Effect of Telavancin on the pharmacokinetics of the cytochrome P450 3A probe substrate midazolam: a randomized, double-blind, crossover study in healthy subjects.
OBJECTIVE
To examine the effect of telavancin, a lipoglycopeptide antibiotic with potent gram-positive activity, on the pharmacokinetics of midazolam, a cytochrome P450 (CYP) 3A probe substrate. Design. Phase I, randomized, double-blind, placebo-controlled, crossover study. Setting. Clinical research center.


METHODS
Sixteen healthy adult volunteers. Intervention. Subjects were randomly assigned to receive an intravenous infusion of telavancin 10 mg/kg or placebo once/day for 7 days. On day 7, a single dose of intravenous midazolam 1 mg was given immediately after completion of the last infusion of telavancin or placebo. Patients crossed over to the alternate treatment regimen after a washout period of at least 7 days.


RESULTS
Pharmacokinetic sampling was performed on study days 7 and 21. Blood was collected before telavancin or placebo dosing and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after midazolam administration. Formal equivalence analysis using the two one-sided t test method showed that the geometric mean ratios for maximum plasma concentration (C(max)) and areas under the plasma concentration-time curve (AUC) for midazolam coadministered with telavancin versus midazolam coadministered with placebo were close to unity. The 90% confidence intervals (CIs) around the ratios fell within the 0.8-1.25 bioequivalence bounds (geometric mean ratio for AUC from time zero to the last measured plasma concentration 0.95, 90% CI 0.910-0.984; C(max) geometric mean ratio 1.03, 90% CI 0.956-1.11). The multiple-dose pharmacokinetic profile of telavancin with concomitant administration of midazolam (C(max) 97 microg/ml, concentration 24 hrs after completion of telavancin infusion 9 microg/ml, terminal-phase elimination half-life 8.9 hrs, clearance 13.3 ml/hr/kg) was consistent with data from earlier studies.


CONCLUSIONS
These pharmacokinetic data show that intravenous telavancin administered at the intended therapeutic dose does not affect the pharmacokinetics of intravenous midazolam. The results indicate that telavancin is unlikely to inhibit hepatic CYP3A activity to a clinically meaningful extent.
Wong
Shekman L
SL
Theravance, Inc., South San Francisco, California, USA.
Goldberg
Michael R
MR
Ballow
Charles H
CH
Kitt
Michael M
MM
Barriere
Steven L
SL
D000293:Adolescent; D000328:Adult; D000617:Aminoglycosides / Q000009:adverse effects* / Q000493:pharmacokinetics; D000890:Anti-Infective Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D004408:Dysgeusia / Q000139:chemically induced; D005260:Female; D006801:Humans; D000077427:Lipoglycopeptides; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*
D000617:Aminoglycosides; D000890:Anti-Infective Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D000077427:Lipoglycopeptides; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; C487637:telavancin