SAN ANTONIO, TX—Updating a population exposure-response (ER) model with data from a randomized, placebo-controlled, double-blind safety and efficacy study that employed fixed doses of asenapine confirmed findings from previous work based on data from flexible dosing, according to research presented at the U.S. Psychiatric & Mental Health Congress.
“Overall, these population exposure-response analyses support the efficacy of asenapine for the treatment of bipolar mania,” reported lead study author Rik de Greef, MSC, of Quantitative Services, Certara Strategic Consulting, in Princeton, NJ, and coauthors.
The antipsychotic asenapine is approved for acute treatment of schizophrenia and acute manic or mixed bipolar I episodes in adult patients, at a recommended dose of 5mg or 10mg twice daily.
Better characterization of dose-response associations for medications like asenapine is “crucial to help guide clinicians in dosing decisions,” the authors noted, but study designs and patient retention issues can complicate assessment of dose-response associations from individual clinical trials.
Population ER models can be developed using data from multiple clinical trials in order to better characterize concentration-efficacy relationships.
The authors took this approach to assess asenapine dosing effects in adults with bipolar disorder. First, they updated an existing pharmacokinetic (PK) model with data from a double-blind, placebo-controlled, fixed-dose Phase 3 clinical trial. The Phase 3 fixed-dose trial had involved fixed 5mg or 10mg twice-daily doses of asenapine, whereas two other Phase 3 trial data included in the model had involved flexible 5mg to 10mg twice-daily dose schedules.
“This model described asenapine PK as a two-compartment model with first-order absorption, a lag time on absorption, dose-dependent bioavailability, and a statistically significant but not clinically meaningful effect of age on clearance,” they noted.
The updated PK model included data from 15 studies in all, representing 1,363 patients, in which patients had received asenapine twice daily for up to 42 days at doses ranging from 0.2mg to 20mg.
Patients in the Phase 3 trials had been evaluated using the Young Mania Rating Scale (YMRS) to quantify changes in symptoms after treatment. These were analyzed using nonlinear modeling, and asenapine plasma concentrations were fitted to PK components to calculate individual exposure estimates.
A significant exposure-response relationship on YMRS response was noted. “No covariates impacted exposure level at clinically-meaningful levels,” they added. “There was no effect of disease state (schizophrenia or bipolar mania) on PK.”
The PK model’s outputs, and efficacy data from the three Phase 3 clinical trials of adults with bipolar disorder, were then used as inputs for the ER model.
“Predicted response at endpoint (Day 21) were similar to the observed responses for each treatment group, indicating that the ER model adequately describes observed asenapine data,” the coauthors reported.
The effect of asenapine was predicted to be “numerically higher at the 10mg dose compared with the 5mg dose, although the differences were not statistically significant,” they reported. “These findings are consistent with those observed in the fixed-dose study, which showed a numerically higher response on the YMRS with asenapine 10mg twice daily compared with 5mg twice daily.”
The findings with the updated model were “generally similar” to those obtained previously from the model, based only on flexible-dose studies, they noted. “Addition of a new fixed-dose study did not result in any appreciable differences.”
The study was funded by Merck and Co., Inc.