Pharmacokinetic assessment of alprazolam-induced neonatal abstinence syndrome using physiologically based pharmacokinetic model.

Sustained benzodiazepine use during pregnancy can induce neonatal abstinence syndrome (NAS). In this study, the association between NAS and plasma alprazolam concentration was examined using the measured neonatal concentrations in the time series as well as simulated plasma concentrations of pregnant woman and neonate by physiologically based pharmacokinetic (PBPK) modeling. A neonate born to a mother taking alprazolam daily throughout pregnancy exhibited symptoms such as apnea and vomiting from 9 h to 4 days after birth. Finnegan score was 7 at birth and decreased to 0 by day 4. Apnea improved by 24 h post-delivery and gastrointestinal symptoms disappeared by day 4. The plasma alprazolam concentration in the neonate was 15.2 ng/mL immediately after birth and gradually decreased over 3 days. Measured neonate and estimated maternal plasma alprazolam concentrations were within the 90% prediction intervals of each concentration by PBPK simulation using "pregnancy" and "pediatrics" population parameters including in Simcyp population-based ADME simulator. In conclusion, NAS symptoms such as apnea and digestive events disappeared in parallel with the decrease of the neonate's plasma alprazolam concentrations. Moreover, PBPK modeling and simulation is a useful methodology for toxicological assessment in special characteristics populations lacking specific experimental data.

Different acute tolerance development to EEG, psychomotor performance and subjective assessment effects after two intermittent oral doses of alprazolam in healthy volunteers.

BACKGROUND/AIMS: Benzodiazepines (BZDs) are the most effective of the psychotropic drugs in the treatment of anxiety disorders. Tolerance has been reported for the majority of BZDs after chronic administration. However, little attention has been paid to the possibility that tolerance might be present after the intermittent oral administration of BZDs. The objectives of the present study were to assess tolerance development after the administration of two intermittent single oral doses of alprazolam given 15 days apart in healthy volunteers, and to compare the results obtained using measures from different domains: neurophysiological, psychomotor and subjective. METHODS: Twenty-four healthy volunteers received 2 mg of alprazolam orally on two experimental days, 15 days apart. Plasma concentrations and pharmacodynamics (PD) were assessed before drug intake and at different times in the following 24 h. PD was assessed through EEG (relative alpha and relative beta-1 activities), cancellation task (total and correct number of responses) and visual analogue scales (activity and drowsiness). RESULTS: No differences were observed in the PKs of alprazolam between occasions. A proteresis was present in both administrations for impairments of psychomotor performance and relative beta-1 activity, whereas it was present only after the second administration for subjective assessments and relative alpha activity. The proteresis on the second occasion was higher than on the first one. CONCLUSIONS: The administration of two single oral doses of alprazolam, 2 weeks apart in healthy volunteers, yielded the same PKs on both occasions, but significant changes were observed in the PD profile. Acute tolerance was observed after the second administration. Two patterns of acute tolerance development were obtained: (1) impairments of psychomotor performance and relative beta-1 activity, and (2) subjective assessments and relative alpha activity.

Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine.

Alprazolam (ALP) and caffeine (CAF) were suggested as probe drugs for the activities of CYP3A4 and CYP1A2, respectively. We investigated the disposition of oral ALP (1 mg) and CAF (100 mg) in 17 normal volunteers to establish and validate a procedure for the simultaneous assessment of CYP3A4 and CYP1A2 enzyme activity. Nine received ALP alone, ALP and CAF and CAF alone in an open three-way crossover study to test for pharmacokinetic interaction. Four received ALP after a 2-day pretreatment with ketoconazole, an inhibitor of CYP3A4, and four normal volunteers received ALP after 4 days of rifampin, an inducer of CYP3A4. AUC values of ALP and CAF administered alone were not different from AUC values when both drugs were administered combined, indicating that there is no metabolic interaction. The ratio formed of paraxanthine and CAF correlated significantly with systemic CAF clearance at 3, 4, 6, 8, 10 and 24 h. There was a strong correlation between AUC values of ALP and CAF and the plasma concentration obtained 6, 8, 10, or 24 h after ingestion of the drug. Ketoconazole and rifampin pretreatment significantly changed AUC values of ALP (mean AUC values in microg/l h: ALP = 242.2, ALP + ketoconazole = 426.2, ALP + rifampin = 28.4, ANOVA F = 17.7, P < 0.001). We conclude that ALP and CAF can be administered simultaneously for the assessment of CYP activity. Plasma concentrations 6, 8, 10, and 24 h after drug ingestion reflect AUC of ALP and CAF and therefore in-vivo CYP3A4 and CYP1A2 activity, respectively.

Coadministration of nefazodone and benzodiazepines: I. Pharmacodynamic assessment.

One hundred two healthy men were evaluated in one of three studies conducted to evaluate the coadministration of nefazodone, 200 mg twice daily, and three benzodiazepines: triazolam, 0.25 mg; alprazolam, 1 mg twice daily; or lorazepam, 2 mg twice daily. In the first study, psychomotor performance, memory, and sedation were assessed at 0, 0.5, 1.5, 2.5, and 9 hours after single doses of triazolam alone and again after 7 days of nefazodone. Data from 6 of 12 subjects in this study were evaluable because of a dosing error in the other 6 subjects. In the subsequent two parallel design studies, groups of 12 volunteers received 7 days of either placebo; nefazodone, 200 mg; alprazolam, 1 mg twice daily; or alprazolam plus nefazodone or, in the second study, either placebo; nefazodone; lorazepam, 2 mg twice daily; or lorazepam plus nefazodone; the studies were identical, double-dummy, double-blind designs. Psychomotor performance, memory, and sedation were assessed at 0, 1, 3, and 8 hours after the 8 a.m. dose on days 1, 3, 5, and 7 of the studies. In all studies, blood samples were also obtained at testing times so that effect/concentration comparisons could be made and so full pharmacokinetic analyses could be done for separate studies. Nefazodone had no effect on psychomotor performance, memory, or sedation relative to placebo in any study. The mean maximum observed effect (MaxOE) on psychomotor performance and sedation were increased when triazolam was given after 7 days of nefazodone (p < 0.05); also, triazolam concentration was 60% higher at this time. Alprazolam and lorazepam impaired performance on day 1 (mean MaxOE, 34 and 30%, respectively) relative to placebo and nefazodone. By day 7 of alprazolam or lorazepam, psychomotor impairment decreased, indicating the development of tolerance. Alprazolam plus nefazodone increased psychomotor impairment (MaxOE, approximately 50%) and sedation relative to alprazolam alone on days 3, 5, and 7 (p < 0.05). Higher alprazolam concentrations explained the increased impairment in the alprazolam plus nefazodone treatment group; however, it is also possible that there was a delay in the development of tolerance. There were no differences in psychomotor impairment, memory, sedation, or lorazepam concentration detected between the lorazepam alone and lorazepam plus nefazodone treatments. This is consistent with the absence of a pharmacokinetic interaction between nefazodone and lorazepam. These results indicate that if the coadministration of a benzodiazepine is required in patients receiving nefazodone therapy, clinically significant interactions would be less likely with those eliminated by conjugative metabolism such as lorazepam. In cases where a benzodiazepine eliminated by oxidative metabolism is required, a reduction in initial dosage and careful clinical evaluation for signs of psychomotor impairment may be appropriate.