Effect of posaconazole on the pharmacokinetics of simvastatin and midazolam in healthy volunteers

Abstract

Objectives: The aim of the study is to determine the effect of posaconazole, an extended-spectrum triazole, on the pharmacokinetics of the HMG-CoA reductase inhibitor, simvastatin.

Methods: This randomized, fixed-sequence, parallel-group, single-center, open-label study was conducted in 35 healthy volunteers randomly assigned to receive one of three doses of oral posaconazole: 50, 100 or 200 mg. All subjects received single doses of the reference drug midazolam (2 mg oral) alone on day -9; simvastatin (40 mg oral) alone on day -6; posaconazole (50, 100 or 200 mg) on days 1 – 7 once daily (q.d.); posaconazole plus midazolam (day 8); posaconazole alone (days 9 – 10); posaconazole plus simvastatin (day 11) and posaconazole alone (days 12 – 13).

Results: Relative to simvastatin alone, posaconazole (50, 100 and 200 mg q.d.) significantly increased the C_max and AUC of simvastatin (5- to 11-fold increase in AUC) and simvastatin acid (5- to 8-fold increase in AUC) during co-administration. Relative to midazolam alone, posaconazole (50, 100 and 200 mg q.d.) significantly inhibited CYP3A4-mediated metabolism of midazolam (three to sixfold increase in AUC).

Conclusion: These findings support the classification of posaconazole as a strong CYP3A4 inhibitor. Simvastatin, or other statins predominantly metabolized by CYP3A4, should not be co-administered with posaconazole. Other statins, whose metabolism/elimination is not affected by CYP3A4 inhibition, should be considered for co-administration.

Keywords:

• antifungal
• drug interaction
• midazolam
• pharmacokinetics
• posaconazole
• simvastatin

Acknowledgements

The authors thank S Hunt, ApotheCom, Yardley, PA, USA for editorial assistance.

Notes

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