Pharmacokinetic and Pharmacodynamic Interactions of Oral Midazolam with Ketoconazole, Fluoxetine, Fluvoxamine, and Nefazodone

Abstract

The objective of this study was to investigate pharmacokinetic and pharmacodynamic interactions between midazolam and fluoxetine, fluvoxamine, nefazodone, and ketoconazole. Forty healthy subjects were randomized to receive one of the four study drugs for 12 days in a parallel study design: fluoxetine 60 mg per day for 5 days, followed by 20 mg per day for 7 days; fluvoxamine titrated to a daily dose of 200 mg; nefazodone titrated to a daily dose of 400 mg; or ketoconazole 200 mg per day. All 40 subjects received oral midazolam solution before and after the 12-day study drug regimen. Blood samples for determination of midazolam concentrations were drawn for 24 hours after each midazolam dose and used for the calculation of pharmacokinetic parameters. The effects of the study drugs on midazolam pharmacodynamics were assessed using the symbol digit modalities test (SDMT). The mean area under the curve (AUC) for midazolam was increased 771.9% by ketoconazole and 444.0% by nefazodone administration. However, there was no significant change in midazolam AUC as a result of fluoxetine (13.4% decrease) and a statistical trend for fluvoxamine (66.1% increase) administration. Pharmacodynamic data are consistent with pharmacokinetic data indicating that nefazodone and ketoconazole resulted in significant increases in midazolam-related cognition impairment. The significant impairment in subjects' cognitive function reflects the changes in midazolam clearance after treatment with ketoconazole and nefazodone. These results suggest that caution with the use of midazolam is warranted with potent CYP3A4 inhibitors.

Time-Dependent Inhibition and Estimation of CYP3A Clinical Pharmacokinetic Drug-Drug Interactions Using Plated Human Cell Systems

“…Fluoxetine is a known weak CYP3A time-dependent inhibitor with generally a lack of reported clinical CYP3A DDI (Lam et al, 2003). After an oral dose of 20 to 60 mg q.d.…”

Effects of three cytochrome P450 inhibitors, ketoconazole, fluconazole, and paroxetine, on the pharmacokinetics of lasofoxifene

“…Although the changes in lasofoxifene C max and AUC 0-∞ observed during the coadministration of lasofoxifene and ketoconazole were statistically significant, the differences were relatively small, suggesting a minor role for CYP3A. Coadministration of ketoconazole with midazolam, a compound metabolized by CYP3A, results in an 7.7-fold increase in AUC [28]. A 67% increase is AUC is noted with zolpidem, a compound with a predicted CYP3A-mediated clearance of 61% [29].…”

Selective Serotonin Reuptake Inhibitor Drug Interactions in Patients Receiving Statins

“…34 Fluoxetine (20-60 mg/d) did not influence the pharmacokinetics of the CYP3A4 substrate midazolam, either. 35 Sertraline also inhibits CYP3A4 in vitro, 36 but 8 days of treatment of healthy volunteers with clinical doses of sertraline did not significantly alter levels of the CYP3A4 substrates erythromycin and alprazolam. 34 Fluvoxamine inhibited the CYP3A4 substrate tandospirone in an animal model 37 but showed little in vitro effect on this enzyme.…”

“…38 Twelve days of treatment with fluvoxamine (200 mg/d) increased the area under the curve of midazolam (a CYP3A4 substrate) by 66%; however, this increase was less than one-tenth of the increase produced by ketoconazole, a strong CYP3A4 inhibitor, and less than one-sixth of the increase produced by nefazodone, another strong inhibitor of this enzyme. 35 In another study, 39 5 days of treatment of healthy volunteers with fluvoxamine (100 mg/d) more than doubled exposure to buspirone, another CYP3A4 substrate.…”

“…Unlike the SSRIs, nefazodone is a potent CYP3A4 inhibitor, 34,35 and the combination of nefazodone with simvastatin has been associated with rhabdomyolysis in at least 4 published case reports. [58][59][60][61] A possible interaction between nefazodone and pravastatin has also been reported.…”