PT  - JOURNAL ARTICLE
AU  - Maria Jove
AU  - Jade A Spencer
AU  - Matthew E Hubbard
AU  - Elizabeth C Holden
AU  - Reuben D O'Dea
AU  - Bindi S Brook
AU  - Roger M Phillips
AU  - Stephen W Smye
AU  - Paul Loadman
AU  - Christopher J Twelves
TI  - Cellular uptake and efflux of palbociclib in vitro in single cell and spheroid models
AID  - 10.1124/jpet.119.256693
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.119.256693
4099  - http://jpet.aspetjournals.org/content/early/2019/06/12/jpet.119.256693.short
4100  - http://jpet.aspetjournals.org/content/early/2019/06/12/jpet.119.256693.full
AB  - Adequate drug distribution through tumours is essential for treatment to be effective. Palbociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor approved for use in patients with hormone receptor (HR) positive, HER2 negative metastatic breast cancer (BC). It has unusual physicochemical properties, which may significantly influence its distribution in tumour tissue. We studied the penetration and distribution of palbociclib in vitro, including the use of multicellular three-dimensional models and mathematical modelling. MCF-7 and DLD-1 cell lines were grown as single cell suspensions (SCS) and spheroids; palbociclib uptake and efflux were studied using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Intracellular concentrations of palbociclib for MCF-7 SCS (Cmax 3.22 µM) and spheroids (Cmax 2.91 µM) were 32 and 29 fold higher and in DLD-1, 13 and 7 fold higher, respectively than the media concentration (0.1 µM). Total palbociclib uptake was lower in DLD-1 cells than MCF-7 cells both in SCS and in spheroids. Both uptake and efflux of palbociclib were slower in spheroids than SCS. These data were used to develop a mathematical model of palbociclib transport that quantifies key parameters determining drug penetration and distribution. The model reproduced qualitatively most features of the experimental data and distinguished between SCS and spheroids, providing additional support for hypotheses derived from the experimental data. Mathematical modelling has the potential for translating in vitro data into clinically relevant estimates of tumour drug concentrations.SIGNIFICANCE STATEMENT This study explores palbociclib uptake and efflux in single cell suspension and spheroid models of cancer. Large intracellular concentrations of palbociclib are found after drug exposure. The data from this study may aid understanding of the intratumoural pharmacokinetics of palbociclib which is useful in understanding how drug distributes within tumour tissue and optimising drug efficacy. Bio-mathematical modelling has the potential to derive intratumoural drug concentrations from plasma pharmacokinetics in patients.