In the case of colistin with a narrow therapeutic area, therapeutic drug monitoring is needed as a way to increase the patient's treatment success rate. It is necessary to study producing pharmacokinetic parameters for proper loading dose·regimen setting by patients and appropriately therapeutic drug monitoring. However, since it is difficult to perform pharmacokinetic studies in which repeated blood collection for calculation of pharmacokinetic parameters is performed in patients, we intend to conduct colistin pharmacokinetics studies in healthy people. Also, we intend to explore an appropriate biomarker that can predict the possibility of nephrotoxicity when colistin is administered to healthy volunteers. We would like to propose that it can be used in future patient research.
By investigating like this pharmacokinetic and biomarkers exploring, if the suitable pharmacokinetic parameters and biomarkers for colistin in Korean patients will be produced, it is expected to improve the successful treatment of patients.

Treatment

Only healthy volunteers undergo screening assessment to determine their eligibility for enrollment into the study from -28 to -1 day (-28d~-1d) before the first administration day (1d). At -1 day, subjects who enrolled are admitted into the Kyung-Hee University hospital clinical trial center and fasted except water. On the first administration day (1d), the investigational product(IP) is administered to subjects after pharmacokinetics blood and urinary collection, biomarker exploration blood and urinary collection, and safety test. The IP dosage is that 2.5 mg/kg of colistimethate sodium (as colistin) mixed with normal saline is administered by constant rate infusion for 1 hour. After the first administration, planned tests are conducted including pharmacokinetics and biomarker exploration blood and urinary collection. The IP is administered repeatedly from 1day evening. On the third day from the first administration, planned tests including pharmacokinetics and biomarker exploration blood and urinary collection are conducted for 24 hours after the last IP administration. Since then, subjects are discharged. In the 5 day morning after 48 hours from 3 day, subjects visit the clinical trial center for pharmacokinetics and biomarker exploration blood and urinary collection. At 7-9 days, after the safety assessment for all subjects who administered the IP is conducted and the study ends.

Arm Label

Target Number of Participant

Arm Type

Arm Description

At -1 day, subjects are admitted into the Kyung-Hee University hospital clinical trial center and fasted except water. On the first administration day (1d), the investigational product(IP) is administered to subjects after pharmacokinetics blood and urinary collection, biomarker exploration blood and urinary collection, and safety test. The IP dosage is that 2.5 mg/kg of colistimethate sodium (as colistin) mixed with normal saline is administered by constant rate infusion for 1 hour. After the first administration, planned tests are conducted including pharmacokinetics and biomarker exploration blood and urinary collection. The IP is administered repeatedly from 1day evening. On the third day from the first administration, planned tests including pharmacokinetics and biomarker exploration blood and urinary collection are conducted for 24 hours after the last IP administration. Since then, subjects are discharged. In the 5 day morning after 48 hours from 3 day, subjects visit the clinical trial center for pharmacokinetics and biomarker exploration blood and urinary collection. At 7-9 days, after the safety assessment for all subjects who administered the IP is conducted and the study ends.

Gender

Age

Description

1) Subject who voluntarily agree with participation and sign informed consent approved by IRB, after a listened explanation about this clinical trial before the screening test
2) Healthy male between 19 and 45 years of age at the time screening tested
3) Bodyweight between 55 and 90 kg, and BMI between 18.0-27.0 kg/m^2  ☞ BMI = (weight [kg])/(height [m])^2
4) Subject who is determined to participate by a protocol by physical exam, clinical laboratory test, inquiry, and others, i.e., Subject who has no congenital or chronic disorders and symptoms or manifestations by internal medical examination

1) History of hepatic, gastrointestinal, circulatory, renal, respiratory, endocrine, neurologic, immunologic, hematologic, psychiatric system, and neoplasm
2) History or clinical evidence of drug abuse
3) History or ongoing of significant allergy of prescription or over-the-counter medication
4) History of hypersensitivity against the investigational product, polymixin B or Colistin
5) Taking any prescription or traditional medication within 2 weeks or over-the-counter medication within 1 week before first investigational drug (IP) administration (but, in the investigator's judgment, when other conditions are suitable, the subject can participate in this trial.)
6) Participation in other clinical trials within 6 months before first IP administration (previous clinical trial's end date is the last administration day)
7) Before first IP administration, whole blood donation within 2 months, apheresis blood donation within 1 month, or blood transfusion within 1 month
8) Smoker over 10 cigarettes per day for 3 months before the first IP administration or who unable to quit smoking from 3 days ago before the first IP administration to last visit
9) Positive result on serology tests (for HBs antigen, HCV antibody, and HIV antibody)
10) Subject who meets any of the following criteria at screening test
  ① At the vital sign check, systolic blood pressure under 90 mmHg or over 150 mmHg, or diastolic blood pressure under 60 mmHg or over 100 mmHg
  ② At the electrocardiogram, QTc over 450 msec or manifestation or significant abnormal rhythm
  ③ Renal insufficiency (as evidenced by an estimated eGFR(estimated Glomerular Filtration Rate) < 60 mL/min/1.73m^2 based on the MDRD(Modification of Diet in Renal Disease) formula)
  ④ Hepatic insufficiency (liver enzymes in the blood (AST and ALT) over 1.5 times of upper limit of normal)
11) In the investigator's judgment, subject who has clinical abnormal manifestations of renal function (e.g., severe renal impairment)
12) Contraindications or precautions to investigational product (patients who have myasthenia gravis or porphyria)
13) Subject who refuse to practice acceptable methods of contraception as follows
  A. Spouse/partner's use of an intrauterine device that proved in failure rate
  B. Use of spermicide in conjunction with a barrier method(male or female)
  C. Subject or partner's surgery (vasectomy, salpingectomy/tubal ligation, hysterectomy)
14) Subject who is unable to intake standard meal provided by the clinical trial center
15) Subject who is unable to read the trial contents such as the informed consent form or to understand this trial (e.g., who not able or limited ability to read to informed consent form)
16) Any other factor including laboratory test that, in the investigator's judgment, inappropriate to participate in this study

C_max of colistin

Day 1, Day 3

C_trough of colistin

Day 1~3

AUC_tau of colistin

Day 3

Plasma biomarkers of nephrotoxicity

Day 1~3

Urinary biomarkers of nephrotoxicity

Day 1~3