Roberto Gomeni, Carla D’Angeli and Alan Bye
GlaxoSmithKline, Via Fleming 2, 37135 Verona (Italy)
Preclinical studies have been conducted on a new compound explored in neurological and psychiatric disorders including pain. A PK/PD model was derived in rodent and validated by comparing the model predicted response to the one observed in a PET experiment conducted in rhesus monkey. Information gathered from drugs acting with a similar mechanism of action suggests that the likely therapeutic effect in man is expected when the brain receptor occupancy (RO) is maintained over 90% during 24 hours in a chronic treatment of a few weeks. Trial Simulation was used to estimate the likely Minimal Effective Dose (MED) in man using PET brain receptor occupancy as a surrogate marker of clinical efficacy. MED was jointly defined by the dose suitable to attain a given therapeutic target (RO > 90%) and by the probability of achieving this target (Prob > 70%). A model, incorporating potential variability and uncertainty on scaled human PK and PD together with receptor affinity adjustment derived from In-Vitro binding studies, was developed at this purpose. MED was estimated by trial simulation using a 7 doses (1, 10, 20, 30, 40, 50, and 60 mg) escalating design. Each subject initially received the first dose and after 7 days of treatment the estimated RO was evaluated: if the RO was < 90% the dose was escalated otherwise the same dose was used. This process was repeated during 7 weeks. At the end of the treatment period the final dose was recorded. If the final RO was < 90% the subject was considered as right censored. The probability of achieving the expected effect at a given dose was estimated using a dose-to-event modelling approach. The models accounted for the influence of PK and PD parameter variability together with the incidence of different rate of non-responders. Multiple simulation scenarios were run and the results were compared across scenarios to assess the impact of potency and variability assumptions.
Reference: PAGE 10 (2001) Abstr 170 [www.page-meeting.org/?abstract=170]
Poster: poster