The Pharmacokinetics of Extended Duration High-dose Cefixime for the Decreased Susceptibility of Neisseria Gonorrhoeae: A Phase I Pilot Study

This study is a Phase I, open label, non-randomized, dose-frequency escalation
pharmacokinetics study among 24 healthy male and female subjects, aged 18 to 45 years to
determine the pharmacokinetics and safety of high multi-dose cefixime for the treatment of
reduced susceptibility gonorrhea. The study will occur in two stages as described below.
Stage 1: Confirm/establish the pharmacokinetics (PK) of 400mg and 800mg doses of cefixime
tablet. Stage 2: Define dosing frequency necessary to achieve total serum cefixime levels
that exceed 2.0 mcg/mL for over 20 hours. Stage 1 (Cohorts A and B): Six subjects will be
admitted to the Johns Hopkins Bayview Clinic Trials Unit to assess each dosing regimen, for a
total of 12 subjects. At time=0, subjects will undergo baseline serum cefixime levels,
followed by ingestion of cefixime. Serum collections will occur at times 0, 1, 2, 4, 8, 12,
16, 20, and 24 hours. Cohort B will have the same serum collection time points as Cohort A.
Cohorts A & B will be run nearly simultaneously as logistically feasible. Stage 2 (Cohorts C
and D): After determining the PK parameters of single dose 800mg, the PK simulation model
will be repeated, adjusting the model as needed based on findings from study Stage 1.
Assuming there are no major discrepancies between Figure 2 (above) and the new PK
simulations, the following regimens will be tested, beginning with Cohort C. Six subjects per
dosing regimen, Cohorts C and D, will be admitted to the Johns Hopkins Bayview Medical
Center, for a total of 12 subjects. The 800mg q12 hour x 2 regimen (Cohort C) will be tested
first. For Cohort C, serum cefixime levels will be drawn at 12, 16, and 26 hours. If the q12
regimen is deemed safe and tolerable after review by the SMC, Cohort D will commence with the
800mg q8 hour x 3 regimen. Total serum cefixime levels will be drawn for Cohort D at 8, 16,
20 and 26 hours (see Section 7.2). All Stages, All Cohorts: All samples collected for PK
analysis will be shipped to the University of Toledo, Dr. Jeffrey Blumer's HPLC lab for
processing. Specimens will be analyzed by high performance liquid chromatography (HPLC) for
total cefixime concentration levels. Targeted clinical evaluations will be used to monitor
for subject reported side effects. Subjects will be asked about specific symptoms they may
have experienced, including abdominal pain, nausea, vomiting, diarrhea, flatulence, headache,
and rash, or any other symptoms. Additionally, subjects will be asked to maintain a Subject
Diary (Appendix E) from Study Day 0 through Day 7 to record information about any symptoms
experienced or medications taken. Study duration is approximately 47 weeks.

Inclusion Criteria:

- Healthy male or female subjects between 18 and 45 years, inclusive

- Ability to understand the consent process and procedures

- Informed consent obtained and signed

- Body mass index (BMI) < 35 kg/m^2

- Subjects agree to be available for all study visits

- Negative Breathalyzer

- Agreement by female subjects with reproductive potential to use an adequate method of
contraception during the study and for 30 days after study drug administration. Female
subjects must agree to the use of TWO reliable methods of contraception while
receiving study drug and for 30 days after study drug administration if sexually
active, which can include: condoms, spermicidal gel, diaphragm, hormonal or
non-hormonal intrauterine device, surgical sterilization, oral contraceptive pill
(OCP), and depot progesterone injections.

Exclusion Criteria:

- Subjects who take any prescription medication on a regular basis (except oral
contraceptives, OCPs), including but not limited to, anti-psychotics,
anti-depressants, anti-epileptics, cardiac medications, anti-hypertensives etc.

- Medical condition that precludes participation, including the following:

- Hypertension with confirmed systolic blood pressure >140 mmHg or confirmed diastolic
blood pressure >90 mmHg, measured after 10 - 15 minutes of rest

- Morbid obesity (BMI>/=35)

- Current diagnosis of pulmonary disease

- History of or current diagnosis of diabetes

- Autoimmune disorder, such as lupus, Wegener's, rheumatoid arthritis

- History of malignancy except low-grade skin cancer, (i.e., basal cell carcinoma
thought to be cured)

- Known diagnosis of prolonged QT interval

- History of alcohol abuse

- History of seizure disorder

- History of renal disease

- Chronic renal, hepatic, or pulmonary disease or other condition that could interfere
with the absorption of the study drug or predispose to adverse gastrointestinal events
(e.g., surgical resection of significant proportions of the stomach or bowel, gastric
bypass, gastric banding, irritable bowel syndrome, inflammatory bowel disease)

- Positive serology results for HIV, HBsAg, or HCV antibodies

- Subjects who have taken any prescription drugs in the previous 14 days or within 5
half-lives before dosing

- Ingestion of over the counter medications or herbal supplements within 7 days of
dosing

- Positive urine toxicology for marijuana, cocaine, amphetamines, opiates, PCP,
barbiturates or benzodiazepines

- History of allergic reaction or intolerance to cephalosporins

- History of allergic reaction to penicillin (all stages)

- Subjects with an allergy to macrolides may not participate in Stage 3

- Subjects with QTc >450ms (Fridericia's correction) on screening ECG may not
participate in Stage 3.

- Positive pregnancy test; pregnant or nursing women

- Screening laboratory tests outside of the acceptable limits presented in Appendix C

- Any specific condition that, in the judgment of the Investigator, precludes
participation because it could affect subject safety