Pharmacokinetic and Pharmacodynamic Analysis of Longitudinal Gd-Enhanced Lesion Count in Subjects with Relapsing Remitting Multiple Sclerosis Treated with Peginterferon beta-1a
Yaming Hang (1), Xiao Hu (1), Shifang Liu (1), Yue Cui (1), Serena Hung (1), Aaron Deykin (1) and Ivan Nestorov (1)
(1) Biogen Idec Inc, Boston, MA, USA
Objectives: To develop a pharmacokinetic (PK) and pharmacodynamic (PD) model to assess the effect of monthly exposure of peginterferon beta-1a (PEGIFN) on the reduction of Gd-Enhanced lesion count over time in patients with Relapsing Remitting Multiple Sclerosis (RRMS).
Methods: PK and Gd-Enhanced lesion count data were obtained from a double blind placebo-controlled Phase III study with RRMS patients (n=1512), where Placebo, PEGIFN 125 µg subcutaneous every 2 (Q2W) or 4 (Q4W) week dosing regimens were evaluated. A population PK model was developed based on both intensive and sparse samples of serum concentrations collected in this study. Poisson and Negative Binomial distributions were explored to describe the relationship between monthly cumulative area-under-concentration-time-curve (AUC) and Gd-Enhanced lesion count collected at Weeks 0, 24, 48 and 96. A variety of models were evaluated: Marginal model, Mixed Effect model with Single Population, Mixture models with two or three subpopulations. The effect of AUC on mean lesion count was described by a log-linear form. The Laplacian approximation method in NONMEM V7.2.0 [1,2] was used for parameter estimation.
Results: The disposition of PEGIFN was well described by a one-compartment linear model with a first-order absorption rate. A Two-population Mixture model with Negative Binomial distribution fits the exposure-response data well. Due to a significant proportion of subjects who had no Gd-Enhanced lesion detected at all visits, the subpopulation with less activity in Gd-Enhanced lesion is assumed to have a degenerative statistical distribution of mean baseline λ (estimate 0.546). The dispersion parameter for this group is 44.6. In the other subpopulation with more activity in Gd-Enhanced lesion, baseline λ is estimated to have a mean of 1.62 and 112% cv for inter-subject variation. The dispersion parameter for this group is estimated to be 0.452. Estimated probability for the low Gd-Enhanced lesion activity group is 59.3%. The estimated slope of AUC effect on log(λ) is -0.026. The latter suggests that at steady state, λ is approximately reduced by 64% and 87% from the baseline at the mean AUC value of the Q4W and Q2W groups (39.6 and 77.3 ng/mL*hr respectively).
Conclusions: The exposure-response model suggests that greater PEGIFN exposure in the Q2W group resulted in greater Gd-Enhanced lesion count reduction and explains the enhanced efficacy observed for the Q2W group, as compared to the Q4W group.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] Elodie L. Plan, Alan Maloney, Inaki F. Troconiz, Mats O. Karlsson, Performance in population models for count data, part I: maximum likelihood approximations, J. Pharmacokinet Pharmacodyn, 2009, 36:353-366
Study sponsored by: Biogen Idec Inc.