Transcript A Phase I Study of The Pharmacokinetics of Extended Duration High

A Phase I Study of The Pharmacokinetics of
Extended Duration High-Dose Cefixime For
Cephalosporin-Resistant Neisseria Gonorrhoeae
Lindley Barbee, Seema Nayak, Jeffrey Blumer,
Jonathan Zenilman, Matthew Golden and J. Mac Griffiss
IUSTI Word Congress May 10, 2016
Marrakech, Morocco
Background
• In 2012, CDC removed cefixime from
recommended GC treatment
• Injectable only treatment issues
– Many physicians’ offices do not stock
– Necessitates second visit
– Potentially decreases use of EPT
Overall Goal
• To define an oral dosing regimen that could
treat pharyngeal gonorrhea with elevated
MICs
Background
• Pharyngeal Gonorrhea
– Common and under-screened
– More difficult to treat
– Likely anatomic site for acquired resistance
Background
• Penicillin effective 40+ years by increasing dose
• Pharmacokinetics/Pharmacodynamics (PK/PD)1
4x MIC for 7-10 hours
• Pharyngeal gonorrhea PK/PD2
4x MIC for >20 hours
1. Jaffe et al AAC 1979
2. Moran & Levine CID, 1995
Methods
• Assuming future cefixime MIC90 = 0.5 µg/mL
– CLSI definition of Decreased Susceptibility
• Goal: 4x MIC90 for >20 hours
• PK parameters from available literature
• Simulation models of varying doses of cefixime
Total Serum Cefixime Concentration Over Time of 800mg Regimens
99
GOAL:
Exceed 4 x MIC
for >20 hours
Total Serum Cefixime Concentration mcg/mL
88
77
400mg
once
66
800mg
q12 x 2
55
800 mg
q8 x 3
44
33
4 x MIC 1.0
mcg/mL
22
11
4 x MIC 0.5
mcg/mL
0
0
4
8
12
Time in Hours
16
20
24
Barbee et al ISSTDR, 2013
Primary Objective
• To determine a cefixime dosing regimen that
would exceed 2mcg/mL total serum cefixime
concentration for >20 hours
Secondary Objectives
• Establish PK of each dosing regimen
• Determine proportion protein bound
• Quantify the concentration of cefixime in
pharyngeal fluid samples
• Assess safety and tolerability of each regimen
NIAID/DMID sponsored:
Phase I Clinical Trials Unit for Therapeutics Against Infectious Diseases
Clinical site: Johns Hopkins Bayview, Baltimore, MD
PK Laboratory: Blumer Lab, University of Toledo, Toledo, OH
Enrollment began: December 2013
Cohort
Dose
A
400 mg
B
800 mg
C
1200 mg
D
800 mg q8
hours x 3
Study concluded: December 2014
Objective
• Re-establish PK of cefixime
• Calibrate assay
• Confirm simulation models
• Establish PK of this regimen
• Quantify pharyngeal fluid concentration
• Determine % protein bound
• Assess safety & tolerability
Clinicaltrials.gov NCT01949363
Methods: Subjects
• Health volunteers (N=25*)
– 18-45 years old
– Chronic medical conditions excluded
– Non-pregnant women (Two forms of birth control)
– Screening tests within normal limits
– No prescription or over the counter medications
*One subject removed from analyses due to late identification of positive Urine toxicology.
Protocol
Cohort
Dose
A
400 mg
B
800 mg
Serum PK Time Points
Pharyngeal PK Time
Points
0,1,2,4,8,12,16,20,
24, 48,168 hours
None
0, 4, 9, 13, and 18
hours
0, 4, 8, 12, 16, 24
hours
C
1200 mg
0, 0.5, 1, 1.5, 2, 4,
9, 13, 18,24, 48,
168 hours
D
800 mg q8
hours x 3
0, 4, 8, 12, 16, 24,
48, 168 hours
Pharmacokinetic Evaluations
• High performance liquid chromatography
• Quantification by LC/MS/MS technique
– Upper limit: 8000 ng/ml
– Lower limit: 50 ng/ml
• Time-concentration plots (individual and mean)
• Estimated PK Parameters using WinNolin
Subject Demographics and Baseline
Clinical Parameters
Total
N=25*
Male (n, %)
Age, years (mean, SD)
Race
White
Black/African-American
Asian
18 (72%)
29.2 (7.0)
8 (32.0%)
16 (64.0%)
1 (4.0%)
BMI (mean, SD)
25.0 (3.8)
Mean (± SD) Total Serum Cefixime
Concentration versus Time:
Cohort A 400mg
Mean (± SD) Total Serum Cefixime
Concentration versus Time:
Cohort B 800mg
Mean (± SD) Total Serum Cefixime
Concentration versus Time:
Cohort C 1200mg
Mean (± SD) Total Serum Cefixime
Concentration versus Time:
Cohort D 800mg q8h x 3
Primary Objective: Results
Mean
T>2mcg/mL
Cohort A
400mg
Cohort B
800mg
Cohort C
1200 mg
Cohort D
800mg q8 h x 3
~6 hours
~ 10 hours
~ 10 hours
~ 23 hours
COHORT D:
50% of subjects > 4x MIC for >20 hours continuously
80% of subjects total time > 4x MIC >20 hours
Protein Binding & Pharyngeal Fluid
Pharyngeal fluid
analysis Cohort C & D:
Negligible amount of
drug at all time points.
PARAMETER
% Free Drug
(Mean, Range)
At 12* hours
400mg
800mg
1200mg
800mg q8 x 3
82%
(54.7% – 116.2%)
65%
(56.4% – 73.6%)
52%
(34.0% – 84.1%)
42%
(25.9% – 62.9%)
Safety & Tolerability
Adverse Events
Total
Study Pop.
N=25
Cohort A
400mg
N=6
Cohort B
800 mg
N=6
Cohort C
1200 mg
N=6
Cohort D
800 mg x 3
N=7
20
(80.0%)
5
(83.3%)
4
(66.7%)
5
(83.3%)
6
(85.7%)
Gastrointestinal
Diarrhea
Nausea
Flatulence
Abdominal Pain
5 (20.0%) 1 (16.7%) 1 (16.7%)
0
6 (24.0%) 1 (16.7%) 1 (16.7%) 2 (33.3%)
6 (24.0%) 1 (16.7%)
0
1 (16.7%)
2 (8.0%)
0
0
0
3 (42.9%)
2 (28.6%)
4 (57.1%)
2 (28.6%)
Summary
• Safe and reasonably well tolerated
– Mild gastrointestinal disturbances
• 800mg q8 h x 3  50% achieved strict goal
• More (80%) exceeded goal for total time
• At increasing doses, bioavailability decreases
and protein binding increases
Limitations
• Small sample size
• No empirically derived PK/PD for pharyngeal GC
• Primary aim extrapolated from penicillin PK/PD
– PK/PD cephalosporins suggest T>MIC for 60-70%
dosing interval
– Others suggest using free drug concentration3
3. Chisholm et al JAC 2010
Using Cephalosporin PK/PD &
Free Drug Concentration Theory
Mean (SD) Free Cefixime Concentration
over Time:
Cohort D 800mg q8 x 3
Conclusions
• 800mg Cefixime q8 hours x 3 doses may be a
reasonable option for treatment of GC with
reduced susceptibility to cefixime
• A clinical trial to test its efficacy and
determine Pharmacodynamics is needed
Acknowledgements
• University of Washington • Johns Hopkins Bayview
– Doug Black
• NIAID/DMID
–
–
–
–
–
Jon Glock
Blaire Osborn
Jill Long
Soju Chang
Carolyn Deal
– Robert Juraro
– Jillian Goodwin
– Melissa Le
• Clinical Research
Management
– Leslie Shupenko
– Howard Proskin
Cohort PK Comparisons
PARAMETER
Cohort A
400mg
Cohort B
800mg
Cohort C
1200mg
Cohort D
800mg q8 x 3
Cmax
(mcg/ml)
3.88 (1.40)
6.10 (1.16)
6.32 (9.55)
5.28 (2.04)
Tmax (hr)
3.88 (0.06)
3.54 (0.84)
3.17 (1.10)
3.87 (0.04)
t½ (hr)
4.23 (1.42)
3.37 (0.57)
3.67 (0.61)
7.03 (4.99)