Objective: To determine the pharmacokinetics of cefuroxime (CXM) oral suspension in healthy, elderly volunteers.
Methods: A single 250 mg dose of CXM oral suspension (250 mg/5 ml) was administered to twelve healthy, elderly volunteers. Serum samples for CXM analysis were collected at baseline (pre-dose), 15, 30, 60, 90 and 120 minutes, and 3, 4, 6, 8, 10, and 12 hours after the dose. Serum CXM concentrations were analyzed using high-performance liquid chromatography. Pharmacokinetic (PK) parameters were determined using noncompartmental analysis.
Results: Twelve subjects (9 male, 3 female) completed the study. Demographic results were as follows (means ± standard deviations): age, 71 ± 3.7 years; weight, 77 ± 13 kg; estimated ClCr 67 ± 13 ml/min. Composite PK parameters were as follows (means ± standard deviations): Cmax, 3.38 ± 0.77 mg/ml; t1/2, 1.9 ± 0.2 hr; kel, 0.36 ± 0.04 hr-1; CL/F, 0.22 ± 0.05 ml/min/kg; AUC0-4, 15.7 ± 2.6 mg*hr/ml; V/F, 0.59 ± 0.12 l/kg. Median Tmax was 3 hours (interquartile range 2 – 4 hours). Previously published PK studies of a 250 mg dose of CXM oral suspension in younger volunteers (19-40 years) reported similar Cmax and Tmax values; however, t1/2 was 0.5 – 0.7 hours. longer and AUC0-4 was 10 – 58% higher in the current study.
Conclusions: Cefuroxime axetil oral suspension in elderly subjects produces similar Cmax and Tmax values compared to previous data in younger subjects. The suspension appears to be an acceptable alternative to CXM tablets in the elderly.
J Inform Pharmacother 2001;5:100-103.
Cefuroxime axetil (CXM) is a second-generation cephalosporin antibiotic with activity against a variety of Gram-positive and Gram-negative organisms. It is effective for the treatment of upper and lower respiratory tract, urinary tract, and skin and soft tissue infections. CXM is available as a film-coated tablet and an oral suspension formulation intended for use in children ages 3 months and older. However, elderly patients may also benefit from a liquid dosage form because factors such as impaired cognition, presence of feeding tubes, dysphagia, and dysmotility may make the administration of tablets difficult or dangerous. To date, no data have been published describing the pharmacokinetics of CXM suspension in elderly volunteers. Determining the pharmacokinetics of CXM suspension in this population is important because it may generate lower peak serum concentrations than tablets. Additionally, elderly patients may have altered CXM pharmacokinetics due to age-related decreases in renal function. The purpose of this study was to determine the pharmacokinetics of CXM oral suspension in healthy, elderly volunteers.
The study was approved by the Western Institutional Review Board and written, informed consent was obtained for all subjects. Inclusion criteria were age > 60 years and ability to give informed consent. Exclusion criteria were history of allergy to penicillin or cephalosporin antibiotics, acute or chronic illness that might alter the pharmacokinetics of CXM (e.g. renal insufficiency, congestive heart failure, gastroparesis), anemia, poor venous access, or treatment with other antimicrobial agents. Prior to beginning the protocol, a medical history, physical examination, and laboratory testing were performed including a complete blood count, comprehensive metabolic panel, and urinalysis.
Each patient received a single 250 mg dose of CXM oral suspension (Ceftin, GlaxoWellcome Inc., Research Triangle Park, NC.) immediately after eating breakfast in order to promote maximal drug absorption. Blood samples were collected at baseline (pre-dose), 15, 30, 60, 90 and 120 minutes, and 3, 4, 6, 8, 10, and 12 hours after the dose. Vital signs were monitored at baseline, 30 and 60 minutes, and 3, 6, and 12 hours after the dose. After blood collection was completed, each patient returned for a follow up study visit within three days for a physical exam and to report adverse drug events.
Blood samples were centrifuged upon collection and the serum stored at -70°C until assayed. Serum samples were analyzed for cefuroxime by high-performance liquid chromatography using a modified version of an assay by Hanes et al. Important assay modifications included monitoring absorbance at 280 nm instead of 255nm and removing the ion-pairing agent from the mobile phase. The CXM retention time was approximately 17.5 minutes. The assay was validated according to consensus guidelines. Extraction efficiency averaged 96% with less than 5% coefficient of variation across the concentration range for standards (0.1 µg/ml, 1 µg/ml, and 10 µg/ml). Within-day and between-day coefficients of variation for control concentrations (0.2 µg/ml, 2 µg/ml, and 7 µg/ml) were less than 5%. Assay results were considered valid only if the accuracy of standard and control concentrations was ± 10% of the known values for that day. The r2 values for standard curves were greater than 0.98 for each day. Cefuroxime concentrations were determined using weighted linear regression (1/concentration2) from a line of best fit to the standard curve for that day.
Pharmacokinetic parameters were calculated from the CXM serum concentrations using noncompartmental analysis. The maximum serum concentration (Cmax) and the time to reach this concentration (Tmax) were visually determined directly from the concentration-time curves. The elimination constant (kel) was determined by linear regression of the natural log of concentrations in the elimination phase. Terminal concentrations that were in a straight line based on visual inspection of a log-linear data plot were used to calculate kel. The t1/2 was determined by 0.693/kel. The area under the curve from time 0 to the last concentration (AUC0-12) was determined using the linear trapezoidal rule. The area under the curve from time 0 to infinity (AUC0-4) was extrapolated by dividing the last measured concentration by the kel and adding this value to the AUC0-12. Oral clearance (CL/F) was determined by dose/AUC0-4. Oral volume of distribution (V/F) was determined by dose/(AUC0-4* kel). Creatinine clearance was estimated using the Cockcroft-Gault equation.
Twelve subjects were enrolled in the study and no adverse drug effects were reported. Patient characteristics and pharmacokinetic results are shown the Table I. A composite concentration-time curve for all study subjects is depicted in the Figure 1. Extrapolated AUC12-4 accounted for only 2 – 6% (mean 3%) of AUC0-4.
Table I. Patient Characteristics and Pharmacokinetic Parameters
|Mean ± SD||71 ± 4||170 ± 12||77 ± 14||67 ± 13||3.38 ± 0.77||0.360 ± 0.04||1.9 ± 0.2||15.8 ± 2.6||0.22 ± 0.05||0.59 ± 0.12|
|Median (25-75%)||3 (2-4)|
CLCr = creatinine clearance, Cmax = maximum concentration, Tmax = time to maximum concentration, kel = elimination constant, t1/2 = half-life, AUC0-4 = area under the curve from time zero to infinity, CL/F = oral clearance, V/F = oral volume of distribution
Figure 1: Composite Concentration-Time Curve for all Subjects.
The concentration-time curve represents the mean CXM concentration (± one standard deviation) at each time point sampled.
In this study, mean CXM Cmax and median Tmax values were similar to those previously reported in younger adult volunteers (19-40 years) following a single 250 mg dose of CXM oral suspension (ranges: 2.48 – 3.85 mg/l and 2.0 – 3.6 h) (2,3,11). These results indicate good bioavailability of CXM oral suspension in elderly subjects; however, two subjects had a delayed Tmax of six hours. The reason for apparent delayed absorption in these subjects is unknown. Mean t1/2 and AUC0-4 were mildly increased compared to previous data in younger volunteers (ranges: 1.2 – 1.4 h and 10 – 14.4 mg·h/l). The modest elevations in t1/2 and AUC0-4 observed are likely due to age-related decreases in renal function and would not be expected to result in clinically significant accumulation with Q12 hour dosing. Cefuroxime has a good safety profile even with high dose intravenous therapy that produces much higher serum concentrations than those observed in this study. A more sophisticated multiple-dose study would be needed to provide definitive dosing guidelines; however, the results of this study suggest that no dose adjustment is needed in elderly subjects with normal renal function. Currently, dosing changes for impaired renal function are not recommended until CLCr is less than 30 ml/min.
The major limitation of this study is that there was not a control group of elderly volunteers who received CXM tablets. A previous study of CXM tablets (250 mg Q12H) in elderly patients has been published and showed a higher Cmax and longer t1/2 than our study. However, comparisons with the current data are difficult. The higher Cmax in the previous study may have been due to a lower mean body weight seen in the former study (57 vs. 77 kg), and the longer t1/2 may have been because of poorer renal function (mean estimated CLCr 35 vs. 67 ml/min). Nonetheless, the present data show that CXM oral suspension in elderly volunteers results in similar Cmax and Tmax values to those previously reported in younger volunteers. Cefuroxime axetil oral suspension appears to be an acceptable alternative to CXM tablets in elderly patients.
This study was funded by an unrestricted grant from GlaxoWellcome Inc., Research Triangle Park, NC. The study sponsor was not responsible for the design, conduct, interpretation, or analysis of the study, nor was it involved in the review or approval of this manuscript.
The authors would like to acknowledge Bernd Meibohm, Ph.D. for his assistance in the pharmacokinetic analysis.