Lack of a pharmacokinetic interaction between a new smoking cessation therapy, varenicline, and digoxin in adult smokers.

OBJECTIVE: This study investigated the effect of varenicline on the multiple-dose pharmacokinetics of digoxin. METHODS: Eighteen smokers were randomized to receive digoxin (Lanoxicaps 0.2 mg QD) with varenicline 1 mg BID or placebo for 14 days. RESULTS: Varenicline had no clinically relevant effect on the digoxin steady-state exposure, as evidenced by the 90% confidence intervals for the ratios of AUC(0-24) (87.5-108%) and C(min) (83.8-116%) wholly contained within 80-125%. Digoxin C(max) and T(max) remained unchanged in the presence of varenicline, consistent with no apparent alteration in digoxin bioavailability. A minimal 11.3% increase in digoxin renal clearance was noted during varenicline treatment while having no impact on its systemic exposure. Results are supported by mechanistic evidence in Caco-2 cell monolayers that varenicline is neither a P-gp substrate nor an inhibitor of P-gp-mediated efflux of digoxin. Co-administration of varenicline and digoxin was well tolerated. CONCLUSION: The results suggest that digoxin can be safely administered with varenicline without the need for dose adjustment.

A comparison of the photosensitizing potential of trovafloxacin with that of other quinolones in healthy subjects.

Treatment with some quinolones is associated with an abnormal skin reaction following exposure to sunlight (photosensitivity). The objective of the current study was to compare the photosensitizing potential of a new quinolone, trovafloxacin, with that of ciprofloxacin, lomefloxacin and placebo. Forty-eight healthy males (age range 19-45 years) were randomized to receive a 7 day course of treatment with: (i) trovafloxacin 200 mg od; (ii) ciprofloxacin 500 mg bd; (iii) lomefloxacin 400 mg od; or (iv) placebo bd. Minimal erythema doses (MEDs) were assessed using a monochromator at baseline and on day 5 of treatment, for wavelengths of 305 +/- 5, 335 +/- 30, 365 +/- 30, 400 +/- 30 and 430 +/- 30 nm; 335 +/- 30 and 365 +/- 30 nm are within the UVA range. Immediate reaction MEDs were similar in all treatment groups. However, between baseline and day 5, the mean decreases in delayed-reaction MED (24 h) at 335 +/- 30 nm were only 18.99% for trovafloxacin versus placebo (P = 0.1267), compared with 53.77% (P 0.0001) and 64.13% (P 0.0001) for ciprofloxacin and lomefloxacin, respectively. Similarly, at 365 +/- 30 nm, trovafloxacin produced the smallest reduction in delayed MED versus placebo (43.66%), compared with ciprofloxacin (61.53%) and lomefloxacin (75.81%). These differences between trovafloxacin and ciprofloxacin and lomefloxacin were significant at both 335 +/- 30 and 365 +/- 30 nm (P 0.029). All MED values returned to baseline levels within 2 days of drug cessation. These results show that trovafloxacin has significantly less photosensitizing potential than either ciprofloxacin or lomefloxacin. This photosensitivity appears to be induced only by wavelengths in the UVA region, is maximal at 24 h and is a short-term effect.

Single- and multiple-dose administration, dosing regimens, and pharmacokinetics of trovafloxacin and alatrofloxacin in humans.

A simplified dosing algorithm for trovafloxacin was evaluated following a single-dose infusion of alatrofloxacin at trovafloxacin equivalent doses of 30, 100, 200, 300 and 400 mg (57 subjects), and multiple doses of 200, 300 and 400 mg (30 subjects). Maximum serum concentration and area under the concentration-time curve for trovafloxacin increased with dose. Trovafloxacin clearance (82-85 ml x h/kg) and volume of distribution (1.3-1.6 l/kg) were independent of dose. Infusion of alatrofloxacin at a trovafloxacin equivalent dose of 300 mg at 1, 2 or 3 mg/ml over 1 h did not alter the pharmacokinetics of trovafloxacin. A plot of the weight-adjusted dose of trovafloxacin in individual subjects against the maximum serum concentration following single and multiple dosing, indicated that the maximum serum concentration increased 1 microg/ml for each 1 mg/kg of trovafloxacin administered. Thus, a prior knowledge of the desired serum concentration will permit appropriate dosing without the use of complex nomograms in patients with normal hepatic function.

An open, controlled, crossover study on the effects of cimetidine on the steady-state pharmacokinetics of trovafloxacin.

Twelve healthy male volunteers participated in this open, randomized, placebo-controlled, two-way crossover study to investigate the effects of cimetidine on the steady-state pharmacokinetics of oral trovafloxacin. Volunteers were randomized to receive either 400 mg cimetidine twice daily or placebo for 5 days. From day 3-5, volunteers received 200 mg trovafloxacin once daily in addition to either cimetidine or placebo. After a minimum 7-day washout period, the study was repeated: those volunteers who received placebo during the first study period were administered cimetidine, and vice versa. The maximum observed serum trovafloxacin concentration, the area under the concentration-time curve of trovafloxacin within the dosing interval of 24 h and the earliest time to the maximum serum concentration for trovafloxacin in volunteers receiving concomitant cimetidine were 2.4 microg/ml. 27.8 microg x h/ml and 1.4 h, respectively, compared with 2.5 microg/ml, 27.1 microg x h/ml and 1.5 h, respectively, in volunteers receiving concomitant placebo. Thus. multiple dosing with cimetidine had no significant effect on the absorption or disposition of trovafloxacin at steady state. Co-administration of cimetidine and trovafloxacin was also well tolerated and without serious adverse effects.

The bioavailability of nasogastric versus tablet-form oral trovafloxacin in healthy subjects.

BACKGROUND: Patients in the hospital, as well as those in home care settings, often require nutritional supplementation with enteral feeding solutions. In addition, patients with serious infections who are clinically unstable often cannot maintain adequate intake by mouth and may require an alternative to oral antibiotic administration. However, delivery of crushed oral formulations of drugs via nasogastric tubes is often carried out without adequate bioavailability data, and this method of administration may not always be equivalent to oral drug delivery. METHODS: In an open-label, randomized, four-period, four-treatment, cross-over study, 24 healthy volunteers were given one dose of each of the following treatments, with a 7-day wash-out between dosing periods: Treatment A: two 100-mg trovafloxacin tablets given orally with 240 mL water; Treatment B: two crushed 100-mg trovafloxacin tablets suspended in water and administered through a nasogastric tube into the stomach; Treatment C: two crushed 100-mg trovafloxacin tablets suspended in water and administered through a nasogastric tube into the duodenum; or Treatment D: two crushed 100-mg trovafloxacin tablets suspended in water and given through a nasogastric tube into the stomach concomitantly with an enteral feeding solution (240 mL full-strength Osmolite). RESULTS: Pharmacokinetic analyses showed that the bioavailability of trovafloxacin after administration of crushed tablets into the stomach with or without concomitant enteral feeding was not significantly different from that of the orally administered whole tablets: the 90% confidence limits of the area under the concentration-time curve (AUC(0-infinity)) for Treatment B versus Treatment A (91.3%, 109.5%) and Treatment D versus Treatment A (91.6%, 109.9%) were well within the bioequivalence criteria of 80% to 125%. Results of analysis of variance (ANOVA) indicated no significant sequence, period, or treatment-by-period interaction effects. Administration of trovafloxacin into the duodenum (Treatment C) resulted in reduced systemic exposure to trovafloxacin, with a 31% decrease in AUC(0-infinity) and a 30% decrease in peak serum concentration (Cmax) compared to oral administration. Time to peak serum concentration (Tmax) was 1.7 hours after oral administration of trovafloxacin and 1.1 hours after administration directly into the stomach or duodenum through a nasogastric tube in the absence of concomitant enteral feeding. All four treatments were well tolerated; no participant discontinued the study due to adverse events and no serious adverse events were reported. CONCLUSIONS: These results showed that administration of crushed trovafloxacin tablets through a nasogastric tube into the stomach, with or without concomitant enteral feeding, achieves absorption and tolerability comparable to those of orally administered trovafloxacin tablets.

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

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-infinity)) 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 (Cmax) estimates of trovafloxacin for the two treatments was 53.8% (95% CI: 36.1% to 80.1%), indicating a 46% reduction in Cmax. The time to Cmax 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, 6beta-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.

A double-blind, placebo-controlled, parallel group study of oral trovafloxacin on bowel microflora in healthy male volunteers.

BACKGROUND: Treatment with oral antibiotic drugs generally influences normal fecal flora. These changes can be both beneficial (eg, elimination of aerobic, gram-negative bacilli) and detrimental (eg, the appearance of resistant pathogenic micro-organisms). Trovafloxacin, a new fluoroquinolone with in vitro activity against anaerobes, and gram-negative, gram-positive, and atypical pathogens, is a potentially beneficial antimicrobial for bowel sterilization. This double-blind trial investigated the effect of trovafloxacin on the normal microbial bowel flora of healthy male subjects. METHODS: Subjects were randomized (in a 2:1 ratio) to receive either 200 mg trovafloxacin once daily for 10 days or a matching placebo. Fecal samples were collected at two baseline occasions, on visit days 4, 7, 10, and 17, and at follow-up. Bacterial species were identified and quantified in the fecal samples. RESULTS: Twelve subjects received the active drug and seven received placebo. No Enterobacteriaceae were found in samples from days 4 to 10 in subjects receiving trovafloxacin. No changes in Enterobacteriaceae were found throughout the study in subjects receiving placebo. Incidental Enterobacteriaceae were isolated from subjects in the trovafloxacin group at the end of the study. No clinically significant differences were found in either group with respect to prevalence, appearance, or disappearance of aerobic gram-positive cocci, anaerobic bacteria, or yeasts. All tested Enterobacteriaceae were highly susceptible to trovafloxacin. No increase in minimum inhibitory concentration values was seen in day 17 and follow-up samples for isolated Escherichia coli strains. No Clostridium difficile was found in day 17 or follow-up samples from subjects in the trovafloxacin group. All tests for clostridium toxin were negative. CONCLUSIONS: During the treatment period, E. coli could not be cultured from the feces of the 12 healthy subjects receiving 200 mg trovafloxacin daily during days 4 to 10. All isolated Enterobacteriaceae were susceptible to trovafloxacin and no changes in susceptibility were found after the treatment period. In subjects treated with trovafloxacin, the prevalence and number of gram-positive bacteria were rapidly reduced. Trovafloxacin is able to selectively and reversibly suppress bowel flora.

Pharmacokinetics and safety of trovafloxacin in healthy male volunteers following administration of single intravenous doses of the prodrug, alatrofloxacin.

Fifteen healthy male volunteers (in four groups) received single 1 h i.v. infusions of alatrofloxacin (CP-116,517) equivalent to 30, 100, 200 or 300 mg of its active metabolite, trovafloxacin (CP-99,219). Blood and urine were sampled over 73 and 72 h, respectively, and plasma levels of alatrofloxacin and serum concentrations of trovafloxacin were determined by HPLC with UV detection. Alatrofloxacin was not detectable in plasma samples collected after the end of infusion, indicating rapid conversion to trovafloxacin. Maximum serum concentrations of trovafloxacin were achieved at the end of the infusions. Mean maximum plasma trovafloxacin concentrations for the four alatrofloxacin doses were 0.4, 1.8, 2.3 and 4.3 mg/L. The mean area under the concentration-time curve increased proportionally with the dose. The elimination half-life (T(1/2)) for trovafloxacin was independent of the dose and the mean T(1/2)s for the 100, 200 and 300 mg equivalent doses of alatrofloxacin were 10.4, 12.3 and 10.8 h. Approximately 10% of the equivalent dose was recovered as unchanged trovafloxacin in the urine. No clinical adverse or laboratory reactions were associated with i.v. administration of alatrofloxacin and its conversion to trovafloxacin. These results indicate that alatrofloxacin is rapidly converted to trovafloxacin and that the pharmacokinetic parameters for this new fluoroquinolone after i.v. administration of its parent compound are similar to those reported after oral administration of equivalent trovafloxacin doses.

Effect of trovafloxacin, a new fluoroquinolone antibiotic, on the steady-state pharmacokinetics of theophylline in healthy volunteers.

Some fluoroquinolone antibiotics interfere with theophylline clearance, thereby raising concentrations of circulating theophylline and increasing the potential for toxicity. The effect of steady-state serum concentrations of the new fluoroquinolone trovafloxacin on the steady-state pharmacokinetics of theophylline was examined in 12 healthy male volunteers. For 7 days, the subjects received morning and evening theophylline doses adjusted to achieve steady-state plasma concentrations of 8-15 mg/L, the lower end of the therapeutic range. From day 8 to day 15, six volunteers received, in addition to theophylline, 200 mg of trovafloxacin in the morning and placebo in the evening (group A) and six received placebo twice daily (group B). Serial plasma samples obtained over 12 h and 60 h after the morning theophylline dose on days 7 and 14, respectively, were analysed for theophylline by HPLC with UV detection. There were no significant differences in mean Cmax or AUC(0-12) between the two groups on day 7 or on day 14, nor were there significant within-group differences on the two days. On day 14, mean Cmax, AUC(0-12) and T(1/2) (measured on day 14 only) in group A were 10.15 mg/L, 107.32 mg x h/L and 9.0 h, respectively. In group B, the values were 10.81 mg/L, 113.73 mg x h/L and 8.3 h, respectively. The study drugs were well tolerated, and no clinically significant changes in vital signs or laboratory test values were noted. We conclude that steady-state concentrations of trovafloxacin have no clinically significant effect on the steady-state concentrations of theophylline within the therapeutic range in healthy subjects.

Effect of Maalox and omeprazole on the bioavailability of trovafloxacin.

To determine the effect of the concurrent administration of Maalox and omeprazole in the bioavailability of trovafloxacin (CP-99,219), an open, placebo-controlled, randomized, four-way crossover study was conducted in 12 healthy male volunteers. Each received treatments of three 100 mg trovafloxacin tablets in the morning 30 min after 30 mL of Maalox (A), 30 min after placebo (B), 2 h before 30 mL of Maalox (C) and 2 h after 40 mg of omeprazole (D). For treatments A and C, Maalox was also given at 22.00 h the night before the study day, 1 and 3 h after meals and at bedtime on the study day. For B and D, placebo and omeprazole, respectively, were also given at 22.00 h the night before the study day. After treatments A and C, mean area under the curve (AUC) was reduced by 66% and 28% (14.2 and 30.2 mg.h/L), respectively, and mean T(1/2) declined by 33% and 31% (8.3 and 8.5 h), respectively, relative to the values after B (42.1 mg.h/L; 12.4 h). The mean Kel-corrected relative bioavailabilities for A and C were 50% and 104%, respectively, suggesting a large reduction in the initial absorption of trovafloxacin with A. Treatment D had no appreciable effect on mean T(1/2) but mean AUC and Cmax were reduced by 18% and 32%, respectively, relative to B. The mean relative bioavailability after D was 82%. We conclude that the concurrent administration of trovafloxacin and aluminium- and magnesium-containing antacids should be avoided but that co-administration with omeprazole is unlikely to have a clinically significant effect on the extent of absorption of the antibiotic.

Oral bioavailability of trovafloxacin with and without food in healthy volunteers.

Two studies determined the oral bioavailability of trovafloxacin (CP-99,219) in healthy volunteers under fasted and fed conditions. In a randomized, two-way crossover study, 12 fasting subjects received two 100 mg tablets of trovafloxacin and an equivalent dose of alatrofloxacin (CP-116,517), administered by i.v. infusion over 1 h. Alatrofloxacin, the L-Ala-L-Ala prodrug of trovafloxacin, is rapidly converted in the body to trovafloxacin. After the oral dose of trovafloxacin, the mean Cmax and AUC were 2.2 mg/L and 30.4 mg x h/L, respectively. After the infusion of alatrofloxacin, the Cmax and AUC of trovafloxacin were 3.2 mg/L and 34.7 mg x h/L, respectively. The mean T(1/2) after both treatments was about 11 h. The mean Cl and Vd(ss) of trovafloxacin after the infusion of alatrofloxacin were 1.32 mL/min/kg and 1.13 L/kg, respectively. The mean oral bioavailability of trovafloxacin was estimated to be 87.6% (range 64.8-122.1%). Another randomized, open, three-way crossover study was conducted in 12 healthy male volunteers to investigate the effect of food in the gastrointestinal tract on the bioavailability of trovafloxacin. Each subject received three 100 mg tablets after fasting overnight (treatment A) or after a standard breakfast (treatment B), or 300 mg as oral aqueous suspension after fasting overnight (treatment C). Mean Tmax after treatment B occurred 2.2 h later (3.6 h vs 1.4 h) than after treatment A. Mean Cmax and AUC were 2.3 and 2.6 mg/L and 38.2 and 39.5 mg x h/L after B and A, respectively. About 5% of the administered dose was recovered unchanged in the 24 h urine sample after all three treatments. Thus, the food reduced mean Cmax by 12% but had no appreciable effect on mean AUC. The mean bioavailability of trovafloxacin administered as treatment regimen B was 96.6% relative to that of treatment A. The respective mean bioavailabilities of trovafloxacin as treatments B and A were 91.3% and 94.5% respectively of that of treatment C. The results of these studies indicate that trovafloxacin has good oral bioavailability and that the ingestion of food is unlikely to have a clinically significant effect on the bioavailability of trovafloxacin.

The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension.

Present product labelling indicates that azithromycin capsules should not be taken with food. However, three recent studies demonstrated that food does not significantly decrease the bioavilabilities of three new formulations of azithromycin (250 mg tablets, 1000 mg sachet, 500 mg paediatric suspension). With a 500 mg dosage, the mean relative bioavailability of azithromycin following ingestion of a standard high-fat breakfast was 96% when administered as two 250 mg tablets and 113% when administered as a suspension. The mean relative bioavailability of a 1000 mg sachet was 112%. The absolute bioavailability of the sachet formulation, relative to a 1 h iv infusion of 1000 mg, was 44%. Thus, azithromycin tablets, suspension and sachet may be given without regard to meals, further enhancing the convenience of once-daily, short-duration dosing regimens.

Method validation revisited: a chemometric approach.

A validation procedure is presented that satisfies the FDA requirements of accuracy (including precision repeatability), sensitivity, linearity, dynamic range, and homoscedasticity, all with a single set of data. The procedure utilizes the corrigible error correction (CEC) technique comprised of three response curves--standard, Youden one-sample, and method of standard additions (MOSA) plots, from a total of 15 to 18 X,Y data pairs. For the bias component of accuracy, the systematic bias error of the method is quantitatively separated into its constant and proportional error components. The overall constant systematic error is further separated into the system (blank) and analyte-matrix (sample) components. The CEC data also provide an internal, i.e., in situ corrected assay for the sample for comparison with alternative method data. Statistical diagnostic tests are used for the final evaluation of the method acceptability, specifically in deciding whether or not the systematic error indicated requires a root source search for its removal or is simply a calibration constant of the method.