pharmaceuticals Article Population Pharmacokinetics of Palbociclib in a Real-World Situation Bernard Royer 1,2,*, Courèche Kaderbhaï 3, Jean-David Fumet 3,4, Audrey Hennequin 3, Isabelle Desmoulins 3, Sylvain Ladoire 3,4, Siavoshe Ayati 3, Didier Mayeur 3, Sivia Ilie 3 and Antonin Schmitt 4,5 1 Laboratoire de Pharmacologie Clinique et Toxicologie, CHU Besançon, 25000 Besançon, France 2 INSERM, EFS BFC, UMR1098, RIGHT, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, University of Bourgogne Franche-Comté, 25000 Besançon, France 3 Oncology Department, Centre Georges-François Leclerc, 21000 Dijon, France; cgkaderbhai@cgfl.fr (C.K.); jdfumet@cgfl.fr (J.-D.F.); ahennequin@cgfl.fr (A.H.); IDesmoulins@cgfl.fr (I.D.); sladoire@cgfl.fr (S.L.); sayati@cgfl.fr (S.A.); dmayeur@cgfl.fr (D.M.); silie@cgfl.fr (S.I.) 4 INSERM U1231, University of Burgundy Franche-Comté, 21000 Dijon, France; aschmitt@cgfl.fr 5 Pharmacy Department, Centre Georges-François Leclerc, 21000 Dijon, France * Correspondence: [email protected] Abstract: Palbociclib is an oral cyclin-dependent kinase inhibitor that is used in combination with aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer. Its metabolism profile is associated with an important interpatient variability. We performed a population pharmacokinetics study of palbociclib in women routinely followed in a cancer center. One hundred and fifty-one samples were analyzed. The sampling times after administration ranged from 0.9 to 75 h and the samples were taken between 1 and 21 days after the beginning of the palbociclib cycle. Palbociclib was determined using a validated mass spectrometry method. The best Citation: Royer, B.; Kaderbhaï, C.; model that described the concentrations was a one-compartment model with first-order absorption Fumet, J.-D.; Hennequin, A.; and an absorption lag time. Interindividual variability could only be estimated on the clearance Desmoulins, I.; Ladoire, S.; Ayati, S.; and the first-order absorption. Creatinine clearance was found to be a significant covariate for the Mayeur, D.; Ilie, S.; Schmitt, A. apparent clearance. No significant covariates could be observed with the first-order absorption. First- Population Pharmacokinetics of order absorption and absorption lag times were difficult to assess because of the constraints linked Palbociclib in a Real-World Situation. to the real-world setting due to the small number of samples used during the absorption process. Pharmaceuticals 2021, 14, 181. However, palbociclib apparent clearance was satisfactorily estimated. Population pharmacokinetics https://doi.org/10.3390/ph14030181 (POP PK) with palbociclib could help to optimize dosing. Academic Editor: Thomas Efferth Keywords: palbociclib; population pharmacokinetics; real-world situation Received: 8 January 2021 Accepted: 19 February 2021 Published: 24 February 2021 1. Introduction Publisher’s Note: MDPI stays neutral Palbociclib is an oral inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6). It was with regard to jurisdictional claims in first approved in 2015 by the Food and Drug Administration and the European Medicines published maps and institutional affil- Agency after a pivotal trial in postmenopausal women with estrogen-positive, human iations. epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer [1]. In this study, the palbociclib plus letrozole displayed a longer median PFS (24.8 months) than the placebo plus letrozole (14.5 months). Further expansions of approval were granted for the treatment of hormone-positive (HR+), HER2-metastatic breast cancer (2016); HR+, Copyright: © 2021 by the authors. HER2-metastatic breast cancer in first-line (2017); and men with HR+, HER2-metastatic Licensee MDPI, Basel, Switzerland. breast cancer (2019). The recommended dose of palbociclib is 125 mg once daily per os for This article is an open access article 21 consecutive days followed by 7 days off for a complete cycle of 28 days. distributed under the terms and After administration, the maximum concentration is generally observed between 6 and conditions of the Creative Commons 12 h with a bioavailability of palbociclib of 46% [2]. Its binding to human plasma protein Attribution (CC BY) license (https:// is approximately 85% and its mean apparent volume of distribution is 2583 L [2]. The creativecommons.org/licenses/by/ mean (± standard deviation) plasma elimination half-life is 29 (±5) hours in patients with 4.0/). Pharmaceuticals 2021, 14, 181. https://doi.org/10.3390/ph14030181 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 181 2 of 14 with advanced breast cancer, and the steady state is achieved within 8 days following Pharmaceuticals 2021, 14, 181 repeated once-daily dosing [2]. Palbociclib is extensively metabolized, mainly via cyto-2 of 12 chrome P450 (CYP) 3A4 and sulfotransferase 2A1 [2]. Fasted conditions greatly decrease the absorption and exposure of palbociclib. Taken together, these characteristics are in favoradvanced of a great breast variability cancer, and of its the pharmacokinetics steady state is achieved (PK), as within shown 8 by days the following 41% to 59% repeated var- iabilityonce-daily for trough dosing concentrations [2]. Palbociclib or is the extensively 29% to 42% metabolized, variability for mainly the area via under cytochrome the curve P450 [3].(CYP) 3A4 and sulfotransferase 2A1 [2]. Fasted conditions greatly decrease the absorption andParadoxically, exposure of palbociclib. while several Taken articles together, have been these published characteristics displaying are in mixed favor pharma- of a great cokinetic–pharmacodynamicvariability of its pharmacokinetics models (PK), [4–6], as the shown population by the 41% PK to(POP 59% PK) variability model of for palbo- trough ciclibconcentrations was only published or the 29% as to a 42%poster variability [7]. The model for the built area underby the theauthors curve was [3]. a two-com- partmentParadoxically, model with whilea first-order several rate articles of absorption have been(Ka) and published a lag time displaying for absorption mixed (Tpharmacokinetic–pharmacodynamiclag). To our knowledge, only the latter models descri [4bes–6 ],the the covariates population that PK partly (POP PK)explain model the of palbociclibpalbociclib PK was parameters’ only published variability: as a poster the food [7]. Theon lag model time built and by bioavailability, the authors was the a age two- andcompartment body weight model on apparent with a first-order clearance rate (CL/ ofF) absorption and the (Kbodya) and weight a lag on time the for peripheral absorption volume(Tlag). of To distribution. our knowledge, These only studies the latterwere describesperformed the with covariates samples thatfrom partly either explaindrug reg- the istrationpalbociclib studies PK parameters’or studies intended variability: for a the special food purpose on lag time (renal and impairment, bioavailability, for theexample). age and Inbody these weight studies, on many apparent samples clearance were (CL/F)taken from and each the body patient weight and onthe the collection peripheral of clinical volume dataof distribution. was intensive These for the studies assessment were performed of covariates. with Based samples on a fromlimited either number drug of registration samples perstudies patient or and studies a less intended exhaustive for a number special purpose of covariates (renal in impairment, the real-life for settings example). of routine In these patientstudies, follow-up, many samples we wanted were to taken confirm from the each impact patient of the and different the collection covariates of clinical in such data a situation.was intensive for the assessment of covariates. Based on a limited number of samples per patient and a less exhaustive number of covariates in the real-life settings of routine patient 2.follow-up, Results we wanted to confirm the impact of the different covariates in such a situation. One hundred and fifty-one samples from 124 patients were available for model build- 2. Results ing. Two samples were taken for 27 patients, but these samples were taken during the same cycleOne hundredfor only two and patients. fifty-one For samples the ot fromher patients, 124 patients the weretwo samples available were for modeltaken dur- build- inging. different Two samples cycles. were Thus, taken no variability for 27 patients, between but these occasion sampless was were calculated, taken during and the samepa- cycle for only two patients. For the other patients, the two samples were taken during tients for whom the samples were taken at different cycles were considered as independ- different cycles. Thus, no variability between occasions was calculated, and the patients ent. The samples were taken between 1 and 21 days after the beginning of the cycle. for whom the samples were taken at different cycles were considered as independent. The Among those, 30 samples (19.9%) were taken during the first 8 days. The samples were samples were taken between 1 and 21 days after the beginning of the cycle. Among those, taken between 0.9 and 197.25 h after the previous palbociclib administration (Figure 1). 30 samples (19.9%) were taken during the first 8 days. The samples were taken between 0.9 The mean concentration was of 81.8 µg/L, while the concentrations ranged from 6 (the and 197.25 h after the previous palbociclib administration (Figure1). The mean concentra- LLOQ—lower limit of quantification) to 226 µg/L. No concentrations were below the tion was of 81.8 µg/L, while the concentrations ranged from 6 (the LLOQ—lower limit of LLOQ. The administered doses were 75 mg (n = 15), 100 mg (n = 33) and 125 mg (n = 101) quantification) to 226 µg/L. No concentrations were below the LLOQ. The administered per day. doses were 75 mg (n = 15), 100 mg (n = 33) and 125 mg (n = 101) per day. Figure 1. Distribution of palbociclib concentrations (n = 151) over time after administration. With the exception of two patients with two samples, only one sample was drawn per patient. The distribution of the palbociclib concentrations after the beginning of the cycle is displayed as a thumbnail on the graph.