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

BACKGROUND: Morphine and antibiotics are frequently coadministered in the s urgical setting. These agents may interact, reducing the efficacy of the an tibiotic or increasing the toxicity of morphine. It is therefore important to determine whether antibiotics that might be used for surgical prophylaxi s have the potential to change the pharmacokinetics of morphine. It is equa lly important to learn whether morphine affects the plasma levels of antibi otics 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 (0.1 5 mg/kg) were coadministered, and the effects on the pharmacokinetics of ea ch drug and on changes in the pharmacologic action of morphine, estimated f rom 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 s erum concentration versus time curve (AUO(0-infinity)) estimates for trovaf loxacin/morphine versus trovafloxacin/placebo was 63.8% (95% confidence int erval [CI], 40.7% to 100.3%), indicating a 36% reduction in the bioavailabi lity of trovafloxacin, The ratio of the mean maximum serum concentration (C -max) estimates of Provafloxacin 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 sta tistically significant changes in either the mean relative bioavailability of morphine or that of its metabolite, 6 beta-glucuronidemorphine. Coadmini stration of trovafloxacin did not exacerbate the reduction in respiratory r ate or increase the number of side effects associated with morphine adminis tration. CONCLUSIONS: Coadministration of trovafloxacin and morphine reduces the bio availability and maximum serum concentrations of trovafloxacin. However, el imination of oral trovafloxacin is not impaired, suggesting that the effica cy of trovafloxacin could be maintained in many patients who receive concom itant morphine. Morphine plasma levels and pharmacologic effects are not si gnificantly altered by coadministration of trovafloxacin. Despite their sim ilar metabolic pathways, the trovafloxacin/morphine combination neither exa cerbates the respiratory depressant effects of morphine nor increases the f requency of side effects when compared with placebo/morphine treatment. The se results suggest that the efficacy of trovafloxacin may be maintained whe n coadministered with morphine. Concurrent administration of trovafloxacin and morphine is unlikely to alter the pharmacologic effects of morphine. (C ) 1998 by Excerpta Medics, Inc.