Denise Morris (1), Jill Fiedler-Kelly (1), Micha Levi (2) and Orit Cohen-Barak (3)
(1) Cognigen Corporation, a SimulationsPlus Company, Buffalo, New York, USA, (2) Teva Pharmaceuticals, Inc., Frazer, Pennsylvania, USA, (3) Teva Pharmaceuticals, Inc., Netanya, Israel
Objectives: Fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide, was found to be effective and well-tolerated as a preventive treatment for migraine in Phase 2 and 3 studies. Modeling and simulation were used to develop a population PK model in healthy subjects and patients with episodic or chronic migraine.
Methods: The population PK analysis, performed using NONMEM, included data after subcutaneous administration from 1 richly sampled Phase 1 study (TV48125‑PK‑10078 [225, 675, and 900 mg single dose]), 2 sparsely sampled Phase 2b studies (LBR‑101‑021 [675-225-225mg monthly or 900mg monthly for 3 doses]; LBR‑101‑022 [225 mg or 675 mg monthly for 3 doses]), and 3 sparsely sampled Phase 3 Studies (TV48125‑CNS‑30049 [675 mg followed by monthly doses of 225 mg for 3 doses or single 675 mg once quarterly]; TV48125‑CNS‑30050 [225 mg once monthly for 3 doses or single 675 mg once quarterly]; TV48125‑CNS‑30051 [225 mg monthly or 675 mg followed by 225 mg monthly or 675 mg once quarterly over 12 months]). The final PK model was validated using prediction-corrected VPC (pcVPC). PK simulations were performed, and calculated exposures were generated based on the final PK model and individual Bayesian estimates of PK parameters assuming a pre-determined set of dosing regimens: 225 mg once monthly for 12 doses; 675 mg loading followed by 225 mg once monthly for a total of 12 doses; 675 mg quarterly for 4 doses.
Results: A total of 8346 fremanezumab concentrations from 2287 individuals were used for the population PK modeling. A 1‑compartment model with first-order absorption and elimination adequately fit the pooled Phase 1/2b/3 data. Following covariate analysis, an effect of body weight on apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) was included in the model. Age, albumin levels, CrCL, sex, race, as well as acute and preventive medications were also tested as covariates and not found to be statistically significant predictors of variability in PK. Anti-drug antibodies (ADA), analgesic migraine specific medication, and liver function were not tested in the covariate analysis as too few patients were present in the population. All parameters were estimated well, with no high correlations between parameter estimates. Bayesian shrinkage was below 30% for CL/F and Vc/F. Eta shrinkage for ka was higher (52%), due to lack of information on the absorption phase in the sparsely sampled patients. For the Phase 1 data, the pcVPC showed a small degree of overprediction around the peak for the Phase 1 data with some underprediction during the post-absorptive phase of the profile. At almost all sampling time points for the Phase 2b/3 data, the pcVPC showed good concordance between observed and simulated data. Higher weight was associated with increased clearance and central volume of distribution resulting in a decrease of fremanezumab exposure. Simulated exposure measures were marginally higher (although overlapping) in female subjects compared to males; Asian subjects compared to other races; and subjects using acute migraine specific medication compared to those that were not. For age, patient status (healthy versus migraine), and preventive/analgesic migraine specific medications, simulated exposures were similar across comparable groups. Although median values for model-predicted exposures tended to be slightly lower in individuals who tested positive for ADA, the range of exposures for these individuals were fully contained within the range of exposures for individuals who tested negative for ADA. Based on simulated data, the estimated median half-life for fremanezumab is 31 days and steady state is expected to be achieved by approximately 168 days for monthly and quarterly doses. The use of 225 mg monthly with a starting dose of 675 mg resulted in faster achievement of plasma concentrations within the steady state range. The median accumulation ratio, based on once-monthly and once-quarterly dosing regimens, was approximately 2.34 and 1.20, respectively.
Conclusions: A 1‑compartment model with first-order absorption and elimination and body weight effect on CL/F and Vc/F adequately described the fremanezumab concentration-time data. Body weight was the only significant predictor of variability in PK with increases in body weight resulting in decreased fremanezumab exposure. The half-life and accumulation ratio support once monthly and once-quarterly dosing of fremanezumab.
Reference: PAGE 27 (2018) Abstr 8448 [www.page-meeting.org/?abstract=8448]
Poster: Drug/Disease Modelling - CNS