A double-blind, randomized trial to evaluate the pharmacokinetics and tolerability of 30 or 40 mg/d oral olanzapine relative to 20 mg/d oral olanzapine in stable psychiatric subjects.

BACKGROUND: Prescription monitoring in the United States suggests that oral olanzapine is prescribed in doses that exceed the approved range of 5 to 20 mg/d.
OBJECTIVE: In this double-blind, randomized study, the pharmacokinetics and tolerability of higher-dose (30 or 40 mg/d) olanzapine were examined relative to the highest approved dose (20 mg/d) among non-treatment-resistant patients with psychiatric illnesses.
METHODS: After a 10-day period in which all patients were stabilized on 20 mg/d olanzapine, 37 patients with schizophrenia, schizoaffective disorder, or bipolar I disorder were randomized to receive treatment with olanzapine 20 mg/d for 20 days (group A, n=12), 30 mg/d for 10 days followed by 40 mg/d for 10 days (group B, n=11), or 40 mg/d for 20 days (group C, n=14). On days 10, 20, and 30, blood samples were collected before dosing and at 1, 2, 5, 6, 10, 14, 18, and 24 hours after dosing. Plasma olanzapine concentrations were assayed using high-performance liquid chromatography with electrochemical detection. Tolerability was assessed by spontaneously reported treatment-emergent adverse events; changes from baseline in vital signs, electrocardiograms, and standard laboratory test values; incidences of categorically defined treatment-emergent akathisia and parkinsonism; and 2-hour standard oral glucose tolerance tests.
RESULTS: Of the 53 subjects who entered the study, 16 were excluded (7 because entry criteria were not met, 6 because of subject's decision, and 3 for other reasons). Subjects were primarily men (group A, 75%; group B, 55%; group C, 79%), approximately 40 years old (mean [SD] age: group A, 40.6 [8.6]; group B, 37.9 [8.6]; group C, 39.4 [9.2] years), and black (group A, 83%; group B, 55%; group C, 64% [the remainder were white]). Mean (SD) baseline weight was 84.0 (17.5) kg for group A, 82.1 (12.0) kg for group B, and 100.9 (23.3) kg for group C. By day 20, dose-proportional increases were observed in plasma olanzapine Cmax,ss and AUC. Geometric mean (percent coefficient of variation) values for groups A, B, and C at day 20 were as follows: Cmax,ss 57.8 (40.2), 75.6 (86.7), and 94.1 (50.2) ng/mL, respectively; and AUC: 997 (38.5), 1220 (88.0), and 1630 (53.9) ng . h/mL, respectively. The most frequently reported adverse events were weight gain (group A, 2/12 [17%]; group B, 3/11 [27%]; group C, 2/14 [14%]) and sedation (group A, 3/12 [25%]; group B, 2/11 [18%]; group C, 2/14 [14%]). Mean (SD) weight gain from baseline to end point was 3.5 (2.81) kg for group A, 3.0 (3.15) kg for group B, and 3.1 (2.22) kg for group C. Changes in glucose tolerance, vital signs, or laboratory parameters did not appear to be dose dependent. During double-blind therapy, 7 subjects experienced akathisia (spontaneously reported, n=3 [group C]; categorically defined, n=3 [group B]; both, n=1 [group C]). Of the subjects with categorically defined akathisia, 2 had a history of akathisia and the other had a score of 1 (questionable) on the Barnes Akathisia Scale at baseline. No cases of parkinsonism were observed at any time.
CONCLUSIONS: Among these subjects with psychiatric illnesses, olanzapine at doses of 30 and 40 mg/d displayed a pharmacokinetic profile consistent with that of 20 mg/d. Higher-dose olanzapine exhibited a tolerance profile similar to that of 20 mg/d; however, akathisia may be more likely to occur at higher doses, particularly in subjects with a history of akathisia.

RCT Entities:   Population Interventions Outcomes