Lack of effect of reboxetine on cardiac repolarization.

OBJECTIVE: The effect of reboxetine on electrocardiographic parameters, particularly the QTc interval, was assessed in 20 healthy subjects (15 male, 5 female). METHODS: In a 5-way crossover study, subjects received placebo, 2 mg, 4 mg, or 6 mg reboxetine, or 6 mg reboxetine and 200 mg ketoconazole twice daily for 7 days. Plasma samples, vital signs, and 12-lead electrocardiograms (ECGs) were obtained during one dosing interval of days 1, 4, and 7. Additional ECGs were recorded immediately after an exercise paradigm, so that the RR versus QT relationship might be used in calculating QTc. Plasma concentrations of R,R (-)reboxetine and the more active S,S (+)reboxetine were measured by HPLC-dual mass spectrometry. RESULTS: No statistically significant differences among treatments in mean dose-corrected pharmacokinetic parameters were observed, except that the dose-corrected area under the concentration-time curve from time zero to 12 hours and the peak plasma concentration were significantly increased on days 4 and 7 in the presence of ketoconazole. As expected, heart rate increased from baseline (approximately 8-11 beats/min) at > or =8 mg reboxetine daily. No statistically significant prolongation of QTc (Fridericia correction) occurred after any of the treatments. No relationships between DeltaQTc and plasma concentrations of reboxetine enantiomers were apparent. Similar results were obtained with Bazett's correction and two linear corrections that relied on exercise data generated before drug administration. CONCLUSIONS: Reboxetine, at systemic exposures approximately twice the recommended dose, did not significantly affect cardiac repolarization in healthy subjects. Use of QT versus RR relationship in the drug-free state to correct QT for heart rate in the drug-treated state may provide an acceptable alternative to classic correction equations.

Ketoconazole inhibits the clearance of the enantiomers of the antidepressant reboxetine in humans.

BACKGROUND: Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme. Reboxetine, a selective norepinephrine reuptake inhibitor, is metabolized by cytochrome P450 3A4. The potential interaction of reboxetine with this representative from the azole derivative class was examined. METHODS: Eleven healthy volunteers received (1) 4 mg reboxetine orally on the second day of a 5-day regimen of 200 mg ketoconazole once daily and (2) 4 mg reboxetine orally in a crossover design. Plasma concentrations of reboxetine enantiomers [R,R(-)-reboxetine and the more active S,S(+)-reboxetine] were measured by high-performance liquid chromatography-tandem mass spectrometry. Effects of ketoconazole on enantiomer pharmacokinetics were assessed by ANOVA. RESULTS: Ketoconazole increased R,R(-)-reboxetine and S,S(+)-reboxetine mean area under the plasma concentration-time curves (AUC) by 58% and 43%, respectively (P < .02). Oral clearance of both enantiomers was consequently decreased 34% and 24%, respectively, by ketoconazole (P < .005). Ketoconazole did not significantly affect maximal plasma concentrations (P > .1). Mean terminal half-life after administration of ketoconazole (21.5 hours and 18.9 hours) was significantly longer than after reboxetine alone (14.8 hours and 14.4 hours; P < or = .005). The AUC ratio for R,R(-)-reboxetine to S,S(+)-reboxetine was reduced by ketoconazole administration (2.76 after ketoconazole versus 2.39; P < .003). CONCLUSION: Ketoconazole decreases clearance of both reboxetine enantiomers. Although the adverse effect profile for reboxetine was not altered by ketoconazole, the results of this study suggest that caution should be used and that a reduction in reboxetine dose should be considered when the two are coadministered.

Pharmacokinetic drug-drug interaction study of delavirdine and indinavir in healthy volunteers.

The potential pharmacokinetic drug-drug interaction between delavirdine, a nonnucleoside analogue reverse transcriptase inhibitor, and indinavir, an inhibitor of HIV protease, was evaluated in healthy volunteers. Subjects received a single 800-mg dose of indinavir sulfate on day 1 (baseline). Delavirdine mesylate 400 mg was administered three times daily on days 2 through 10. On day 9, a single 400-mg dose and on day 10 a single 600-mg dose of indinavir were given along with morning doses of delavirdine. Pharmacokinetic evaluations of indinavir were made on days 1, 9, and 10, and of delavirdine on days 8, 9, and 10. Fourteen healthy male volunteers completed the study. Single doses of indinavir had no clinically important effects on the pharmacokinetics of delavirdine. Mean indinavir Cmax values for the 400-mg and 600-mg doses administered concomitantly with delavirdine were dose proportionally lower than that observed following the 800-mg dose administered alone. Mean Tmax values were similar and ranged from 1.0 +/- 0.3/hour for indinavir 800 mg administered alone to 1.3 +/- 0.4/hour for indinavir 600 mg administered with delavirdine. These results indicate that delavirdine had no clinically important effect on the rate of indinavir absorption. In contrast, the mean indinavir AUC0-infinity, value following the 400-mg dose administered with delavirdine was only 14% lower than the baseline value determined for the 800-mg indinavir dose (25,400 +/- 6960 nM hour versus 29,600 +/- 7920 nM hour), and the mean indinavir AUC0-infinity value for the 600-mg indinavir dose administered with delavirdine (42,700 +/- 9800 nM hour) was 44% greater than the baseline value. All differences among mean AUC0-infinity values were statistically significant. Mean indinavir half-life values were slightly longer when indinavir was given in a dose with delavirdine than when indinavir was administered alone. These results suggest that delavirdine inhibits metabolism of indinavir and support the possibility of a reduction in the magnitude or frequency of indinavir dosage when given in combination with delavirdine.

Effect of fluconazole on the steady-state pharmacokinetics of delavirdine in human immunodeficiency virus-positive patients.

Fluconazole, an inhibitor of certain human cytochrome P-450 isozymes, is used for the prevention and treatment of a broad range of fungal infections that predominantly affect immunocompromised individuals. This study evaluated the influence of fluconazole on the steady-state pharmacokinetics of delavirdine, a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, in 13 HIV-1-infected patients with CD4 counts ranging from 186 to 480/mm3. Both the control group (n = 5) and the fluconazole group (n = 8) received 300 mg of delavirdine mesylate every 8 h for 30 days; subjects in the fluconazole group took a 400-mg, once-daily dose of fluconazole on study days 16 to 30. Harvested plasma from serial blood samples collected on days 15, 16, and 30 were assayed for concentrations of delavirdine and its N-desalkyl metabolite by a reversed-phase high-pressure liquid chromatography (HPLC) method. Blood samples obtained on days 16 and 30 were also assayed for fluconazole by HPLC. Delavirdine mesylate alone and in combination with fluconazole was well tolerated. There were no significant differences (P > 0.16) in delavirdine pharmacokinetic parameters between treatment groups on day 15 or day 30. After coadministration of fluconazole and delavirdine mesylate for 2 weeks (day 30), no significant differences (P > 0.058) were observed in any delavirdine pharmacokinetic parameters relative to those after receiving delavirdine mesylate alone (day 15) after in the fluconazole group. Fluconazole pharmacokinetic parameters were similar to those previously reported for healthy volunteers and HIV-positive patients. On the basis of these findings, fluconazole and delavirdine mesylate may be taken concurrently without adjustment of the dose of either drug.

The effect of bulking agent on the solid-state stability of freeze-dried methylprednisolone sodium succinate.

The rate of hydrolysis of methylprednisolone sodium succinate in the freeze dried solid state at 40 degrees C was determined in the presence of two common bulking agents--mannitol and lactose--at two different ratios of drug to excipient. Residual moisture levels were less than 1% in all samples tested, with no significant difference in residual moisture among different formulations. Rate of hydrolysis was significantly higher in mannitol-containing formulations versus lactose-containing formulations, and the rate of hydrolysis increases with increasing ratio of mannitol to drug. Thermal analysis and x-ray diffraction data are consistent with a composition-dependent rate of crystallization of mannitol in the formulation and its subsequent effect on distribution of water in the freeze-dried matrix. Increased water in the microenvironment of the drug decreases the glass transition temperature of the amorphous phase, resulting in an increased rate of reaction. The physical state of lactose remained constant throughout the duration of the study, and the rate of hydrolysis was not significantly different from the control formulation containing no excipient. Thermal analysis and x-ray diffraction data are consistent with formation of a liquid crystal phase in freeze-concentrated solutions of methylprednisolone sodium succinate containing no excipient.