M Macpherson (1), A Viberg (1, 2), R Riley (1)
(1) AstraZeneca, UK, (2) qPharmetra, Stockholm, Sweden
Introduction: Two doses of drug x were explored in initial phase IIa trials in over 300 patients. The lower dose was judge to be the minimally efficacious dose based on preclinical data and the other dose was chosen to represent maximum anticipated well tolerated dose. A consequence of target inhibition with drug x, was an increase in serum levels of a biomarker and this biomarker was used as a surrogate for receptor occupancy. A review of internal and external data suggested that this compound/target could be repositioned into another therapy area and, in order to robustly test the hypothesis, the dose required for a clinically relevant response was targeted to achieve ≥ 90% receptor occupancy in 80% of patients.
Objectives: Develop a PKPD model from the patients in these trials and investigate the dose required for 90% receptor occupancy in 80% of patients in a new patient population.
Methods: A two-step sequential population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed using NONMEM 7.2.0. A two-compartment population PK model was fitted to the PK data and subsequently an inhibitory Emax pharmacodynamic model was fitted to the biomarker data accounting for the relationship between drug concentration and effect. Various simulations of the final sequential PK-PD model were performed.
Results: Based on simulations of the final model, it is unlikely that 90% receptor occupancy will be achieved in 80% of patients at the highest investigated dose. A doubling of exposure would be required to approach this target value. In the populations under consideration, this could be achieved through a reduction in CL/F or an increase in dose. It is also likely that variability in exposure may increase in the new target population as a consequence of reduced hepatic and renal function and an indication of this effect was demonstrated.
Conclusions: This analysis demonstrates a range of possible receptor occupancies and the impact patient specific variables may have on this assessment. Given the higher doses required and the additional potential DMPK and safety risks in the target patient population at these doses, an informed decision was made to suspend the project.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2012. Icon Development Solutions, Ellicott City, Maryland, USA
Reference: PAGE 22 () Abstr 2858 [www.page-meeting.org/?abstract=2858]
Poster: Other Modelling Applications