Profile of Moxifloxacin Drug Interactions

Abstract

We report a brief description of the interaction profile of moxifloxacin. After oral administration, the absorption of moxifloxacin was unaffected by ranitidine or by food consumption. Drugs containing multivalent cations (e.g., Mg⁺⁺, Al⁺⁺⁺, and Fe⁺⁺, but not Ca⁺⁺) impaired absorption. No clinically relevant effect of moxifloxacin was seen on the pharmacokinetics of digoxin under combination steady state conditions. Also, moxifloxacin did not affect the pharmacokinetics of theophylline or vice versa. This result, plus further data proving lack of interaction with glyburide, warfarin, and oral contraceptives, confirms the absence of metabolic interactions involving the cytochrome P-450 system, as previously reported. Concomitant administration of probenecid did not affect the elimination of moxifloxacin. Moxifloxacin thus has a unique drug interaction profile that is advantageous for its safe use.

Several studies have investigated the activity of moxifloxacin in comparison with other fluoroquinolones against respiratory tract pathogens and have shown that it has especially good activity against streptococci [1]. Moxifloxacin was also found to be the most active fluoroquinolone against pneumococci [2]. Whether moxifloxacin will emerge as a valuable antibiotic in the clinical setting will also depend on its drug-drug interaction profile. Certainly, the interaction profile outside the tight surveillance of a hospital clinical trial setting will be the key to determining dosing recommendations.

Clinical pharmacological phase 1 studies showed an excellent safety and tolerability profile; moxifloxacin has an oral tablet formulation and uncomplicated pharmacokinetics, making it suitable for once-daily dosing. Kinetics were linear up to 800 mg after a single dose and over 10 days with 600-mg daily dosing. Studies in healthy subjects and special populations support the use of a simple and flexible dosing regimen for moxifloxacin that should lead to high patient adherence. These factors recommend moxifloxacin as a candidate for treating respiratory tract infections in general practice.

The current studies address pharmacokinetic interactions with other medications that were selected on the basis of either their known interactions with fluoroquinolones or the adverse event risks associated with their narrow therapeutic range (e.g., digoxin [Lenoxin tablet, Glaxo Wellcome]) or the frequency of their coadministration (e.g., oral contraceptives). Studies on the interactions that might affect absorption and bioavailability (food, dairy products, ranitidine, Maalox 70 [Rorer], and Eryfer [Cassella-med]) have been presented elsewhere [3]. Studies investigating the results of a possible interaction with warfarin, theophylline, probenecid, and glyburide have been reviewed elsewhere [4].

Materials and Methods

Unless otherwise stated, all studies reported were conducted in healthy men aged 18–45 years. Studies are reported here in summary only; these and studies in progress will be covered in more detail in the future.

Sucralfate. Twelve healthy men were studied in a randomized open 2-way crossover design evaluating a single dose of 400 mg of moxifloxacin versus a single dose of 400 mg of moxifloxacin with 190 mg of Al⁺⁺⁺ (Sucralfate-ratiopharm 1000 [Ratiopharm]) given immediately before and 5, 10, 15, and 24 h after moxifloxacin administration. There was a 2-week washout period between treatments [5].

Calcium supplements. Twelve healthy men aged 18–55 years were studied in a randomized open 2-way crossover design evaluating a single dose of 400 mg of moxifloxacin versus a single dose of 400 mg of moxifloxacin with 500 mg of Ca⁺⁺ (Calcium-Sandoz forte [Sandoz AG]) given immediately before and 12 and 24 h after moxifloxacin administration. There was a 2-week washout period between treatments [6].

Digoxin. Twelve men and 12 women, all healthy subjects aged 24–52 years, were studied in a randomized, double-blind, placebo-controlled, 2-way crossover design evaluating 2 consecutive treatments of 400 mg of moxifloxacin or placebo once daily for 14 days (without washout phase) during 28 days of concomitant digoxin therapy (0.25 mg of digoxin q.d.) [7].

Oral contraceptives. A total of 29 healthy women were studied according to a randomized, double-blind, 2-way crossover design evaluating moxifloxacin (400 mg q.d.) versus placebo (q.d.) during days 1–7 of their menstrual cycles while taking ethynylestradiol (0.03 mg) and levonorgestrel (0.15 mg; Microgynon [Schering AG]) after a 3-month run-in phase. A 1-cycle washout period was allowed between moxifloxacin and placebo treatments [8] (Bayer, data on file; study identifier BAY 12-8039/0147). Concentrations of moxifloxacin [9] and other substrates were determined by specific assays with the appropriate sensitivity and accuracy. The pharmacokinetics were evaluated noncompartmentally.

Results

Absorption studies. Moxifloxacin pharmacokinetics were only marginally changed (slightly lower peak concentration [C_max], somewhat longer maximum time [t_max], unchanged area under the curve [AUC]) when the oral dose (400 mg) was administered after eating a standard American breakfast (high fat and high calories) or after ingesting dairy products. Changes in gastric pH caused by pretreatment with ranitidine had no influence on drug uptake. The absorption of moxifloxacin was decreased by concomitant administration of Maalox 70, sucralfate (table 1) [5], and iron supplements. However, calcium supplements did not interact significantly with moxifloxacin (table 2) [6]. This suggests that moxifloxacin is sensitive to the presence of multivalent cations—except calcium—and is likely to form nonabsorbable complexes. This is an absorption-type interaction accepted as an effect for the fluoroquinolone class of drugs [3].

Table 1

Pharmacokinetics of moxifloxacin during moxifloxacin-sucralfate combination treatment in 12 healthy subjects.

Table 2

Pharmacokinetics of moxifloxacin during moxifloxacin-calcium supplement combination treatment in 12 healthy subjects.

The steady state pharmacokinetics of theophylline were unaltered by concomitant moxifloxacin both in terms of C_max,ss and AUC_τ,ss. Similarly, the steady state pharmacokinetics of moxifloxacin were unaltered by concomitant theophylline both in terms of C_max,ss and AUC_τ,ss [4]. This indicates absence of cytochrome P-450–1A2 metabolism in the biotransformation of moxifloxacin, a pathway competitively inhibited by some fluoroquinolones. Concomitant repeated dosing of moxifloxacin, 400 mg q.d., had no effect on the pharmacokinetics of S- and R-warfarin and the related pharmacodynamic properties [4].

Pretreatment for 2 days with probenecid (500 mg b.i.d.) was without significant effect on the plasma and urinary pharmacokinetics of moxifloxacin: the time courses of the plasma concentrations were comparable, the mean C_max and AUC values were equivalent, and the amount excreted into urine was unchanged (13.1% and 1.38% and 13.8% and 1.31% of the dose administered for reference and test treatment, respectively) [4].

Concomitant treatment with glyburide and moxifloxacin, 400 mg q.d. a.m., did not have a significant effect on serum insulin concentrations. CIs for all pharmacodynamic parameters tested were 88.6%–102.3%. Although there were statistically significant increases in AUC_0–6h and C_max,0–6h of 7% and 6%, respectively, for serum glucose with moxifloxacin cotreatment, it was judged that these changes were unlikely to be clinically important. Pharmacokinetic results indicated a decrease in glyburide AUC and C_max values, but these did not result in increased plasma glucose or changes in insulin levels (Bayer, data on file; Bayer study identifier BAY 12-8039/D97-012).

After concomitant administration of digoxin with moxifloxacin, peak concentrations for digoxin were increased by 33%. AUC_τ,ss and plasma concentrations at the end of the dosing interval (C_24h) were equivalent for both treatments (table 3). The variability of pharmacokinetic parameters was comparable for both treatments, and the increase in C_max,ss was judged clinically irrelevant. Both treatments were well tolerated, and there were no clinically important changes in any of the safety parameters monitored [7].

Table 3

Pharmacokinetics of digoxin during moxifloxacin-digoxin combination treatment in 23 healthy subjects.

With regard to the use of oral contraceptives, analysis of subjects' hormones (table 4) showed that moxifloxacin does not interfere with oral hormonal contraception: suppression of progesterone as well as estradiol, luteinizing hormone, and follicle-stimulating hormone was evident, indicating absence of ovulation. CIs for the ratio of test to reference were 87%–115% for the ethynylestradiol and levonorgestrel AUC_0–24,norm and C_max,norm parameters [8] (Bayer, data on file; Bayer study identifier BAY 12-8039/0147).

Table 4

Pharmacokinetics of contraceptive hormones and pharmacodynamic parameters during moxifloxacin-oral contraceptive combination treatment in 29 healthy women.

Discussion

Moxifloxacin was observed to be safe and well tolerated at single and repeated doses under the study conditions reported here. Also, moxifloxacin showed no clinically relevant food effect, having only a slightly lower C_max, somewhat longer t_max, but unchanged AUC when taken after consumption of a high-fat meal or dairy products. The bioavailability of moxifloxacin was also unaffected by changes of gastric pH produced by administration of ranitidine. Absorption of moxifloxacin was reduced when taken concomitantly with antacids and minerals containing multivalent cations (except calcium), which form nonabsorbable complexes with quinolones. This effect can be avoided if administration of moxifloxacin is done 2 h before or 4 h after the comedication. When given together with calcium supplements, no special dose recommendations need be given for moxifloxacin (table 5).

Table 5

Moxifloxacin interaction profile.

There was no significant or clinically relevant interaction observed between moxifloxacin and probenecid, digoxin, theophylline, warfarin, glyburide, or oral contraceptives. Together with preclinical data, the results of phase 1 studies indicate absence of metabolic interactions with the cytochrome P-450 system.

Except for the well-recognized absorption-type class interactions between quinolones and antacids and minerals, no other clinically relevant interactions were discovered during clinical development. The straightforward drug interaction profile of moxifloxacin might pose an advantage for the future safe use of moxifloxacin in less stringently controlled community settings.