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PHARMACOKINETICS |
From the Department of Pharmacokinetics and Department of Early Clinical Research & Experimental Medicine, Schering-Plough Research Institute, Kenilworth, New Jersey (Dr Krishna, Dr Wang); MDS Pharma Services, Lincoln, Nebraska (Dr Kisicki); and Bristol-Myers Squibb Co, Princeton, New Jersey (Mr Olsen, Dr Grasela).
Address for reprints: Address for correspondence: Gopal Krishna, PhD, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033; e-mail: Gopal.Krishna{at}spcorp.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Bioavailability • drug interaction • garenoxacin • omeprazole • pharmacokinetics • quinolone
The pharmacokinetic profile of garenoxacin is favorable, with rapid and essentially complete absorption, dose-proportional and time-independent pharmacokinetics within the therapeutic dose range, and a terminal disposition half-life (t
) supportive of once-daily dosing.12 The oral bioavailability of garenoxacin, as measured by maximum observed concentration (Cmax) and area under the concentration-time curve (AUC), is not significantly affected by food ingestion.13 Garenoxacin is excreted by renal and nonrenal pathways, with approximately 30% to 50% of the dose excreted unchanged in the urine.13,14 Metabolism of phase 2 enzymes, mainly sulfate conjugation, is responsible for the nonrenal elimination of garenoxacin.
The potential of omeprazole to interact with other drugs can occur through competitive inhibition of the cytochrome P450 system or by raising gastric pH, which could alter the absorption of some drugs.15 Garenoxacin is neither a substrate for nor an inhibitor of major cytochrome isoenzymes. However, the aqueous solubility of garenoxacin is pH dependent such that solubility decreases at a pH above 4 and increases at a pH above 10 (Schering-Plough Corporation, data on file, 2004). Thus, similar to the fluoroquinolone trovafloxacin,16 the solubility of garenoxacin is greater in acidic conditions than at neutral pH (Schering-Plough Corporation, data on file, 2004). Proton pump inhibitors, such as omeprazole, have been shown to reduce the relative bioavailability of trovafloxacin17 and to modestly increase systemic exposure to gemifloxacin.18 Thus, it is possible that the absorption of garenoxacin could be affected by drugs that inhibit gastric acid production. This study was designed to evaluate the potential effect of omeprazole on the bioavailability of garenoxacin.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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18 and 
30 kg/m2, were eligible for enrollment. Key exclusion criteria included history of gastrointestinal surgery or gastrointestinal abnormality that might affect drug absorption; any physical or laboratory evidence of organ dysfunction; history of allergy to quinolones, omeprazole, or related compounds; recent use of any drugs known to affect hepatic or renal excretory function; and prior exposure to garenoxacin. Written informed consent was obtained before the study from all subjects. The protocol and informed consent form were approved by the Institutional Review Board of MDS Pharma Services (Lincoln, Neb), and the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.
Study Protocol
This was a nonrandomized, open-label, single-sequence pharmacokinetic study. Subjects were admitted to the clinical facility 24 hours prior to the administration of study drug (day -1) and were required to remain in the clinic throughout the study. On day 1, a single oral dose of garenoxacin 600 mg, administered as one 200-mg and one 400-mg tablet, was given with 240 mL of water to determine the single-dose pharmacokinetics of the drug. Blood samples for measurement of plasma garenoxacin concentration were obtained before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours after dosing. On the day after the end of the initial pharmacokinetic assessment, omeprazole (Prilosec®, AstraZeneca Pharmaceuticals LP, Wilmington, Del) 40-mg delayed-release capsules were administered once daily with 240 mL of water for 4 days to produce a steadystate inhibition of gastric acid secretion. On day 8, a second single-dose pharmacokinetic assessment of garenoxacin was conducted with the concomitant administration of garenoxacin and omeprazole. Omeprazole treatment was continued on days 9 and 10. Subjects were required to fast for at least 8 hours before each drug dosing. On days 1 and 8, subjects also were required to fast for at least 4 hours after each dosing. No smoking, alcohol, caffeine, or grapefruit-containing products were permitted for at least 3 days before dosing through the end of the study. Drugs known to affect hepatic metabolism, renal elimination, gastric acid production, or gastrointestinal motility were prohibited. In addition, patients were not permitted to take over-the-counter or herbal preparations within 1 week prior to enrollment or use an oral, injectable, or implantable hormonal contraceptive agent within 3 months of enrollment.
Pharmacokinetic Assessments
Each subject underwent garenoxacin pharmacokinetic assessments on days 1 (absence of omeprazole) and 8 (with concurrent omeprazole treatment). For each subject, a total of 32 blood samples were collected into evacuated tubes containing tripotassium ethylenediaminetetraacetic acid as an anticoagulant. Centrifugation of the blood samples (10 minutes at 1000 times gravity) was performed to generate the plasma samples. The samples were transferred to labeled tubes and stored at -20°C until shipped frozen to the analytical site.
Plasma samples were assayed for garenoxacin concentration using a validated liquid chromatography/mass spectrometry/mass spectrometry method at MDS Pharma Services (Sunnyvale, Calif).19,20 Nine quality control samples at concentrations of 0.03, 4.00, 8.00, and 80.00 µg/mL (dilution quality control) were analyzed in a total of 3 analytical runs. For the garenoxacin plasma assay, predicted concentrations of at least three fourths of the standards and two thirds of the quality control samples had to be within ±15% of their individual nominal concentration value (±20% for the lowest concentration standard). At least 1 quality control sample at each concentration had to be within 15% of its individual nominal concentration value. Analysis of variance was used to calculate the quadratic regression analysis (weighted by 1/x) of standard peak area ratio versus concentration of standard and estimates of within- and between-run assay variability for quality control samples. Quantifiable limits for garenoxacin ranged from 0.010 to 10.0 µg/mL. The plasma assay method was determined to be precise and accurate. Between- and within-run precision for analytical quality control samples was within 7.5% (range, 0%-7.5%) and 8.6% (range, 5.3%-8.6%) coefficients of variation (CV), respectively. Deviation from the nominal concentrations ranged from -6.0% to 3.3%.
Time to maximum concentration (Tmax) and Cmax values were recorded directly from experimental observations. A minimum mean square error was calculated from the slope of the terminal phase of the plasma concentration-time profile (K), which was determined by log-linear regression of at least 3 data points using no weighting factor. The absolute value of K was used to estimate t, defined as t = ln 2/K. AUC from time 0 extrapolated to infinity (AUC
) was calculated by trapezoidal and log-trapezoidal summations of the garenoxacin concentration curves.
Safety Assessments
Tolerability and safety were assessed in all subjects. Vital signs, clinical laboratory tests, 12-lead electrocardiogram (ECG), and physical examinations were assessed at screening (day -21 to day -2), before initial dosing (day -1), and at the time of discharge from the study (day 11). Subjects also were monitored for the occurrence of adverse events (AEs) throughout the study (days 1-4 and 7-11) and up to 30 days after discharge from the study.
Statistical Analyses
All statistical analyses were performed using SAS/STAT® Version 6.12 (SAS Institute Inc, Cary, NC). Twelve subjects were needed to provide at least 99% power to conclude absence of effect on AUC and Cmax for garenoxacin. Absence of an effect on garenoxacin AUC and Cmax was concluded if the 90% confidence interval (CI) for the ratio of the geometric means with and without omeprazole was within 0.80 to 1.25 and 0.70 to 1.43, respectively.
Subjects who fully completed the study were included in the summary statistics and statistical analyses for garenoxacin pharmacokinetics. Analysis of the effects of omeprazole on the pharmacokinetics of garenoxacin was determined by analysis of variance of the log-transformed AUC and Cmax for garenoxacin, with treatment differences reported as geometric means and CV. The mean ± standard deviation (SD) was reported for t, whereas the medians, with minima and maxima, were reported for Tmax by treatment.
All subjects who received garenoxacin were included in the safety data sets. Recorded AEs were listed and tabulated by primary term, body system, and treatment. Vital signs and clinical laboratory tests were listed and summarized by treatment. Significant ECG and physical examination findings were listed.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetic Findings
The mean plasma concentration-time profiles of a single oral dose of garenoxacin alone and in combination with omeprazole at steady state are shown in Figure 1. The concentration-time profiles were similar between garenoxacin alone and garenoxacin concomitantly administered with omeprazole. Garenoxacin was readily absorbed, with a median Tmax of 1.5 hours. Geometric means for Cmax and AUC of garenoxacin alone were 9.6 µg/mL (CV 18.2%) and 132.0 µg·h/mL (CV 18.9%), respectively. Corresponding values for garenoxacin when administered with omeprazole were 9.3 µg/mL (CV 21.6%) and 140.4 µg·h/mL (CV 22.1%). The adjusted geometric means are shown in Table I. The 90% CIs for AUC and Cmax were contained within the prespecified limits of 0.80 to 1.25 and 0.70 to 1.43, respectively, indicating a lack of effect of omeprazole on the bioavailability of garenoxacin. Mean t (12.9 vs 14.0 h) and median Tmax (1.5 vs 1.8 h) were similar following administration of garenoxacin alone or concomitantly with omeprazole.
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Safety
Treatment-emergent AEs were reported by 3 of 14 (21%) subjects receiving the initial garenoxacin dose on days 1 to 3 (6 events), 6 of 14 (43%) subjects receiving omeprazole on days 4 to 7 (18 events), 3 of 12 (25%) subjects receiving concomitant garenoxacin (second dose) and omeprazole (days 8-11, 6 events), and 2 of 12 (17%) subjects receiving omeprazole alone (days 9 and 10). Overall, 33 treatment-emergent AEs were reported in 9 of 14 (64%) subjects. Twelve events were considered probably or possibly related to study medication, and all of the reported events were of mild to moderate intensity. The remaining 21 events were considered as either not likely to be related (n = 11) or unrelated (n = 10) to administration of study medication. The AEs reported most frequently, regardless of relationship to study medication, were abdominal pain, headache, nausea, and dysmenorrhea. There was a higher incidence of AEs reported when subjects were treated with omeprazole alone (43%) than when they received garenoxacin alone (21%). The incidence of AEs following concomitant garenoxacin plus omeprazole administration (25%) was similar to that observed following garenoxacin alone. Study treatments did not have any clinically relevant effects on vital sign measurements, clinical laboratory parameters, ECG, or physical examination findings.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The findings reported here contrast with those reported for trovafloxacin17 and gemifloxacin18 but are similar to those reported for ciprofloxacin and lomefloxacin.22 In a small, randomized, open-label pharmacokinetic study, administration of trovafloxacin 300 mg 2 hours after omeprazole 40 mg resulted in an 18% (90% CI, 0.7-0.9) and 32% (90% CI, 0.6-0.8) reduction in AUC and Cmax, respectively, compared with administration of trovafloxacin alone.17 A randomized, double-blind crossover study found the bioavailability of single oral doses of lomefloxacin 400 mg and ciprofloxacin 500 mg to be unaffected when administered 2 hours after 4 days of omeprazole 20 mg compared with administration of these antibiotics alone.22 The administration of omeprazole 40 mg increased the AUC and Cmax of gemifloxacin compared with administration of gemifloxacin alone, on average 10% and 11%, respectively; however, both parameters fell outside the predefined 90% CI (0.8-1.25), indicating that a lack of effect could not be concluded.18
Garenoxacin was well tolerated when given alone or in combination with omeprazole. As has been reported in other pharmacokinetic studies evaluating healthy subjects12,13 or subjects with respiratory tract infections,23 common AEs included headache and nausea. All the reported AEs were of mild to moderate intensity, which is consistent with other studies of garenoxacin in healthy subjects.12,13
Findings from the present study are limited by factors inherent to an open-label study. The pharmacokinetic effects of omeprazole on multiple doses of garenoxacin are not known. Further study is needed to assess the effects of steady-state omeprazole on multiple oral doses of garenoxacin in patients with bacterial infections.
In conclusion, oral administration of omeprazole 40 mg/d at steady state did not affect the pharmacokinetics of a single oral dose of garenoxacin 600 mg. Concomitant administration of garenoxacin and omeprazole was well tolerated. Therefore, garenoxacin can be administered with omeprazole or other agents that influence gastric pH to a similar or lesser extent.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Drs Krishna and Wang are employees of Schering-Plough Research Institute. Dr Grasela is an employee of Bristol-Myers Squibb Company and has an equity interest in the company. Mr Olsen is an employee of Bristol-Myers Squibb Company. Dr Kisicki has no personal conflicts to disclose; however, the clinical center with which he is affiliated has received grant research support from Bristol-Myers Squibb Company and Schering-Plough Research Institute.
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REFERENCES |
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6. Credito KL, Jacobs MR, Appelbaum PC. Time-kill studies of the antianaerobe activity of garenoxacin compared with those of nine other agents. Antimicrob Agents Chemother. 2003;47: 1399-1402.
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10. Weller TM, Andrews JM, Jevons G, Wise R. The in vitro activity of BMS-284756, a new des-fluorinated quinolone. J Antimicrob Chemother. 2002;49: 177-184.
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13. Gajjar DA, Sukoneck SC, Bello A, Ge Z, Christopher L, Grasela DM. Effect of a high-fat meal on the pharmacokinetics of the des-F(6)-quinolone BMS-284756. Pharmacotherapy. 2002;22: 160-165.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Stewart C, Gajjar D, Bello A, et al. Safety, tolerability and pharmacokinetics of BMS-284756, a novel des-F(6)-quinolone, following 28 days of once daily oral dosing in healthy subjects. Paper presented at: 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; September 22-25, 2001; Chicago, Ill.
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19. Toussaint B, Chedin M, Bordin G, Rodriguez AR. Determination of (fluoro)quinolone antibiotic residues in pig kidney using liquid chromatography-tandem mass spectrometry: I. laboratory-validated method. J Chromatogr A. 2005;1088: 32-39.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Toussaint B, Chedin M, Vincent U, Bordin G, Rodriguez AR. Determination of (fluoro)quinolone antibiotic residues in pig kidney using liquid chromatography-tandem mass spectrometry: Part II. intercomparison exercise. J Chromatogr A. 2005;1088: 40-48.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
21. Prilosec (omeprazole) [full prescribing information]. Wilmington, Del: AstraZeneca Pharmaceuticals LP; 2003.
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