Rik Schoemaker (1), Armel Stockis (2)
(1) SGS Exprimo, (2) UCB Pharma
Objectives: To determine the population PK/PD relationship between brivaracetam (BRV) concentration and daily seizure counts in three Phase III studies in the adjunctive treatment of partial onset seizures.
Methodology: A population PK/PD model describing the effect of BRV on daily seizure counts was developed where seizure frequencies were described using a negative binomial distribution taking previous-day seizure frequencies into account [1], and using a mixture model to separate a placebo-like and a responder sub-population. Daily seizure count sequences with dependence on preceding-day seizures were simulated using NONMEM. A covariate analysis was performed to investigate factors influencing the effect of BRV on daily seizure counts.
Results: The population exposure-response model provided an excellent description of the data, where visual predictive checks (VPCs) for median % change in daily seizure frequency from baseline and proportion of subjects with ≥50% reduction in daily seizure frequency from baseline indicated that the model was perfectly capable of simulating the observed outcomes.
Covariate analysis indicated that levetiracetam (LEV) co-administration reduced the fraction of subjects in the mixture-model responder population to close to zero. Covariate analysis also indicated that subjects with high baseline seizure rates had a much lower probability of ending up in the mixture-model responder population. In the absence of LEV co‑medication, the probabilities for ending up in the mixture-model responder population were estimated to be 54.8% at 4 seizures/month, 29.3% at the median baseline seizure frequency (0.32 seizures/day), and 0.8% at 6 seizures/day. No further significant covariates influencing BRV effectiveness were detected.
The concentration at half the maximum response (EC50) in the mixture-model responder population was estimated to be 0.57 mg/L in the final model corresponding to the exposures obtained after BRV doses of 50 to 100 mg/day.
Conclusions: A population PK/PD model was developed allowing the mathematical description of the relationship between BRV exposure and its effect on daily seizure counts. Only LEV co-administration and baseline seizure frequency were shown to significantly influence the response to BRV treatment.
References:
[1] Ahn JE, Plan EL, Karlsson MO and Miller R. Modeling Longitudinal Daily Seizure Frequency Data From Pregabalin Add-On Treatment. J Clin Pharmacol 2012 52: 880-892.c
Reference: PAGE 24 (2015) Abstr 3559 [www.page-meeting.org/?abstract=3559]
Poster: Drug/Disease modeling - CNS