Aripiprazole: PHARMACOKINETICS

In: Drug

19 Jun 2010

date, no therapeutic drug concentrations of aripiprazole have been established. Although quantitative data are limited with respect to the drug’s bio-availability, Yokoi et al. reported that administration  for 14 days in 15 males, in doses of 0.5, 1, 2, 10, and 30 mg/day, resulted in dose-dependent receptor occupancy between 40% and 95%. The investigators found that it was possible to obtain an adequate occupancy and that the data might be useful at predicting appropriate therapeutic doses.

Lawler et al. examined aripiprazole and its interaction with receptor subtypes reported on liver metabolism but did not clarify the extent of metabolism. The major metabolite, as observed from in vivo animal data, was hydroxyaripipra-zole, but the authors did not establish the extent of its activity.
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EFFICACY

Petrie et al. studied the basic efficacy and tolerability of aripiprazole in phase II trials. Two double-blind, four-week studies enrolled 410 hospitalized patients with acutely relapsing schizophrenia. In the first study, aripiprazole was titrated to 30 mg over 13 days; in the second study, patients received a fixed dose of 2, 10, or 30 mg/day from the start. From both studies, 143 patients participated in the ongoing, follow-up, open-label outpatient trial in which all patients received a maximum dose of 30 mg/day.

The fixed-dose study showed that 30 mg could be given without titration. That dose showed a significant effect on all assessments, including the Positive and Negative Syndrome Scale (PANSS)-Negative score, starting at one-week evaluations. The 2- and 10-mg doses showed an effect on many assessment findings, but not all (and not on the PANSS-Nega-tive), starting at week two or week three. All doses were well tolerated; no weight gain, elevated prolactin levels, neurological or cardiovascular effects, sedation, or anticholinergic reactions were observed.

Kane et al. compared haloperidol and placebo with aripiprazole in a phase III double-blind, four-week clinical trial. Two fixed doses of aripiprazole (15 and 30 mg), haloperidol (10 mg), and placebo were administered to more than 400 patients with a diagnosis of acute relapsing schizophrenia or schizoaffec-tive disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The efficacy of both doses of aripiprazole and haloperidol was significantly superior to that of placebo (a change in PANSS-Total, Brief Psychiatric Rating Scale [BPRS]-Total, at last observation carried forward; P < .01). However, the responder analysis (a 30% decrease from the baseline in PANSS-Total at the last visit) indicated that both doses of aripiprazole worked significantly better than placebo (P < .05), whereas the response to haloperidol was not significantly different from the response to placebo (P< .1). canadian pharmacy generic viagra

Aripiprazole was well tolerated, and the number of patients who discontinued the medication because of adverse effects was lower than the number taking placebo or haloperidol. The investigators observed no clinically meaningful increase in QTc prolongation in patients receiving aripiprazole. Extrapyramidal symptoms in patients taking aripiprazole did not differ in patients taking placebo.

Kern et al. compared aripiprazole with olanzapine in a multicenter, randomized, open-label clinical trial to test its efficacy at remediating neurocognitive deficits. The authors observed a sample of 256 chronic, stable outpatients with a diagnosis of schizophrenia or schizo-affective disorder for 26 weeks. Patients were randomly assigned to receive one of two treatments: 30 mg/day of aripipra-zole or 15 mg/day of olanzapine. After administering a series of tests to measure verbal fluency, executive functioning, verbal and visual secondary memory, working memory, vigilance, and manual dexterity, the authors suggested that aripiprazole might help ameliorate neurocognitive deficits associated with schizophrenia.


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