Levofloxacin Pharmacokinetics (PK) in the Severely Obese
Condition: Obesity; Critical Illness
MeSH terms: Critical Illness
Study type: Interventional
Phase: Phase 4

Summary: 
      Obesity is known to affect the concentrations of certain medications in the body.
      Levofloxacin is a commonly used antibiotic. Based on what the investigators know about
      levofloxacin and how it moves through the body, obesity may affect levofloxacin
      concentrations. This study aims to show the effect of obesity on levofloxacin concentrations.

      The hypothesis is as follows: A 750 mg intravenous (IV) dose of levofloxacin administered to
      severely obese, critically ill patients will yield serum concentrations that are likely to be
      therapeutic.
    

Detailed description: 
      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.
    

Intervention name(s): Levofloxacin 750 mg IV
Intervention type(s): Drug
Intervention description(s): PK in obesity
Other intervention name(s): Levaquin
Intervention MeSH terms: Levofloxacin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment