Levofloxacin Pharmacokinetics (PK) in the Severely Obese

Although the pharmacokinetics of levofloxacin have been consistent in various study
populations, obese and critically ill individuals are likely to demonstrate altered
distribution and clearance of levofloxacin, in addition to potentially having altered serum
concentrations. Thus, the following study proposes to address the question: What are the
effects of the combination of critical illness and severe obesity on the pharmacokinetics of
levofloxacin. The data from this investigation will also be combined with obese ambulatory
volunteer data to more accurately define the effects of obesity on the pharmacokinetic
parameters of levofloxacin.

There are no comparisons in this study. The specific aims are:

1. Characterize pharmacokinetic parameters of levofloxacin in obese critically ill
individuals: Cmax, Tmax, area under the concentration-time curve (AUC), volume of
distribution, elimination rate, serum half-life, and urine clearance.

2. Determine the percentage of patients that achieve an AUC/MIC ratio* of 88, which is
achieved in 72% of non-obese, non-critically ill patients and is correlated with
efficacy.

Hospitalized subjects will be identified by medical or pharmacy house staff officers
providing care in the intensive care unit and through computerized medication profiles
provided by UKCMC or UTMB Pharmacy Services. Once an investigator determines eligibility, a
recommendation will be made to enroll the patient in the study to the attending physician.

After obtaining permission to enroll the subject, the investigator will obtain informed
consent from the patient or his/her appropriate surrogate. The decision of competence will be
made by the physician, in conjunction with family members, if available. Assessment of
competence for providing informed consent will be documented in the medical record via the
statement below:

"The patient was fully assessed and is/is not competent to agree to the study. Family
members, including the patient's surrogate, were present for the assessment and agree the
patient is/is not competent for purposes of study entry. This assessment and conversation
with the family was witnessed by nurse assigned to the patient's care."

The informed consent document will be signed and an original copy will be placed in the
patient's medical record. No study related orders will be written until the signed consent
form is included in the medical record.

Ambulatory subjects will be identified by medical staff. Participants are likely to be
recruited from physician clinics such as sleep clinic.

Research Procedures:

Ambulatory volunteers will be admitted for 24 hours to the UTMB or UK General Clinical
Research Center. Hospitalized participants will be admitted to the UKCMC or UTMB hospital for
reasons other than participation in the study. Each participant will receive a 750 mg
intravenous levofloxacin dose.

A peripheral intravenous catheter will be placed in each arm for drug administration and
serial blood sampling. Pre-existing intravenous access will be utilized when possible.
Baseline serum chemistry and complete blood count will be obtained for each individual prior
to the levofloxacin dose for screening purposes. Subjects will rest in a supine position
while receiving a 750 mg intravenous dose of levofloxacin over 90 minutes. Serial blood
samples will be obtained 1.5, 3, 4, 5, 8, 12, and 24 hours after the beginning of
administration of levofloxacin. Urine collection will also be completed during the 24 hour
study period.

Venous blood samples will be collected in 10 ml standard red-top vacuum tubes. The samples
will be centrifuged for 10-15 minutes at 5000 rpm, the serum removed, and placed in a plastic
vial suitable for freezing. The samples will be placed in a -80oC freezer until ready for
shipment to the site for assay. Urine will also be collected during the 24 hour study period
to assess renal function as well as measure drug elimination. Two aliquots will be extracted
from the total urine volume: one for levofloxacin assay (storage procedure as above) and one
for urine creatinine measurement (for 24 hour creatinine clearance). Urine aliquots and serum
samples will be transported to the University of Kentucky College of Pharmacy for
levofloxacin assay.

Ambulatory participants at the University of Texas Medical Branch will undergo a whole body
potassium-40 counter scan in order to determine the percentage of adipose and lean body mass.
This will consist of subjects lying in a supine position for 30 to 45 minutes under the whole
body counter that is housed in the General Clinical Research Center at the University of
Texas Medical Branch. The ambulatory volunteers will be scanned during the 24 hour study
period.

Initial data to be collected include: age, height, weight, admitting diagnosis, serum
creatinine, blood urea nitrogen, fluid intake/output, concomitant medications, concomitant
disease states that might affect pharmacokinetics, any operating room procedures, documented
or suspected infection site, pertinent microbiological culture results, and adverse drug
reactions. Levofloxacin pharmacokinetics will be analyzed assuming a two-compartment model
with first order elimination using WinNonLin 4.01 (Pharsight Corp, Mountainview, CA).
Patients will be followed for 24 hours.

Inclusion Criteria:

1. 18 to 55 years of age

2. Body mass index > 35 kg/m2

3. Has been prescribed levofloxacin, but the medication has not yet been administered
(hospitalized cohort only)

Exclusion Criteria:

1. Hypersensitivity to fluoroquinolones

2. Creatinine clearance < 50 ml/min

3. Administration of levofloxacin within the previous 7 days

4. Pregnant or lactating females

5. Participation in another investigational protocol within the past 30 days