Pharmacodynamics

Although the exact mechanism of SYMBYAX is unknown, it has been proposed that the activation of 3 monoaminergic neural systems (serotonin, norepinephrine, and dopamine) is responsible for its enhanced antidepressant effect. This is supported by animal studies in which the olanzapine/fluoxetine combination has been shown to produce synergistic increases in norepinephrine and dopamine release in the prefrontal cortex compared with either component alone, as well as increases in serotonin.

Olanzapine is a psychotropic agent with high affinity binding to the following receptors: serotonin 5HT_2A/2C, 5HT₆, (K_i=4, 11, and 5 nM, respectively), dopamine D_1-4 (K_i=11 to 31 nM), histamine H₁ (K_i=7 nM), and adrenergic α₁ receptors (K_i=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT₃ (K_i=57 nM) and muscarinic M_1-5 (K_i=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABAA, BZD, and β -adrenergic receptors (K_i > 10 μ M). Fluoxetine is an inhibitor of the serotonin transporter and is a weak inhibitor of the norepinephrine and dopamine transporters.

Antagonism at receptors other than dopamine and 5HT₂ may explain some of the other therapeutic and side effects of olanzapine. Olanzapine's antagonism of muscarinic M_1-5 receptors may explain its anticholinergic-like effects. The antagonism of histamine H₁ receptors by olanzapine may explain the somnolence observed with this drug. The antagonism of α₁-adrenergic receptors by olanzapine may explain the orthostatic hypotension observed with this drug. Fluoxetine has relatively low affinity for muscarinic, α₁-adrenergic, and histamine H₁ receptors.

Pharmacokinetics

Fluoxetine (administered as a 60-mg single dose or 60 mg daily for 8 days) caused a small increase in the mean maximum concentration of olanzapine (16%) following a 5-mg dose, an increase in the mean area under the curve (17%) and a small decrease in mean apparent clearance of olanzapine (16%). In another study, a similar decrease in apparent clearance of olanzapine of 14% was observed following olanzapine doses of 6 or 12 mg with concomitant fluoxetine doses of 25 mg or more. The decrease in clearance reflects an increase in bioavailability. The terminal half-life is not affected, and therefore the time to reach steady state should not be altered. The overall steady-state plasma concentrations of olanzapine and fluoxetine when given as the combination in the therapeutic dose ranges were comparable with those typically attained with each of the monotherapies. The small change in olanzapine clearance, observed in both studies, likely reflects the inhibition of a minor metabolic pathway for olanzapine via CYP2D6 by fluoxetine, a potent CYP2D6 inhibitor, and was not deemed clinically significant. Therefore, the pharmacokinetics of the individual components is expected to reasonably characterize the overall pharmacokinetics of the combination.

Absorption and Bioavailability

SYMBYAX — Following a single oral 12-mg/50-mg dose of SYMBYAX, peak plasma concentrations of olanzapine and fluoxetine occur at approximately 4 and 6 hours, respectively. The effect of food on the absorption and bioavailability of SYMBYAX has not been evaluated. The bioavailability of olanzapine given as Zyprexa, and the bioavailability of fluoxetine given as Prozac were not affected by food. It is unlikely that there would be a significant food effect on the bioavailability of SYMBYAX.

Olanzapine — Olanzapine is well absorbed and reaches peak concentration approximately 6 hours following an oral dose. Food does not affect the rate or extent of olanzapine absorption when olanzapine is given as Zyprexa. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation.

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