mean t1/2: 22.03–23.90 h). Relative to the fasted condition, ratios of adjusted geometric means for high fat, low fat, and moderate fat conditions were 121%, 112%, and 113%, respectively, for AUCinf and 138%, 127%, and 124%, respectively, for Cmax; the slight increase in exposure in the fed versus fasted conditions was driven mainly by a subgroup of subjects (n = 3) with significantly lower exposure in the fasted condition. PK variability (% coefficient of variation) was reduced in the fed (AUCinf, 23%–27%; Cmax, 21%–24%) versus fasted (AUCinf, 39%; Cmax, 73%) conditions. In a supplemental analysis excluding the 3 subjects with significantly lower exposure in the fasted condition, food intake did not affect P exposure, and PK variability was similar across fed and fasted conditions.

Conclusions

Overall, P exposure was marginally affected, but PK variability was greatly reduced, in the fed versus the fasted condition. Thus, P should be administered with food.

Disclosure

A. Ruiz-Garcia: Employment: Pfizer Inc Stock ownership: Pfizer Inc.; A. Plotka: Employment: Pfizer Stock ownership: Pfizer; S. Pawlak: Speakers’ bureau: Pfizer Employment: Pfizer Stock ownership: Pfizer; M. O'Gorman, S. Nidadavolu and S. Phillips: Employment: Pfizer; M. Kosa: Employment: Contractor at Pfizer (Clinical Assay Group) through Atrium Services. D.D. Wang: Employment: Pfizer Stock ownership: Pfizer.