Application of PK/PD modelling in the development eletriptan DR for the treatment of acute migraine and prevention of headache recurrence.
Marshall, Scott1, Mike K Smith1, Eugene Cox2,3 and Jaap Mandema2,4
1)Pfizer Global Research and Development, UK , 2)Pharsight Corporation, USA 3) J&J Pharmaceutical R & D, Belgium (Current) 4) Quantitative Solutions, USA (Current)
Introduction: Eletriptan (Relpaxâ) is a potent, selective, 5-HT1B\1D receptor agonist which is approved as an immediate release (IR) formulation for the acute treatment of migraine with or without aura. Headache recurrence within the first 24 hours of treatment was found to be 21-23% after treatment with 40-80mg of eletriptan IR and is a clinically important issue for all migraine treatments 1, occurring in 25 to 78% of subjects treated with other 5HT1 agonists 2-5.
Objective: To develop an integrated PK/PD model to describe the relationship between plasma concentration and both pain relief and headache recurrence in patients with acute migraine with the aim of providing: a) A target profile to guide the development of a dual release (DR) formulation for the treatment of acute migraine and prevention of headache recurrence. b) Dose response predictions to guide the selection of the optimal IR and MR dose combination for achieving and maintaining headache relief.
Methods: PK models for each of the eletriptan formulations were established using data from healthy volunteer studies. A PK/PD model was developed by simultaneously estimating the joint likelihood of pain relief and headache recurrence across ~5000 subjects receiving placebo, 20, 40 and 80mg of eletriptan IR. The probability of pain relief was described by a logistic model, which included a placebo effect across time, a baseline effect, a study effect and a drug effect (related to effect site concentration). The probability of recurrence at a given time was modelled using a survival model, where the log of the hazard was a function of the probability of pain relief. Separate parameters for the hazard model were estimated for a general migraine and a frequent recurrer patient population. The later were from a POC study (n= 473) where subjects received a second dose 5 hours after the initial dose and provide recurrence data out to 48 hours after dose. The joint model allowed prediction of the dose response for endpoints (i.e. sustained relief) which could be used to integrate the effects of the IR and MR components of the DR formulation.
Results: Simulations from the developed model were used in conjunction with PK data from probe DR formulations to optimise the release properties of the MR component of the DR formulation. Dose response relationship for headache recurrence and sustained relief to 48 hours in a general migraine population were generated. On the basis of these simulations it is expected that the optimal 40mg/40mg DR formulation will provide a relative reduction in headache recurrence of ~40% in comparison 40mg IR and an increase in sustained response to 48 hours from 30 to 42%.
Conclusion: The PK-PD model established using the phase III database for the IR formulation has been used to guide the development and subsequent dose selection for DR formulation being developed for the treatment of acute migraine and prevention of headache recurrence.
References
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