AIMS: To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters. METHODS: PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK. Individual exposure values were used to investigate the relationship with response evaluation criteria in solid tumours (RECIST 1.1) efficacy parameters and key safety parameters (rash, diarrhoea, QTcF). RESULTS: A popPK model that adequately described osimertinib and its metabolite AZ5104 in a joint manner was developed. Body weight, serum albumin and ethnicity were identified as significant covariates on PK in the analysis, but were not found to have a clinically relevant impact on osimertinib exposure. No relationship was identified between exposure and efficacy over the dose range studied. A linear relationship was observed between exposure and the occurrence of rash or diarrhoea, and between concentration and QTcF, with a predicted mean (upper 90% confidence interval) increase of 14.2 (15.8) ms at the maximum concentration for an 80 mg once-daily dose at steady state. CONCLUSIONS: PopPK and exposure-response models were developed for osimertinib and AZ5104. There was no relationship between exposure and efficacy but a linear relationship between exposure and safety endpoints (rash, diarrhoea and QTcF) was observed.
AIMS: To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters. METHODS: PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK. Individual exposure values were used to investigate the relationship with response evaluation criteria in solid tumours (RECIST 1.1) efficacy parameters and key safety parameters (rash, diarrhoea, QTcF). RESULTS: A popPK model that adequately described osimertinib and its metabolite AZ5104 in a joint manner was developed. Body weight, serum albumin and ethnicity were identified as significant covariates on PK in the analysis, but were not found to have a clinically relevant impact on osimertinib exposure. No relationship was identified between exposure and efficacy over the dose range studied. A linear relationship was observed between exposure and the occurrence of rash or diarrhoea, and between concentration and QTcF, with a predicted mean (upper 90% confidence interval) increase of 14.2 (15.8) ms at the maximum concentration for an 80 mg once-daily dose at steady state. CONCLUSIONS: PopPK and exposure-response models were developed for osimertinib and AZ5104. There was no relationship between exposure and efficacy but a linear relationship between exposure and safety endpoints (rash, diarrhoea and QTcF) was observed.
Authors: Stephen Ph Alexander; Doriano Fabbro; Eamonn Kelly; Neil Marrion; John A Peters; Helen E Benson; Elena Faccenda; Adam J Pawson; Joanna L Sharman; Christopher Southan; Jamie A Davies Journal: Br J Pharmacol Date: 2015-12 Impact factor: 8.739
Authors: D E Coutant; P Kulanthaivel; P K Turner; R L Bell; J Baldwin; S R Wijayawardana; C Pitou; S D Hall Journal: Clin Pharmacol Ther Date: 2015-05-19 Impact factor: 6.875
Authors: David Planchard; Kathryn H Brown; Dong-Wan Kim; Sang-We Kim; Yuichiro Ohe; Enriqueta Felip; Philip Leese; Mireille Cantarini; Karthick Vishwanathan; Pasi A Jänne; Malcolm Ranson; Paul A Dickinson Journal: Cancer Chemother Pharmacol Date: 2016-02-22 Impact factor: 3.333
Authors: Pasi A Jänne; James Chih-Hsin Yang; Dong-Wan Kim; David Planchard; Yuichiro Ohe; Suresh S Ramalingam; Myung-Ju Ahn; Sang-We Kim; Wu-Chou Su; Leora Horn; Daniel Haggstrom; Enriqueta Felip; Joo-Hang Kim; Paul Frewer; Mireille Cantarini; Kathryn H Brown; Paul A Dickinson; Serban Ghiorghiu; Malcolm Ranson Journal: N Engl J Med Date: 2015-04-30 Impact factor: 91.245
Authors: Christopher Southan; Joanna L Sharman; Helen E Benson; Elena Faccenda; Adam J Pawson; Stephen P H Alexander; O Peter Buneman; Anthony P Davenport; John C McGrath; John A Peters; Michael Spedding; William A Catterall; Doriano Fabbro; Jamie A Davies Journal: Nucleic Acids Res Date: 2015-10-12 Impact factor: 16.971
Authors: Paul A Dickinson; Mireille V Cantarini; Jo Collier; Paul Frewer; Scott Martin; Kathryn Pickup; Peter Ballard Journal: Drug Metab Dispos Date: 2016-05-25 Impact factor: 3.922
Authors: Darren A E Cross; Susan E Ashton; Serban Ghiorghiu; Cath Eberlein; Caroline A Nebhan; Paula J Spitzler; Jonathon P Orme; M Raymond V Finlay; Richard A Ward; Martine J Mellor; Gareth Hughes; Amar Rahi; Vivien N Jacobs; Monica Red Brewer; Eiki Ichihara; Jing Sun; Hailing Jin; Peter Ballard; Katherine Al-Kadhimi; Rachel Rowlinson; Teresa Klinowska; Graham H P Richmond; Mireille Cantarini; Dong-Wan Kim; Malcolm R Ranson; William Pao Journal: Cancer Discov Date: 2014-06-03 Impact factor: 39.397
Authors: Stefanie L Groenland; Ron H J Mathijssen; Jos H Beijnen; Alwin D R Huitema; Neeltje Steeghs Journal: Eur J Clin Pharmacol Date: 2019-06-07 Impact factor: 2.953
Authors: René J Boosman; Jacobus A Burgers; Egbert F Smit; Neeltje Steeghs; Anthonie J van der Wekken; Jos H Beijnen; Alwin D R Huitema; Rob Ter Heine Journal: Drugs Date: 2021-12-11 Impact factor: 9.546
Authors: Karthick Vishwanathan; Paul A Dickinson; Karen So; Karen Thomas; Yuh-Min Chen; Javier De Castro Carpeño; Anne-Marie C Dingemans; Hye Ryun Kim; Joo-Hang Kim; Matthew G Krebs; James Chih-Hsin Yang; Khanh Bui; Doris Weilert; R Donald Harvey Journal: Br J Clin Pharmacol Date: 2018-03-23 Impact factor: 4.335