Population Pharmacokinetics of Capivasertib in Patients with Advanced or Metastatic Solid Tumours
Background and Objective Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic a...
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| Published in | Clinical pharmacokinetics Vol. 63; no. 8; pp. 1191 - 1204 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Cham
Springer International Publishing
01.08.2024
Springer Nature B.V |
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| Online Access | Get full text |
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| Abstract | Background and Objective
Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib.
Methods
Pharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80–800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2 days on, 5 days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariates assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A) inducers, CYP3A inhibitors and acid-reducing agents.
Results
A total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance (
CL/F
) presented a moderate time-dependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial
CL/F
was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours,
CL/F
decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration–time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80–480 mg after multiple doses but more than proportional beyond 480 mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib
CL/F
, with a 12% reduction in
CL/F
at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference).
Conclusions
Capivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors. |
|---|---|
| AbstractList | Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib.BACKGROUND AND OBJECTIVEOveractivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib.Pharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80-800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2 days on, 5 days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariates assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A) inducers, CYP3A inhibitors and acid-reducing agents.METHODSPharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80-800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2 days on, 5 days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariates assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A) inducers, CYP3A inhibitors and acid-reducing agents.A total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance (CL/F) presented a moderate time-dependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial CL/F was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours, CL/F decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration-time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80-480 mg after multiple doses but more than proportional beyond 480 mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib CL/F, with a 12% reduction in CL/F at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference).RESULTSA total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance (CL/F) presented a moderate time-dependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial CL/F was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours, CL/F decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration-time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80-480 mg after multiple doses but more than proportional beyond 480 mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib CL/F, with a 12% reduction in CL/F at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference).Capivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors.CONCLUSIONSCapivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors. Background and Objective Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib.Methods Pharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80-800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2 days on, 5 days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariatcs assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A) inducers, CYP3A inhibitors and acid-reducing agents.Results A total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance (CL/F) presented a moderate timedependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial CL/F was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours, CL/F decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration-time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80-480 mg after multiple doses but more than proportional beyond 480 mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib CL/F, with a 12% reduction in CL/F at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference).Conclusions Capivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors. Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib. Pharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80-800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2 days on, 5 days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariates assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A) inducers, CYP3A inhibitors and acid-reducing agents. A total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance (CL/F) presented a moderate time-dependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial CL/F was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours, CL/F decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration-time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80-480 mg after multiple doses but more than proportional beyond 480 mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib CL/F, with a 12% reduction in CL/F at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference). Capivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors. Background and Objective Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib. Methods Pharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80–800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2 days on, 5 days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariates assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A) inducers, CYP3A inhibitors and acid-reducing agents. Results A total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance ( CL/F ) presented a moderate time-dependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial CL/F was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours, CL/F decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration–time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80–480 mg after multiple doses but more than proportional beyond 480 mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib CL/F , with a 12% reduction in CL/F at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference). Conclusions Capivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors. |
| Author | Barry, Simon T. Zhou, Diansong Eberlein, Cath Fernandez-Teruel, Carlos Cullberg, Marie |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/39127854$$D View this record in MEDLINE/PubMed |
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| PublicationTitleAlternate | Clin Pharmacokinet |
| PublicationYear | 2024 |
| Publisher | Springer International Publishing Springer Nature B.V |
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| References | Lindsley (CR1) 2010; 10 CR4 Davies, Greenwood, Dudley, Crafter, Yu, Zhang (CR2) 2012; 11 CR6 Miller, Sommavilla, O'Bryant, Barve, Dowlati, Luke (CR19) 2024 CR5 CR8 Dean, Banerji, Schellens, Krebs, Jimenez, van Brummelen (CR12) 2018; 81 CR7 Crabb, Birtle, Martin, Downs, Ratcliffe, Maishman (CR13) 2017; 35 Jones, Casbard, Carucci, Cox, Butler, Alchami (CR14) 2020; 21 CR17 Turner, Oliveira, Howell, Dalenc, Cortes, Gomez Moreno (CR3) 2023; 388 CR21 Tamura, Hashimoto, Tanabe, Kodaira, Yonemori, Seto (CR10) 2016; 77 Miller, Sommavilla, Murphy, Morris, Khatun, Cullberg (CR16) 2023; 89 Miller, Sommavilla, Barry, Eberlein, Morris, Wadsworth (CR18) 2023; 12 Turner, Alarcon, Armstrong, Philco, Lopez Chuken, Sablin (CR11) 2019; 30 Gidal, Clark, Anders, Gilliam (CR22) 2017; 129 Banerji, Dean, Pérez-Fidalgo, Batist, Bedard, You (CR9) 2018; 24 Lindbom, Pihlgren, Jonsson (CR20) 2005; 79 Shore, Mellado, Shah, Hauke, Costin, Adra (CR15) 2023; 21 E Dean (1407_CR12) 2018; 81 BR Davies (1407_CR2) 2012; 11 C Miller (1407_CR18) 2023; 12 C Miller (1407_CR19) 2024 1407_CR5 1407_CR4 1407_CR7 CW Lindsley (1407_CR1) 2010; 10 1407_CR6 1407_CR8 NC Turner (1407_CR3) 2023; 388 BE Gidal (1407_CR22) 2017; 129 RH Jones (1407_CR14) 2020; 21 1407_CR21 K Tamura (1407_CR10) 2016; 77 C Miller (1407_CR16) 2023; 89 NC Turner (1407_CR11) 2019; 30 L Lindbom (1407_CR20) 2005; 79 U Banerji (1407_CR9) 2018; 24 SJ Crabb (1407_CR13) 2017; 35 1407_CR17 N Shore (1407_CR15) 2023; 21 |
| References_xml | – ident: CR21 – volume: 24 start-page: 2050 issue: 9 year: 2018 end-page: 2059 ident: CR9 article-title: A phase I open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in -mutated breast and gynecologic cancers publication-title: Clin Cancer Res doi: 10.1158/1078-0432.Ccr-17-2260 – volume: 388 start-page: 2058 issue: 22 year: 2023 end-page: 2070 ident: CR3 article-title: Capivasertib in hormone receptor-positive advanced breast cancer publication-title: N Engl J Med doi: 10.1056/NEJMoa2214131 – volume: 79 start-page: 241 issue: 3 year: 2005 end-page: 257 ident: CR20 article-title: PsN-Toolkit—a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM publication-title: Comput Methods Programs Biomed doi: 10.1016/j.cmpb.2005.04.005 – ident: CR4 – year: 2024 ident: CR19 article-title: Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors publication-title: Cancer Chemother Pharmacol doi: 10.1007/s00280-024-04667-3 – ident: CR17 – volume: 10 start-page: 458 issue: 4 year: 2010 end-page: 477 ident: CR1 article-title: The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation: a 2009 update publication-title: Curr Top Med Chem doi: 10.2174/156802610790980602 – volume: 129 start-page: 26 year: 2017 end-page: 32 ident: CR22 article-title: The application of half-life in clinical decision making: Comparison of the pharmacokinetics of extended-release topiramate (USL255) and immediate-release topiramate publication-title: Epilepsy Res doi: 10.1016/j.eplepsyres.2016.10.020 – volume: 21 start-page: 345 issue: 3 year: 2020 end-page: 357 ident: CR14 article-title: Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial publication-title: Lancet Oncol doi: 10.1016/s1470-2045(19)30817-4 – volume: 35 start-page: 599 issue: 5 year: 2017 end-page: 607 ident: CR13 article-title: ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer publication-title: Invest New Drugs doi: 10.1007/s10637-017-0433-4 – volume: 89 start-page: 3330 issue: 11 year: 2023 end-page: 3339 ident: CR16 article-title: The effect of food and acid-reducing agents on the pharmacokinetic profile of capivasertib: results from a randomised, cross-over study publication-title: Br J Clin Pharmacol doi: 10.1111/bcp.15831 – ident: CR6 – volume: 77 start-page: 787 issue: 4 year: 2016 end-page: 795 ident: CR10 article-title: Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors publication-title: Cancer Chemother Pharmacol doi: 10.1007/s00280-016-2987-9 – 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publication-title: Clin Genitourin Cancer doi: 10.1016/j.clgc.2022.11.017 – volume: 30 start-page: 774 issue: 5 year: 2019 end-page: 780 ident: CR11 article-title: BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population publication-title: Ann Oncol doi: 10.1093/annonc/mdz086 – volume: 12 start-page: 856-62 issue: 9 year: 2023 ident: CR18 article-title: Pharmacokinetics of the Akt serine/threonine protein kinase inhibitor, capivasertib, administered to healthy volunteers in the presence and absence of the CYP3A4 inhibitor itraconazole publication-title: Clin Pharmacol Drug Dev. doi: 10.1002/cpdd.1307 – volume: 12 start-page: 856-62 issue: 9 year: 2023 ident: 1407_CR18 publication-title: Clin Pharmacol Drug Dev. doi: 10.1002/cpdd.1307 – ident: 1407_CR5 doi: 10.1016/j.esmoop.2023.101395 – volume: 24 start-page: 2050 issue: 9 year: 2018 ident: 1407_CR9 publication-title: Clin Cancer Res doi: 10.1158/1078-0432.Ccr-17-2260 – ident: 1407_CR6 doi: 10.1200/JCO.2020.38.15_suppl.TPS1109 – volume: 11 start-page: 873 issue: 4 year: 2012 ident: 1407_CR2 publication-title: Mol Cancer Ther doi: 10.1158/1535-7163.MCT-11-0824-T – volume: 81 start-page: 873 issue: 5 year: 2018 ident: 1407_CR12 publication-title: Cancer Chemother Pharmacol doi: 10.1007/s00280-018-3558-z – volume: 10 start-page: 458 issue: 4 year: 2010 ident: 1407_CR1 publication-title: Curr Top Med Chem doi: 10.2174/156802610790980602 – volume: 21 start-page: 278 issue: 2 year: 2023 ident: 1407_CR15 publication-title: Clin Genitourin Cancer doi: 10.1016/j.clgc.2022.11.017 – volume: 129 start-page: 26 year: 2017 ident: 1407_CR22 publication-title: Epilepsy Res doi: 10.1016/j.eplepsyres.2016.10.020 – ident: 1407_CR4 – ident: 1407_CR17 doi: 10.1124/dmd.124.001636 – volume: 21 start-page: 345 issue: 3 year: 2020 ident: 1407_CR14 publication-title: Lancet Oncol doi: 10.1016/s1470-2045(19)30817-4 – year: 2024 ident: 1407_CR19 publication-title: Cancer Chemother Pharmacol doi: 10.1007/s00280-024-04667-3 – volume: 89 start-page: 3330 issue: 11 year: 2023 ident: 1407_CR16 publication-title: Br J Clin Pharmacol doi: 10.1111/bcp.15831 – ident: 1407_CR7 doi: 10.1200/JCO.2023.41.6_suppl.TPS287 – ident: 1407_CR8 doi: 10.1200/JCO.2021.39.6_suppl.TPS178 – volume: 30 start-page: 774 issue: 5 year: 2019 ident: 1407_CR11 publication-title: Ann Oncol doi: 10.1093/annonc/mdz086 – volume: 79 start-page: 241 issue: 3 year: 2005 ident: 1407_CR20 publication-title: Comput Methods Programs Biomed doi: 10.1016/j.cmpb.2005.04.005 – ident: 1407_CR21 – volume: 35 start-page: 599 issue: 5 year: 2017 ident: 1407_CR13 publication-title: Invest New Drugs doi: 10.1007/s10637-017-0433-4 – volume: 388 start-page: 2058 issue: 22 year: 2023 ident: 1407_CR3 publication-title: N Engl J Med doi: 10.1056/NEJMoa2214131 – volume: 77 start-page: 787 issue: 4 year: 2016 ident: 1407_CR10 publication-title: Cancer Chemother Pharmacol doi: 10.1007/s00280-016-2987-9 |
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| Snippet | Background and Objective
Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The... Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were... Background and Objective Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The... |
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| SubjectTerms | Administration, Oral Adult Aged Aged, 80 and over Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics Breast cancer Cancer therapies Creatinine Cyclin-dependent kinases Dose-Response Relationship, Drug Female Food Fulvestrant - administration & dosage Fulvestrant - pharmacokinetics Humans Internal Medicine Kinases Male Medicine Medicine & Public Health Metabolism Metastasis Middle Aged Models, Biological Neoplasms - drug therapy Neoplasms - metabolism Original Original Research Article Paclitaxel - administration & dosage Paclitaxel - pharmacokinetics Pharmacokinetics Pharmacology/Toxicology Pharmacotherapy Plasma Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - pharmacokinetics Pyrimidines - administration & dosage Pyrimidines - pharmacokinetics Pyrroles - administration & dosage Pyrroles - pharmacokinetics Regulatory approval Schedules Tumors |
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| Title | Population Pharmacokinetics of Capivasertib in Patients with Advanced or Metastatic Solid Tumours |
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