Significant differences in estradiol bioavailability from two similarly labelled estradiol matrix transdermal systems.

OBJECTIVE: To compare the bioavailabilities of estradiol delivered by two transdermal estradiol matrix systems; Alora and Evorel. STUDY DESIGN: A single-center, open-label, randomized, two-period cross-over study in 33 postmenopausal women. The subjects received two successive 84-h applications of either Alora or Evorel (each labelled to deliver 50 micrograms/day 17 beta-estradiol) in a randomized sequence. Serial serum samples, collected over the 84-h period following the application of the second patch, were analyzed for estradiol using a validated radioimmunoassay method. RESULTS: The fluctuation index produced by Evorel was significantly higher than that produced by Alora (Evorel, 135%; Alora, 76%; p < 0.0005). In addition, the estradiol baseline-corrected area under the curve for Evorel was significantly lower than that for Alora (Alora, 2871.8 pg h/ml; Evorel, 1870.6 pg h/ml; p < 0.0005). Both patches were found to be generally well tolerated. CONCLUSION: Alora delivered a higher, more consistent concentration of estradiol into the systemic circulation over the entire dosing interval than did Everol. Although the full clinical significance of these findings is currently unknown, this study demonstrates that there are significant differences in estradiol delivery from these two products, although they are labelled with the same nominal delivery rate.

Single and multiple dose pharmacokinetics of nefazodone in subjects classified as extensive and poor metabolizers of dextromethorphan.

1. The single and multiple dose pharmacokinetics of nefazodone (NEF) and its active metabolites hydroxynefazodone (HO-NEF) and m-chlorophenyl-piperazine (mCPP) were evaluated in subjects classified as extensive metabolizers (EM) or poor metabolizers (PM) of dextromethorphan. 2. In a parallel design study, 10 subjects from each phenotype received either 50 mg or 200 mg oral doses of NEF as single doses on Day 1 and multiple (twice daily) doses on Days 12-22. 3. Serial plasma and urine samples were collected at specified time intervals after dosing on Days 1, 16, 18, 20 and 22. Plasma samples were analyzed for NEF, HO-NEF and mCPP. Urine samples were analyzed for mCPP and its metabolite p-hydroxy-mCPP (p-HO-mCPP) before and after hydrolyzing the samples with beta-glucuronidase. 4. For the 200 mg dose group, the single dose plasma results showed no significant differences in pharmacokinetic parameters for NEF and HO-NEF in EM compared with PM subjects. However, for mCPP, Cmax was 89 ng ml-1 in the PM subjects compared with 44 ng ml-1 in the EM subjects, AUC was higher in the PM than EM subjects (1642 ng ml-1 h and 412 ng ml-1 h, respectively), and mCPP elimination half-life increased from 6.1 h in the EM subjects to 16.4 h in the PM subjects. Upon multiple dosing, plasma levels for NEF and all metabolites reached steady state within 3 days of dosing in both groups of subjects. Steady state pharmacokinetic parameters for NEF and HO-NEF in EM and PM subjects were not significantly different. The steady state Cmax and AUC values for mCPP in the PM subjects were 182 ng ml-1 and 1706 ng ml-1 h, respectively, compared with 49.6 ng ml-1 and 182 ng ml-1 h in the EM subjects. 5. The cumulative urinary excretion of mCPP and p-HO-mCPP was different for EM and PM subjects. Excretion of total mCPP and total p-HO-mCPP was approximately four-fold lower and five-fold higher, respectively, in the EM subjects than PM subjects. 6. These results indicate that the conversion of mCPP to p-HO-mCPP is attributable to metabolism by cytochrome P450 2D6. The differences in mCPP pharmacokinetic parameters in PM subjects did not affect the time required for NEF and its metabolites to attain steady state or the number of adverse experiences in either group of subjects. Based on the results of this study, NEF may be dosed to EM and PM patients without regard to their cytochrome P450 2D6 phenotype.

A study of the effect of age and gender on the pharmacokinetics of nefazodone after single and multiple doses.

The single-dose (S-D) and steady-state (S-S) pharmacokinetics of nefazodone (NEF) and two of its pharmacologically active metabolites, hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP), in healthy elderly (> 65 years) men and women (N = 12 each) were compared with those in healthy younger (18-40 years) men and women (N = 12 each). All subjects were classified as extensive metabolizers of dextromethorphan (cytochrome P4502D6). Subjects were administered a 300-mg dose of nefazodone hydrochloride for the evaluation of S-D pharmacokinetics. For the evaluation of S-S pharmacokinetics, 300-mg doses of NEF were administered twice daily (every 12 hours) for 8 days (single morning dose on day 8). Serial blood samples were collected after the single dose and the morning dose on day 8 of the twice-daily administration; a blood sample for trough level was collected from each subject just before the morning dose on days 2 to 8 of the twice-daily dosing to assess the attainment of steady state. Plasma samples were assayed for NEF, HO-NEF, and mCPP by a specific, validated high-performance liquid chromatography assay. After a single dose of NEF, the mean peak concentrations in plasma and the area under the curves (AUC) for NEF and HO-NEF were about twofold higher in elderly versus young subjects, but mean AUCs for mCPP were similar. Levels in plasma for NEF, HO-NEF, and mCPP reached steady state by day 3 of multiple dosing. At steady state, exposure to NEF and HO-NEF, based on AUC(TAU) values, was quite variable among age/gender groups but on the average was about 50% higher in elderly women compared with the other three groups of subjects; the exposure to mCPP at steady state was similar in elderly and young subjects. Because all subjects were extensive metabolizers, the effect of gender or age on the pharmacokinetics of NEF and its metabolites in poor metabolizers is not known. There were no serious or unexpected adverse experiences observed in this study. Assuming that similar systemic exposure to NEF and its active metabolites will result in similar therapeutic effects in young and elderly individuals, the difference in systematic exposure to NEF and HO-NEF in elderly subjects suggests that NEF treatment should be initiated at half the usual dose with titration upward and that the usual precautions exercised in treating elderly patients should be used.

A study of pharmacokinetic interaction between buspirone and alprazolam at steady state.

The steady-state pharmacokinetic interaction between buspirone and alprazolam was evaluated in a parallel study with two groups of 12 male volunteers each. On days 1 to 7, group I subjects received a 1-mg alprazolam tablet every 8 hours (q8h) (TRT 1) and group II subjects received 2 x 5-mg buspirone tablets q8h (TRT 2). On days 8 through 14, all subjects received a combination of 1-mg alprazolam and 2 x 5-mg buspirone tablets q8h (TRT 3). Plasma samples, collected 0 to 8 hours after the morning dose on days 7 and 14, were analyzed for buspirone, alprazolam and their metabolites, 1-PP, and alpha-HO-alprazolam, respectively. Additional samples were collected before the morning dose on days 5 and 6 of each session to monitor the attainment of steady state. Steady-state pharmacokinetic parameters Cmax, Tmax, AUC0-8, and Cmin were calculated. The results indicated that for alprazolam, there was a small (< 10%) increase in Cmax and AUC when coadministered with buspirone. For buspirone, there was a 10% and 29% increase in Cmax and AUC, when coadministered with alprazolam. These values were within the normal variability observed with this class of drugs. Except for a 14% decrease in Cmin for alpha-HO-alprazolam, coadministration of buspirone and alprazolam did not affect the parameters for the metabolites. The results of this study suggest that coadministration of buspirone and alprazolam did not markedly affect the steady-state pharmacokinetics of either drug.