Objectives: To characterize dose-response effects for lurasidone and to simulate lurasidone responses at Week 6 in patients with bipolar depression.
Methods: The exposure-efficacy response analyses were derived from two 6-week, double-blind, placebo-controlled, flexible-dose studies of lurasidone in patients with bipolar I depression (20-60 mg/d or 80-120 mg/d in a monotherapy study; 20-120 mg/d in an adjunctive therapy study with lithium or valproate; combined N=825). Data from the primary efficacy measure, the Montgomery-Asberg Depression Rating Scale (MADRS), were fitted with nonlinear mixed effects modeling methodology implemented using NONMEM software. The exposure-efficacy response model characterized the time course of the placebo effect. Effect of background medications and effect of lurasidone were added to the time course of the placebo effect. The exposure-efficacy response model was then used to predict exposure-response results from a simulated fixed-dose, placebo-controlled study design.
Results: MADRS vs time profiles for lurasidone and placebo were adequately described using a linear dose-response relationship, built on an exponential asymptotic placebo model. A net improvement in MADRS due to lurasidone treatment (drug effect) was significant (P<0.001) and a positive dose-response was detected. Age and use of concomitant medication had statistically significant covariate effects on placebo change. Overall, the dose-dependent effect of lurasidone indicates that higher doses are likely to produce greater improvement for both monotherapy and adjunctive therapy.
Conclusions: The effect of lurasidone was described using a linear dose-response model for drug effect, with increased treatment response in patients with bipolar depression observed at higher doses of lurasidone.