Aerosolized and Intravenous Colistin in Healthy Adults

"Colistin" (the first breakdown product colistimethate sodium, also known as polymyxin E) is
comprised of approximately 30 different polymyxins, with colistin A (polymyxin E1) and
colistin B (polymyxin B) accounting for upwards of 85% of the mass. It is amphipathic,
cannot be absorbed from the gastrointestinal tract and is administered intramuscularly,
intravenously (IV) or via inhalation. While approved for aerosolized use in the United
Kingdom, and used in Europe for decades as such, aerosolized colistin is not FDA-approved in
the United States. The intravenous formulation is approved for use in the U.S., but due to
the age of the drug, it did not undergo rigorous studies of safety prior to FDA-approval.
Thus, detailed pharmacokinetic data are limited and dosing is not standardized, although the
maximum IV dose should not exceed 5mg/kg/day, divided into two to four equal doses. In the
United Kingdom, the recommended dosing of nebulized colistin for adults is one million units
(1MIU) twice daily. Despite the paucity of dosing and safety guidelines, aerosolized
colistin is being prescribed regularly out of necessity given the emergence of multi-drug
resistant organisms (MDROs). MDROs are strongly associated with nosocomial pneumonia and
several strains are only susceptible to this older drug, thus there is an urgent need for
clarification on the safe use of colistin, including in aerosolized form as this delivers a
high concentration of drug directly to the infection site. This is a randomized,
open-labeled Phase 1 trial of aerosolized and/or IV formulations of colistin as multiple
doses over seven days. 39 healthy male and female subjects, 18-45 years of age will be
admitted for an inpatient study with outpatient follow-up. The primary objective of this
trial is to evaluate the safety and tolerability of multiple doses of aerosolized and
intravenous colistimethate sodium separately or in combination in healthy adult subjects.
The secondary objective of this trial is to determine the pharmacokinetics of multiple daily
doses of aerosolized and intravenous colistimethate sodium separately or in combination in
healthy adult subjects. Subjects will participate for up to 25 days plus a screening and a
follow-up appointment. The duration of this study shall be for two years, including
screening, study conduct (including scheduled SMC reviews), study follow-up and preparation
of all reports.

Inclusion Criteria:

1. Informed consent obtained and signed 2. Aged between 18 and 45 years, inclusive 3. Body
Mass Index (BMI, weight in kg divided by the square of height in meters) between 18 and
35.0 kg/m^2, inclusive 4. Able to comply with protocol requirements for the entire
duration of the study 5. Healthy on the basis of a screening medical evaluation (including
physical examination, vital signs, blood biochemistry and hematology, urinalysis, and
history).

Exclusion Criteria:

1. Heterosexually active females of child-bearing potential, defined as being
physiologically capable of becoming pregnant, unless they agree to use two of the
following acceptable methods of contraception throughout their participation in the study
and for at least 12 weeks after the final dose: (a) established use of oral, injected or
implanted hormonal contraception, (b) intrauterine Device (IUD or Coil) (c) a female
barrier method (diaphragm or cervical/vault cap) and/or (d) condom plus spermicidal
cream/gel 2. Heterosexually active males unless they agree to use two concomitant
acceptable methods of contraception throughout their participation in the study and for at
least 12 weeks after receiving their final dose of study medication (examples include:
vasectomy combined with latex condom with spermicide, latex condom with spermicide
combined with a female partner who practices an acceptable method of contraception as
indicated above) 3. History or current abuse of alcohol, barbiturates, amphetamines,
tetrahydrocanninol, phencyclidine, cocaine, heroin, or other narcotics, as evidenced by a
reported history or positive screen for these agents 4. Any clinically significant (as
deemed by the Principal Investigator) history of asthma; cardiovascular, pulmonary,
hepatic, renal, hematologic, gastrointestinal (including eating disorders), endocrine,
metabolic, immunologic, dermatologic, neurologic (including a history of seizures, ataxia,
or Myastenia Gravis), psychological, or psychiatric disease; and/or a past or family
history of porphyria 5. Use of tobacco/nicotine within 3 months prior to Screening and for
the entire duration of the study); 6. Treatment with another investigational drug 60 days
prior to and/or during the study 7. Co-enrollment in another study involving the intake of
medication 8. Immunocompromised status, including a positive HIV-1 (Human Immunodeficiency
Virus) or HIV-2 test by ELISA at screening 9. Previously demonstrated clinically
significant allergy or hypersensitivity to colistimethate sodium or its excipients 10.
Donation of blood or significant blood loss within 56 days of study Enrollment or during
study duration, or plasma donation within 28 days preceding study Enrollment 11. Hepatitis
B, or C infection (confirmed by hepatitis B surface antigen, or hepatitis C virus
antibody, respectively) at screening 12. Laboratory abnormalities at Screening as outlined
below: a. Serum creatinine (>/=1.1 x ULN), b. Hemoglobin (<11.0 or >17.5g/dL), c. Platelet
count (<125,000 or >450,000/mm^3), d. Absolute neutrophil count (<1300mm^3), e. Serum
blood urea nitrogen (>/=1.2 x ULN) f. Aspartate aminotransferase (AST, >/=1.2 x ULN), g.
Alanine aminotransferase (ALT, >/=1.2 x ULN), h. Proteinuria (spot urine) greater than
trace and/or hematuria greater than trace; Note: Subjects may undergo a repeat screening
test of out-of-range analyte(s) at the discretion of the investigator to confirm a
plausible alternative explanation that will be indicated in the source documentation. A
repeat laboratory test may be used to satisfy eligibility requirements. 13. Intake of any
of the following medications within 30 days prior to Screening and during the study:
acyclovir, adefovir, aminoglycosides, amphotericin, cisplatin, cyclosporine,
fluoroquinolones, foscarnet, ganciclovir, pamidronate, sirolimus, tacrolimus, and
vancomycin, and/or any neuromuscular blockers;- Intake of NSAIDs (ibuprofen, naproxen,
etodolac) within 48 hours of dosing and any inhaled medication within 5 days of dosing.
Additionally, subjects may be excluded due to intake of medications not listed here at the
discretion of the PIs (Principal Investigators) 14. Intake of NSAIDs (ibuprofen, naproxen,
etodolac) within 48 hours of dosing and any inhaled medication within 5 days of dosing.
Additionally, subjects may be excluded due to intake of medications not listed here at the
discretion of the PIs; 15. FEV1 (Forced Expiratory Volume) <80 percent predicted 16. Prior
evidence (symptoms within the past year) of vestibular problems or neuropathy 17. Abnormal
QT interval at screening ECG (Electrocardiogram) (Bazett correction >450 milliseconds) or
significant abnormities according to the cardiologist's final reading 18. A grade 3 or 4
clinical or confirmed laboratory toxicity (as outlined in Appendix C) which does not
return to grade 2 or lower; 19. Any condition that would, in the opinion of the
investigator, place the subject at an unacceptable risk or injury, or render the subject
unable to meet the requirements of the protocol.