Effect of food on the bioavailability of palbociclib
- 813 Downloads
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 (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.
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.
KeywordsPalbociclib CDK4/6 inhibitor Phase I Bioavailability Pharmacokinetics Food effect
The authors would like to thank the study volunteers. Editorial support was provided by Johna Van Stelten, PhD, of Complete Healthcare Communications, LLC, and was funded by Pfizer Inc.
AR-G, AP, MO, and DW wrote manuscript, designed research, performed research, analyzed data, and contributed new agents/analytical tools.
Compliance with ethical standards
Conflict of interest
This study (A5481021; NCT01904747) was sponsored by Pfizer Inc. All authors are employees of and shareholders in Pfizer Inc.
- 2.Toogood PL, Harvey PJ, Repine JT, Sheehan DJ, VanderWel SN, Zhou H, Keller PR, McNamara DJ, Sherry D, Zhu T, Brodfuehrer J, Choi C, Barvian MR, Fry DW (2005) Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 48:2388–2406. doi: 10.1021/jm049354h CrossRefPubMedGoogle Scholar
- 3.Saab R, Bills JL, Miceli AP, Anderson CM, Khoury JD, Fry DW, Navid F, Houghton PJ, Skapek SX (2006) Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells. Mol Cancer Ther 5:1299–1308. doi: 10.1158/1535-7163.MCT-05-0383 CrossRefPubMedGoogle Scholar
- 5.Marzec M, Kasprzycka M, Lai R, Gladden AB, Wlodarski P, Tomczak E, Nowell P, Deprimo SE, Sadis S, Eck S, Schuster SJ, Diehl JA, Wasik MA (2006) Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity. Blood 108:1744–1750. doi: 10.1182/blood-2006-04-016634 CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ (2015) The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 16:25–35CrossRefPubMedGoogle Scholar
- 7.Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Huang Bartlett C, Koehler M, Slamon DJ (2016) Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 17:425–439CrossRefPubMedGoogle Scholar
- 8.US Food and Drug Administration (2016) Palbociclib (IBRANCE Capsules). Available at: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm487080.htm. Accessed December 27, 2016
- 9.Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, Courtney R, O’Dwyer PJ (2011) Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (schedule 2/1). Br J Cancer 104:1862–1868. doi: 10.1038/bjc.2011.177 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Flaherty KT, Lorusso PM, DeMichele A, Abramson VG, Courtney R, Randolph SS, Shaik MN, Wilner KD, O’Dwyer PJ, Schwartz GK (2012) Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 18:568–576. doi: 10.1158/1078-0432.CCR-11-0509 CrossRefPubMedGoogle Scholar
- 11.DeMichele A, Clark A, Tan KS, Heitjan DF, Gramlich K, Gallagher M, Lal P, Feldman M, Zhang P, Colameco C, Lewis D, Langer M, Goodman N, Domchek SM, Gogineni K, Rosen M, Fox KR, O’Dwyer P (2014) CDK 4/6 inhibitor palbociclib (PD0332991) in Rb + advanced breast cancer: phase II activity, safety and predictive biomarker assessment. Clin Cancer Res 21:995–1001. doi: 10.1158/1078-0432.CCR-14-2258 CrossRefPubMedGoogle Scholar
- 12.Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, Landa J, Qin LX, Rathbone DD, Condy MM, Ustoyev Y, Crago AM, Singer S, Schwartz GK (2013) Phase II trial of the CDK4 Inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol 31:2024–2028. doi: 10.1200/JCO.2012.46.5476 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.IBRANCE® (palbociclib) (Full Prescribing Information) (2016) Full Prescribing Information. Pfizer Inc, New York, NYGoogle Scholar
- 15.Sun W, Klamerus KJ, Yuhas LM, Pawlak S, Plotka A, O’Gorman M, Kosa M, Wang D (2015) Impact of acid-reducing agents (ARAS) on the pharmacokinetics of palbociclib, a weak base with ph-dependent solubility, under differing food intake conditions [abstract 315]. Eur J Cancer 51: S59–S60. doi: 10.1016/S0959-8049(16)30180-0 CrossRefGoogle Scholar
- 16.Sun W, Klamerus KJ, Yuhas LM, Pawlak S, Plotka A, O’Gorman M, Kosa M, Wang D (2015) Impact of acid-reducing agents on the pharmacokinetics of palbociclib, a weak base with pH-dependent solubility, under different food intake conditions. Presented at: European Cancer Congress; September 25–29; Vienna, AustriaGoogle Scholar