Aripiprazole

Additional information

Pharmacokinetics and dosing

A higher exposure of aripiprazole and its active metabolite dehydro-aripiprazole was noted in female versus male subjects after similar oral doses according to data presented by the manufacturer [1]. Approximately 30-40% higher mean values of Cmax and AUC were reported respectively, for both the parent compound and the metabolite [1]. A large part of this difference might have been attributable to sex-related differences in weight, which was also indicated by pharmacokinetic analyses from six bioequivalence studies comprising 148 healthy volunteers (85 men, 63 women) [2]. Of note, the differences in mean exposure (AUC, Cmax) between male and female subjects in the bioequivalence studies were small (<15 % difference in unadjusted Cmax and AUC, and ≈ 7 % difference after adjusting for weight) and arguably clinically insignificant [2].

No dosage adjustment based on patient’s sex is recommended in the drug label information [1, 3]. Interestingly, no dosage adjustment based on weight is recommended either, which may result in higher exposures in women as a consequence of lower average body weights. The magnitude and clinical significance of differences in exposure should be regarded as uncertain and may be influenced by several other factors. Interindividual variability in cytochrome P450 2D6 and 3A4 activity may be more important than sex differences regarding aripiprazole pharmacokinetics [2]. In light of these different sources of pharmacokinetic variability, the potential value of therapeutic drug monitoring should be considered.

Effects

No sex-related differences in therapeutic response were evident from subgroup analyses based on the pivotal clinical trials of aripiprazole for the treatment of schizophrenia and bipolar mania, respectively, according to the pharmaceutical company [1].

In a very short-term (24 hour), open-label trial including acutely agitated patients (112 men, 89 women) with schizophrenia or a manic/mixed episode of type 1 bipolar disorder, a slightly higher reduction of excitatory symptoms specifically (PANSS-EC total score and selected individual components) was noted in women than in men receiving similar doses of aripiprazole [6]. The difference between the sexes was statistically significant but small (71% vs. 67% reduction in PANSS-EC total score, respectively) and should arguably be interpreted with caution.

According to the U.S. drug label information, a smaller mean reduction in MADRS total score was noted in men than in women treated with adjunctive aripiprazole for major depressive disorder [1]. This appears to be based on a subgroup analysis from a short-term (6-week) double-blind, multicenter RCT (133 men, 225 women) [4]. However, no sex-related efficacy difference was demonstrated in a later, similar trial (127 men, 254 women) [5]. It should be noted that major depressive disorder is not an approved indication for aripiprazole in Europe.

Adverse effects

In relation to other antipsychotic agents, aripiprazole is generally accepted to be less prone to cause hyperprolactinemia [7], a well-characterized antidopaminergic side effect. On account of its partially D2-agonistic properties, aripiprazole use has in fact frequently been associated with decreased prolactin levels, especially when switching from other antipsychotic agents in the setting of established hyperprolactinemia [7, 8]. This propensity to decrease prolactin levels appears to be more pronounced in men than in women treated with aripiprazole, conceivably due to stimulatory effects on prolactin secretion exerted by estrogens [8, 9]. The same relationship has been indicated in adolescents (10-17 years of age), where the incidence of hypoprolactinemia was higher in boys than in girls receiving aripiprazole in the context of clinical trials, according to the European product information [3].

It has been suggested that women might be disproportionately affected by hemodynamic (decreases in blood pressure, increases in heart rate) [10] and gastrointestinal (nausea/vomiting) [2] side effects of aripiprazole. The proposed cause would be a higher mean exposure of aripiprazole in women after similar doses (refer to “Pharmacokinetics and dosing” above) [2, 10]. However, these claims are based on reviews of pharmacovigilance reports [10] prone to several forms of bias, and single-dose observations in healthy volunteers [2], respectively. Thus, a cautious interpretation is warranted.

No clear evidence of sex-related differences in the incidence of adverse reactions were revealed in subgroup analyses of pivotal clinical trial data, according to the pharmaceutical company [1].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).