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PEDIATRICS |
From the Clinical Pharmacology Research Center, Department of Adult and Pediatric Medicine, Bassett Healthcare, Cooperstown, New York (Dr. Amsden, Ms. Whitaker); Center for Anti-Infective Research and Development (Dr. Nicolau, Dr. Maglio) and Division of Infectious Diseases (Dr. Nicolau), Hartford Hospital, Hartford, Connecticut; and Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey (Dr. Bello, Dr. Russo, Mr. Barros, Dr. Gajjar).
Address for reprints: Guy W. Amsden, PharmD, FCP, Clinical Pharmacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326.
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ABSTRACT |
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Key Words: Garenoxacin • breast milk • lactation • pediatrics • breastfeeding
Garenoxacin (BMS-284756 or T-3811ME) is a novel des-F(6)-quinolone with a broad spectrum of antimicrobial activity that is being developed for a number of indications. As the development of resistant isolates or the potential side effects from altering normal bowel flora would be a concern with an inadvertent exposure of infants to low amounts/concentrations of an antibiotic obtained from their mothers' milk, identification of any potential exposure via this route is necessary. This is especially true when one considers that a number of related antibiotics (i.e., ciprofloxacin, pefloxacin, and ofloxacin) have demonstrated clearance via lactation.6 Based on this, the purpose of this study was to characterize the penetration of a single oral dose of garenoxacin into human breast milk and to assess the time after administration at which garenoxacin was no longer detectable.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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18 and 
35 kg/m2; were in good health, as determined by medical history, physical examination, electrocardiogram (ECG), and clinical laboratory determinations (hematology, serum chemistry, urinalysis, serum/urine pregnancy, urine toxicology, hepatitis B surface antigen, hepatitis C antibody, and HIV) within 21 days prior to garenoxacin administration; and were using a nonhormonal barrier method of contraception for 1 month prior to the study and were willing to continue using it during and for 1 month after the study if they were still of childbearing potential postpartum. Women who met any of the following criteria were excluded from the study: history or current evidence of any significant acute or chronic illness, including known or suspected hepatitis or HIV; any major surgery within 4 weeks of enrollment; history of any gastrointestinal disease, surgery, or abnormality that may negatively affect drug absorption; donation of or receiving blood products within 4 weeks of enrollment; inability to tolerate oral medication or venipuncture; history of alcohol or drug abuse within the past 6 months; evidence of organ dysfunction, history of seizures, or central nervous system disorder or clinically significant deviations from normal found during screening tests/exams; history of allergy to quinolones or any other related compounds; prior exposure to garenoxacin; use of an agent known to affect hepatic metabolism within 4 weeks of enrollment; use of an agent known to affect renal elimination, gastric acid production, or gastrointestinal motility within 2 weeks of enrollment; exposure to any investigational drug or placebo within 4 weeks of enrollment; or use of any other drugs, including over-the-counter and herbal/homeopathic preparations, within 1 week of enrollment. All screening laboratories were obtained after an overnight fast of at least 8 hours and, with the exceptions of the HIV and hepatitis antibody tests, were repeated within 24 hours of garenoxacin administration.
On study Day 1 for each subject, they were admitted to the enrolling study unit and administered a single oral 600-mg (1 x 400-mg tablet and 1 x 200-mg tablet, supplied by Bristol-Myers Squibb) dose of garenoxacin with 240 mL of water. Blood samples were collected in potassium EDTA-containing tubes predose and 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24, 48, and 72 hours postdose. Blood samples were centrifuged, and plasma was separated and stored at -20°C until assayed. Immediately prior to dosing, subjects expressed and collected the total amount of milk from both breasts. After dosing, expressed breast milk was collected over 0 to 6, 6 to 12, and 12 to 24 hours and, for 12-hour intervals, up to 120 hours, with a final attempt at collection being conducted by the subject at the end of each interval. Breast milk was collected by the subjects in polypropylene containers that were maintained at 5°C until delivered to the investigator at the study site. Once obtained, each interval's collection was mixed thoroughly, measured for volume, and a 5-mL aliquot stored at -20°C until assayed. Subjects had fasted for at least 8 hours prior to drug administration and continued fasting for an additional 4 hours postdose. Subjects were instructed to remain in an upright (seated) position for at least 2 hours after dosing and were not permitted to take any concomitant cation containing compounds (i.e., antacids, bismuth subsalicylate, zinc) for at least 12 hours predose and 12 hours postdose. Although subjects were ambulatory during their participation, they were restricted to the study site for at least the first 24 hours after study drug administration. Consumption of alcohol, grapefruit, grapefruit juice, and caffeinated products was prohibited for 72 hours prior to dosing and until the subject was discharged from the study.
Plasma and breast milk samples were shipped frozen in adequate amounts of dry ice for assay of garenoxacin concentrations by MDS Pharma Services (Sunnyvale, CA) and the Clinical Discovery Analytical Sciences Department of Bristol-Myers Squibb (Brunswick, NJ), respectively. Plasma and breast milk samples were assayed using validated liquid chromatography with tandem mass-spectrometry (LC/MS/MS) methods and internal standards of a stable isotope. Standard curves were analyzed by quadratic regression, using a weighting factor of 1/nominal concentration. The criteria for acceptance of an analytical run specified that predicted concentrations of at least three-fourths of the standards and two-thirds of the quality control samples be within ±15% of their individual nominal concentration values (±20% for standards at the lowest concentrations in the standard curves). The standard curves for the analysis of garenoxacin concentrations in both biomatrices were well fitted to the quadratic regression models over the concentration range of 0.01 to 10.00 µg/mL. The between-run precision and within-run precision for analytic quality control samples were no greater than 8.9% and 8.0% coefficient of variation (CV), respectively, with deviations from nominal concentrations of no more than ±8.5%.
The plasma concentration-time data for garenoxacin were analyzed via noncompartmental methods using the WinNonlin Professional 3.1 software package.7 The peak plasma concentration (Cmax) values and times to Cmax (tmax) were identified directly from the experimental observations. The area under the plasma concentration-time curve was calculated from time zero to T (AUCT), the last quantifiable concentration by trapezoidal and natural log-trapezoidal summation. The AUC from time zero to infinity (AUC
) was calculated from the summation of the AUCT and the final detectable plasma concentration, divided by the terminal elimination rate constant, which was determined from the slope of the terminal phase of the plasma profile determined by log-linear regression (using no weighting factor) of at least three data points to yield a minimum mean square error. The percentage of the garenoxacin dose secreted in breast milk (%BR) was calculated by dividing the amount of unchanged garenoxacin recovered in the breast milk over the entire collection period of 120 hours by the dose and multiplied by 100. Garenoxacin clearance from breast milk (CLB) was calculated by dividing the amount of drug recovered in the breast milk for the first 72 hours divided by AUCT. Milk/plasma ratios for the first 24 hours of the study period were calculated by dividing garenoxacin breast milk concentrations determined for each collection interval by the corresponding garenoxacin plasma concentration (determined at the midpoint of the breast milk collection interval). Summary statistical analyses of pharmacokinetic data and demographics were conducted using SAS version 6.12.8 The sample size for this study was not based on statistical power considerations.
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RESULTS |
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Summary garenoxacin plasma and breast milk pharmacokinetic parameters are provided in Tables I and II and Figure 1. Garenoxacin plasma concentrations were quantifiable for at least 72 hours after dosing in all subjects, and the AUC extrapolated following the last quantifiable time point (i.e., AUC-AUCT) was < 5% of the AUC in all cases. Mean peak garenoxacin breast milk concentrations were 3.0 mcg/mL (0- to 6-h collection interval), and concentrations appeared to decrease at a rate similar to that seen for plasma. Garenoxacin breast milk concentrations fell below the assay's limit of quantitation between the 72- to 84-hour and 108- to 120-hour collection intervals, with only 1 subject demonstrating quantifiable concentrations during the latter collection intervals (96-108 and 108-120 h). Mean breast milk to plasma garenoxacin concentration ratios ranged from 0.35 to 0.44 and appeared to be constant over a period of 24 hours postdose. A mean of 0.07% (0.42 mg) of the single 600-mg oral dose was recovered in the subjects' breast milk within 120 hours postdose.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The current study not only investigated the extent of the penetration into and clearance of garenoxacin, a novel des-F(6)-quinolone antimicrobial, via breast milk in women who had completed weaning their infants, but also attempted to determine when an infant would be able to safely restart breastfeeding after administration of a dose of the drug to their mother. Garenoxacin achieved moderate and constant penetration into breast milk, as reflected by breast milk to plasma concentration ratios ranging from 0.35 to 0.44 over the initial 24-hour postdose interval. This consistency is in sharp contrast to the high degree of variability noted with other fluoroquinolones such as ciprofloxacin and ofloxacin, which have ratios that range from minor fractions to multiples (0.02 to 3.79) of corresponding plasma concentrations.6 Although the breast milk concentrations of garenoxacin during the first 24 hours after dosing were readily detectable using a sensitive LC/MS/MS assay, the overall proportion of the 600-mg dose secreted over a 120-hour period could be considered minimal (0.07%). As such, an infant nursing from a mother who had received a single 600-mg oral dose of garenoxacin could theoretically be exposed to 0.42 mg of garenoxacin (0.105 mg/kg/day for a 4-kg infant over the period of 5 days of nursing). If extrapolated to a 14-day course of garenoxacin 600 mg once daily, total exposure would be approximately 5.88 mg.
Whether breastfeeding should be interrupted when it may be necessary to have a mother take garenoxacin was not a conclusion that this study was designed to answer. As with any drug that needs to be prescribed to a mother who is breastfeeding her infant, the decision rests with the potential risks to the infant once it has been established that the drug penetrates and is cleared via breast milk to any degree. Other than the inherent adverse effects of the drug itself, general risks that would be considered with exposure to any antimicrobial through breastfeeding are alteration of the infant's normal gastrointestinal flora, which may result in antibiotic-related diarrhea, and resistance development due to bacteria being exposed to sublethal concentrations of drug.
In conclusion, garenoxacin's penetration into breast milk results in concentrations that are approximately one-third those of corresponding plasma concentrations and decline in parallel to them. Overall potential exposure of an infant to a single 600-mg oral dose of garenoxacin administered to the mother is minimal and would most likely remain so even with repeated dosing during a full course of treatment.
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FOOTNOTES |
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Submitted for publication April 30, 2003; Revised version accepted November 14, 2003.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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1. American Academy of Pediatrics Work Group on Breastfeeding: Breastfeeding and the use of human milk (RE9729). Pediatrics 1997;100: 1035-1039.
2. Beaudry M, Dufour R, Marcoux S: Relation between infant feeding and infections during the first six months of life. J Pediatr 1995;126: 191-197.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Duncan B, Ey J, Holberg CJ, Wright AL, Martinez FD, Taussig LM: Exclusive breast-feeding for at least 4 months protects against otitis media. Pediatrics 1993;91: 867-872.
4. American Academy of Pediatrics Committee on Drugs: The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108: 776-789.
5. Hale TW, Kristensen JH, Hackett LP, Kohan R, Ilett KF: Transfer of metformin into human milk. Diabetologia 2002;45: 1509-1514.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Giamarellou H, Kolokythas E, Petrikkos G, Gazis J, Aravantinos D, Sfikakis P: Pharmacokinetics of three newer quinolones in pregnant and lactating women. Am J Med 1989;87(Suppl. 5A): 49S-51S.[Medline] [Order article via Infotrieve]
7. WinNonlin Professional 3.1 Model 2000. Mauntain View, CA: Pharsight Corporation, 1999.
8. SAS Institute: SAS/STAT User's Guide, Version 6, 4th ed., vol. 1. Cary, NC: SAS Institute, 1989.
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