The pharmacokinetic effects of coadministration of morphine and trovafloxacin in healthy subjects

Abstract

Background: Morphine and antibiotics are frequently coadministered in the surgical setting. These agents may interact, reducing the efficacy of the antibiotic or increasing the toxicity of morphine. It is therefore important to determine whether antibiotics that might be used for surgical prophylaxis have the potential to change the pharmacokinetics of morphine. It is equally important to learn whether morphine affects the plasma levels of antibiotics and thus may potentially influence their efficacy or tolerability. Methods: This open, randomized, placebo-controlled, three-treatment, three-period cross-over study enrolled 19 healthy volunteers. Oral trovafloxacin (200 mg), a novel fluoroquinolone antibiotic, and intravenous morphine (0.15 mg/kg) were coadministered, and the effects on the pharmacokinetics of each drug and on changes in the pharmacologic action of morphine, estimated from its effects on respiratory rate and level of sedation, were examined. Results: When trovafloxacin was coadministered with morphine, the half-life of trovafloxacin was unchanged; however, the ratio of the area under the serum concentration versus time curve (AUC 0–∞) estimates for trovafloxacin/morphine versus trovafloxacin/placebo was 63.8% (95% confidence interval [CI], 40.7% to 100.3%), indicating a 36% reduction in the bioavailability of trovafloxacin. The ratio of the mean maximum serum concentration (C max) estimates of trovafloxacin for the two treatments was 53.8% (95% CI: 36.1% to 80.1%), indicating a 46% reduction in C max. The time to C max was delayed by 4 hours. With trovafloxacin coadministration, there were no statistically significant changes in either the mean relative bioavailability of morphine or that of its metabolite, 6β-glucuronide-morphine. Coadministration of trovafloxacin did not exacerbate the reduction in respiratory rate or increase the number of side effects associated with morphine administration. Conclusions: Coadministration of trovafloxacin and morphine reduces the bioavailability and maximum serum concentrations of trovafloxacin. However, elimination of oral trovafloxacin is not impaired, suggesting that the efficacy of trovafloxacin could be maintained in many patients who receive concomitant morphine. Morphine plasma levels and pharmacologic effects are not significantly altered by coadministration of trovafloxacin. Despite their similar metabolic pathways, the trovafloxacin/morphine combination neither exacerbates the respiratory depressant effects of morphine nor increases the frequency of side effects when compared with placebo/morphine treatment. These results suggest that the efficacy of trovafloxacin may be maintained when coadministered with morphine. Concurrent administration of trovafloxacin and morphine is unlikely to alter the pharmacologic effects of morphine.