To evaluate the safety and tolerability of multiple escalating doses of intravenous WCK 4282 in healthy, adult, human subjects.To evaluate the pharmacokinetics (PK) of multiple escalating doses of 1g:1g (1 vial) of intravenous (IV) WCK 4282 every 8…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety, tolerability and pharmacokinetics
Secondary outcome
N.A.
Background summary
The Investigational Product (IP) is WCK 4282, Wockhardt*s proprietary
injectable, antibacterial combination product consisting of cefepime and
tazobactam. Each vial of WCK 4282 is available in a fixed dose combination of
1g cefepime and 1 g tazobactam. Cefepime is a *fourth generation* cephalosporin
with an extended spectrum of activity against Gram-negative and Gram-positive
pathogens. Cefepime was introduced in clinical practice in 1994. Cefepime is
approved for the treatment of moderate to severe infections such as pneumonia,
empiric therapy for febrile neutropenia, uncomplicated and complicated urinary
tract infections (including pyelonephritis), uncomplicated skin and skin
structure infections, and complicated intraabdominal infections (United States,
Food and Drug Administration [FDA] approved indications). Cefepime doses for
the treatment of the above-mentioned indications range from 0.5 to 2 g every 8
to 12 hours (q8h to q12h) daily for approximately 7 to 10 days.
Unlike other extended spectrum cephalosporins, the methylpyrrolidinium group of
cefepime confers a zwitterionic charge that enhances bactericidal activity by
rapid penetration through porin channels in the outer membrane of Gram-negative
pathogens. Being a fourth generation cephalosporin, cefepime is more potent
than third generation cephalosporins such as ceftazidime. Most importantly, it
tends to be superior to even ceftazidime against Pseudomonas strains. One of
the important attributes of cefepime is that it withstands the hydrolysis by
varieties of extended spectrum lactamase enzymes (ESBLs). In particular,
Enterobacteriaceae that harbor inducible chromosomal AmpC Beta-lactamases, such
as Citrobacter, Enterobacter, Proteus, Serratia, etc, are typically resistant
to third generation cephalosporins, but demonstrate susceptibility to cefepime.
Even Enterobacteriaceae which are high-level producers of AmpC Beta-lactamases,
and are ceftazidime resistant, may still show a moderate rise in cefepime
minimum inhibitory concentration (MIC). Consequently, cefepime is an attractive
choice for combining with an appropriate lactamase inhibitor active against
both class A and class C enzymes. Such a combination is also likely to remain
effective even against strains co-expressing Class A and Class C lactamases.
Tazobactam, triazolyl-substituted penicillanic acid sulphone, is a
Beta-lactamases inhibitor that has been successfully combined with piperacillin
to protect this antibiotic from Class A ESBLs which mediate hydrolysis.
Tazobactam is safe and has been used extensively clinically in combination with
piperacillin by various manufacturers, including under the brand name Zosyn,
which is approved for a range of indications. United States FDA approved
indications include appendicitis/peritonitis, uncomplicated and complicated
skin and soft tissue infections, postpartum endometritis, community-acquired
pneumonia, and nosocomial pneumonia. The usual daily dose of Zosyn for adults
is 3.375 g every 6 hours totaling 13.5 g (12 g piperacillin and 1.5 g
tazobactam). The recommended dose for nosocomial pneumonia subjects is 4.5 g
every 6 hours totaling 18 g (16 g piperacillin and 2 g tazobactam).
While ESBL inhibition by tazobactam is comparable to clavulanic acid for most
Class A enzymes such as SHV and TEM, it is many folds superior to clavulanic
acid with respect to inhibition of Class C enzymes such as AmpC. However, this
property of tazobactam (i.e., AmpC inhibition) has not been clinically
realizable since it was combined with readily hydrolyzable Beta-lactams such as
piperacillin and cephalosporins such as ceftriaxone and ceftazidime
(combinations available in India and emerging markets). Additionally, the lower
proportion [cephalosporin: tazobactam = 8:1] of tazobactam in these current
combinations does not result in the in vitro activity against Class C ESBL
producing strains. Therefore, the present product of WCK 4282 was designed
using the unique properties of cefepime and tazobactam such as high potency,
relative ESBL stability, and AmpC inhibition. Moreover, the increased
proportion [1:1] of tazobactam in the combination of WCK 4282 translates into
clinically relevant synergy against AmpC and Klebsiella pneumoniae
carbapenemase (KPC) strains in addition to Class A ESBL strains. An important
consideration for choosing cefepime is the higher susceptibility breakpoint (8
micro g/mL) assigned to it, which suggests very favorable pharmacokinetics (PK)
pharmacodynamics (PD), which in turn could be useful in harnessing synergistic
interactions based on the higher proportion of tazobactam found in WCK 4282.
WCK 4282 could find significant clinical utility in the treatment of inhibitor
resistant ESBLs, AmpC, KPCs and derepressed ESBLs which are not treatable by
currently marketed cephalosporin based combinations and other combinations such
as piperacillin-tazobactam, ampicillin-sulbactam, and amoxicillin-clavulanic
acid. Moreover, owing to multidrug resistant features of ESBL producing
organisms, fluoroquinolones and aminoglycosides would likely also have very
limited clinical use against such pathogens. The wider coverage of pathogens by
WCK 4282 could circumvent the need of carbapenem usage as the first line of
treatment (*carbapenem sparing*) for infections caused by ESBL pathogens and
would be expected to address all indications which are currently approved for
cefepime. The established safety profile of both cefepime and tazobactam along
with significant coverage of ESBL could lead to empiric use particularly for
complicated urinary tract infections, pneumonia, complicated intraabdominal
infections, and acute bacterial skin and skin structure infections.
Study objective
To evaluate the safety and tolerability of multiple escalating doses of
intravenous WCK 4282 in healthy, adult, human subjects.
To evaluate the pharmacokinetics (PK) of multiple escalating doses of 1g:1g (1
vial) of intravenous (IV) WCK 4282 every 8 hours (q8h), and 2g:2g (2 vials) of
WCK 4282 every 12 hours (q12h) and every 8 hours (q8h) in healthy, adult, human
subjects.
Study design
This study is a Phase 1, randomized, double-blind, single center, prospective,
placebo-controlled, comparative, sequential, cohort study in 30 healthy male
and female subjects
Intervention
The study will start with a screening visit. During the screening visit
standard medical assessments including safety laboratory tests (blood draw,
urine collection), an alcohol breath test, urine drug screen, a physical
examination, ECG and a vital signs measurement will be performed.
During study the subjects will enter the clinic, will receive medication q8h or
q12h, will be asked on a regular basis for possible side effects, blood will be
drawn for safety and PK measurements, urine will be collected for safety and PK
measurements and vital signs and ECG will be checked regularly during the
confinement period.
Finally a follow-up examination will be performed. During this visit the
subjects will be asked for possible side effects, blood will be drawn for
safety, the vital signs/ECG will be checked and a physical examination will be
conducted.
Study burden and risks
The risk is small. The subjects will be closely monitored. The subjects will be
regularly questioned for any side effects and regular safety tests are
scheduled (ECG / Vital Signs/Lab). In addition the subjects will be asked to
report, as soon as possible, any changes in physical and/or mental well being.
The blood collection procedure is not dangerous, but may cause discomfort or
bruising. Occasionally fainting or an infection at the blood sampling site may
occur.
Shaving may be required for proper placement of the ECG patches. This may cause
irritation or bleeding of the skin. The ECG patches may cause redness of the
skinn, itching or rash. In addition when the paches are removed hairloss may
occur.
Grafenauweg 6
Zug 6300
CH
Grafenauweg 6
Zug 6300
CH
Listed location countries
Age
Inclusion criteria
1. Male or female, 18-65 years of age both inclusive
2. Have a body Mass Index (BMI) between 18 to 30 kg/m2 (both inclusive) calculated as weight (kg) / height (m2)
3. Medical history without any major pathology
4. Resting supine blood pressure 90-139 (systolic) / 40-89 (diastolic) mmHg, a resting pulse rate of 40-100 beats per minute or higher, computerized 12-lead electrocardiogram (ECG) recording without signs of clinically relevant pathology and showing no clinically relevant deviations as judged by the Principal Investigator
5. Glomerular filtration rate (GFR) > 80 mL/min.
6. All values for blood and urine tests within the normal range or showing no clinically relevant deviations as judged by the Principal Investigator. Re-screening may be allowed only once.
7. Abstain from alcohol, methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, "powerdrinks"), grapefruit or grapefruit (juice) from 48 hours prior to entry in the clinical research center (Day -1) until discharge
8. Females must be non-pregnant and not breast feeding (non-pregnancy will be confirmed by a serum pregnancy test conducted at screening and prior to any dosing period), or of no childbearing potential at screening.
9. In sexually active subjects, willingness to use 2 effective methods of contraception, of which one must be a physical barrier method (a condom, a diaphragm or cervical/vault cap), and other could be oral contraceptives, intra-uterine device or spermicidal jelly. Since a systemic or individual effect of WCK 4282 on the PK of oral contraceptives cannot not be ruled out, females on oral contraceptives will be informed of a possible effect and asked to continue their contraceptive daily between screening and the last follow-up (i.e., also continue with contraceptive during a possible planned stop week).
10. Males should not donate sperm until 90 days after the follow-up visit.
11. Willing to sign the Informed Consent Form and adhere to the study restrictions and assessment schedule.
Exclusion criteria
1. Receipt of WCK 4282 in the past.
2. History or evidence of clinically relevant pathology which might compromise the haemopoietic, renal, hepatic, endocrine, pulmonary, central nervous, cardiovascular, immunological, dermatological, gastrointestinal or any other body system.
3. History of epilepsy
4. Active Candida infection
5. Cystic fibrosis
6. Mental handicap
7. History of relevant drug and/or food allergies particularly known hypersensitivity to cefepime or tazobactam, cephalosporins or penicillins.
8. Receipt of a prescription or non-prescription drug within 14 days prior entry into clinical research centre (Day -1) except for acetaminophen (paracetamol) which is allowed for up to 3 days prior entry into clinical research centre (Day -1). Multivitamins and vitamin C are allowed up to 7 days before entry into the clinical research centre (Day -1).
9. Smoking within 60 days prior to drug administration and through the follow-up visit.
10. History of alcohol abuse and/or drug addiction (including soft drugs like cannabis products)
11. Intake of more than 21 units of alcohol per week (1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 30 mL of spirits)
12. Participation in a drug study within 90 days prior study start.
13. Donation of blood (500 mL or more) within 90 days prior to study start (Day -1).
14. Positive drug screen (opiates, methadone, cocaine, amphetamines, cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, and alcohol)
15. Positive screen on hepatitis B surface antigen (HBsAg), anti hepatitis C virus (HCV) antibodies or anti human immunodeficiency virus (HIV) 1/2 antibodies
16. Illness within 5 days prior to drug administration that may impact safety assessments, in the opinion of the Principal Investigator
17. Strenuous activity (e.g., sports) is not allowed from 96 hours (4 days) prior to entry into the clinical research center (Day -1) and throughout the study (until the final follow-up visit has been conducted)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-002633-55-NL |
| CCMO | NL49891.056.14 |