Lack of multiple dosing effect of sertindole on the pharmacokinetics of alprazolam in healthy volunteers

Abstract

The effect of sertindole (a new selective antipsychotic compound) on the pharmacokinetic disposition of alprazolam was investigated. Fourteen subjects who completed the study received a single 1 mg dose of alprazolam without or with concomitant sertindole 12 mg daily. Coadministration of sertindole and alprazolam led to a half-hour decrease (P < 0.05) in mean Tmax value (alone: 1.2 h, in combination: 0.7 h) and a 1.6-h increase in the mean t1/2 value (12.5 +/- 3.2 versus 14.3 +/- 3.4 h, P < 0.05) of alprazolam. The mean Cmax (18.5 +/- 4.9 versus 18.5 +/- 4.8 ng/ml) and AUC (266 +/- 68 versus 275 +/- 57 ng x h/ml) values of alprazolam did not change statistically significantly in the presence of sertindole (P > 0.05). These pharmacokinetic changes are minor and not considered to be of clinical significance. Although both sertindole and alprazolam are substrate for CYP3A4 (cytochrome P-450 3A4), the results in this study suggest that sertindole is not an inhibitor of the metabolism of alprazolam.

Clinical Pharmacology, Clinical Efficacy, and Behavioral Toxicity of Alprazolam: A Review of the Literature

“…They have been reported for erythromycin (285), ketoconazole (111), itraconazole (286), venlafaxine (3), nefazodone (112,154), fluoxetine (107,160), fuvoxamine (91), carbamazepine (97), cimetidine (1,207), and propoxyphene (2). However, other substrates for CYP3A4 such as grapefruit juice (287) and sertindole (281) did not significantly alter alprazolam metabolism.…”

A statistical approach for classifying change in cognitive function in individuals following pharmacologic challenge: an example with alprazolam

“…These cognitive tests were administered three times for more than three days before baseline (day 3, day 2, day 1), then at baseline and then again at C max for alprazolam. Because the time to maximum concentration (T max ) for alprazolam is approximately 1 h post dosing (Wong et al 1998;D'Souza et al 2001) and the test battery required 30 min to complete testing always began 45 min after dosing so that we bracketed around T max for this drug. The order of administration for the CogState and GMLT was pseudo-randomized across subjects and test sessions to control for test order effects, although the tests in the CogState battery were always given in the same order.…”

“…The benzodiazepine alprazolam is known to induce marked impairment in cognitive function after a single dose as low as 0.5 mg and this impairment has been observed most reliably in psychomotor, attentional, and memory functions (Vester et al 2002;Vester and Volkerts 2004;Snyder et al 2005). Alprazolam reaches maximum concentration in plasma (e.g., C max ) in approximately 1 h and has few side effects (D'Souza et al 2001;Wong et al 1998). Given these features, alprazolam treatment provides a good challenge for measuring the magnitude of impairment in individual subjects according to the statistical and methodological principles outlined above.…”

Efficacy and Safety of Sertindole in Schizophrenia

“…31 On the other hand, the coadministration of CYP2D6 and CYP3A4 inducers such as carbamazepine, rifampicin, phenobarbital and phenytoin may decrease plasma sertindole concentrations. 36,37 Sertindole is contraindicated in patients receiving drugs known to significantly increase the QTc interval, such as antihistamines (terfenadine and astemizole), class I and III antiarrhythmics (amiodarone and quinidine), quinolone and macrolides antibiotics, many antipsychotics, antidepressants, and lithium. 35 Based on this evidence, sertindole should not interfere with the metabolism of concomitantly given medications; as further confirmed by formal kinetic trials in healthy volunteers, the coadministration of sertindole did not significantly change the pharmacokinetic parameters of alprazolam and terfenadine (at dosages of 12 and 20 mg/d, respectively).…”