Palbociclib (PD-0332991) pharmacokinetics in subjects with impaired renal function
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ORIGINAL ARTICLE
Palbociclib (PD‑0332991) pharmacokinetics in subjects with impaired renal function Yanke Yu1 · Justin Hoffman1 · Anna Plotka2 · Melissa O’Gorman3 · Haihong Shi3 · Diane Wang1 Received: 8 July 2020 / Accepted: 30 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose This publication describes an evaluation of the impact of different degrees of renal impairment on the pharmacokinetics and safety of palbociclib after a single 125-mg oral dose. Methods Thirty-one subjects were assigned to different renal function groups. Serial blood sampling for pharmacokinetics was performed up to 120 h and 168 h post-palbociclib dose for subjects with normal and impaired renal function, respectively. A separate blood sample was collected at pre-dose and 8 h after dosing to measure plasma protein binding. Plasma palbociclib was measured using a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method. Plasma protein binding samples were processed by equilibrium dialysis and measured by a validated LC–MS/MS method. Results Plasma palbociclib exposure was higher in subjects with renal impairment than in subjects with normal renal function; however, there were no marked differences in exposure across subjects with mild, moderate, and severe renal impairment. Total plasma exposure AUCinf increased by 39%, 42%, and 31% with mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. Peak exposure Cmax increased by 17%, 12%, and 15% for mild, moderate, and severe impairment, respectively. There was no obvious trend in the mean fu with worsening renal function. The PBPK model adequately described palbociclib exposure observed in subjects with moderate or severe renal impairment from this study. Conclusion Palbociclib was safe and well-tolerated in a small population of subjects with normal and impaired renal function after a single oral 125 mg dose. No dose adjustment is required in patients with renal impairment. Keywords CDK4/6 inhibitor · Palbociclib · Renal impairment · Pharmacokinetics · PBPK
Introduction Palbociclib (PD-0332991) is a highly selective, reversible inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Inhibition of CDK 4/6 blocks deoxyribonucleic acid (DNA) synthesis by prohibiting the progression of the cell cycle from G1 to S phase, which results in cancer cell death [1, Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04163-4) contains supplementary material, which is available to authorized users. * Diane Wang [email protected] 1
Clinical Pharmacology, Pfizer Inc, 10555 Science Center Dr, San Diego, CA 92130, USA
2
Biostatistics, Pfizer Inc, Collegeville, PA, USA
3
Clinical Pharmacology, Pfizer Inc, Groton, CT, USA
2]. Currently, palbociclib is approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combinatio
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