Population Pharmacokinetics of Capivasertib, a Potent Selective AKT Inhibitor, in Patients with Solid Tumours
Carlos Fernandez,1 Marie Cullberg,2 S. Y. Amy Cheung,1 Philip Delff,3 and Helen Tomkinson1
1Clinical Pharmacology and Quantitative Pharmacology, BioPharmaceuticals R&D, AstraZeneca R&D, Cambridge, UK. 2Clinical Pharmacology and Quantitative Pharmacology, BioPharmaceuticals R&D, AstraZeneca R&D, Gothenburg, Sweden. 3Clinical Pharmacology and Quantitative Pharmacology, BioPharmaceuticals R&D, AstraZeneca R&D, Boston, MA, USA
Introduction/Objectives: The PI3K/AKT/PTEN signalling pathway has crucial roles in cell growth and survival and is associated with various cancers. Capivasertib is a potent selective inhibitor of all three isoforms of the AKT serine/threonine kinase (AKT1, -2 and -3) [1]. Capivasertib is currently in Phase III development for breast cancer (NCT03997123, NCT04305496 and NCT04862663) and prostate cancer (NCT04493853) with exploratory investigations for a range of other therapeutic indications. The objectives of this analysis were to obtain estimates of population pharmacokinetics (PK) parameters for capivasertib and to quantify between-subject variability (BSV). We also quantitatively assessed the impact of several intrinsic and extrinsic factors on the PK of capivasertib.
Methods: Data from four Phase I and II clinical studies (NCT01226316 [2], NCT01625286 [3], NCT01353781 [4] and NCT01895946 [5]) were combined to generate a dataset for population analysis (363 patients, 3623 observations). Capivasertib was administered orally at a dose of 80 to 800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel, respectively, using continuous dosing or one of two intermittent dosing schedules (with either 4 days on, 3 days off, or 2 days on, 5 days off). Plasma concentrations of capivasertib were fitted by NONMEM v7.3.0 [6] using log-transformed data with a combined proportional and additive residual error. Several models and approaches (e.g., first-order, zero-order, double absorption pathways, and transit compartments) were tested for their ability to describe capivasertib absorption and oral clearance (CL/F). The analysis also evaluated the effect of time, capivasertib dose, formulation (tablet versus capsule), concurrent paclitaxel therapy, administration of acid reducing agents, food (fasted, fed and semi-fasted states) and patient smoking behaviour, as well as the following intrinsic factors: patient ethnicity, age, sex, body weight, and the presence of hepatic or renal impairment.
Results: The PK of capivasertib was adequately described by a three-compartment model with two simultaneous first-order and zero-order absorption mechanisms with lag time, and with auto-inhibition of CL/F managed by a sigmoid Emax process. Mild dose-dependent auto-inhibition of capivasertib metabolism was observed, including that the initial CL/F was 65 L/h (with 41% BSV), but decreased by 20% at ~120 h upon repeated 400mg dosing. The majority of other extrinsic and intrinsic factors had minimal impact on the PK of capivasertib, which was not significantly affected by formulation, concurrent paclitaxel therapy, patient smoking behaviour, ethnicity, age, sex, mild to moderate hepatic impairment or mild to moderate renal impairment. However, the geometric mean ratio (GMR) CL/F was 0.85 (95% confidence interval (CI) 0.79, 0.91) and 1.20 (1.11, 1.31) in patients weighing 47 kg and 100 kg, respectively, compared with the typical patient of 67 kg. There was no effect of food on the area under the concentration-time curve (AUC) or peak plasma concentration (Cmax), however capivasertib absorption was delayed by 0.4 h and 1.4 h in the semi-fasted and fed states, respectively, compared to the fasted state. Additionally, while acid reducing agents did not modify the AUC, they delayed capivasertib absorption by 0.5 h and decreased the GMR Cmax by 0.85 (95% CI 0.79, 0.92).
Conclusions: This analysis of data from Phase I and Phase II studies found that capivasertib PK was adequately described by a three-compartment model with moderate variability and no major covariate effects. The need for dose adjustment based on extrinsic and intrinsic factors will be further evaluated in dedicated drug-drug interaction studies and ongoing Phase III clinical trials.
Acknowledgements: This study was funded by AstraZeneca. S. Y. Amy Cheung is currently employed by Certara, Princeton, NJ, USA. Philip Delff is currently employed by Vertex Pharmaceuticals, Boston, MA, USA. Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). We thank Rose Goodchild, PhD, of Oxford PharmaGenesis, Oxford, UK, for editing assistance.
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