Martina Sahre1, Sreedharan Sabarinath1, PhD
Maria Grant2, MD, Christoph Seubert3, MD, PhD,
Carisa deAnda4, PharmDHartmut Derendorf1, PhD
University of Florida, College of Pharmacy, Departments of
Pharmaceutics1, Therapeutics and Pharmacology2, Anesthesiology3,
Trius Therapeutics4, San Diego, California
Evaluation of Tissue Distribution of TR-Evaluation of Tissue Distribution of TR-700 in Healthy Volunteers Using 700 in Healthy Volunteers Using
MicrodialysisMicrodialysis
TR-700TR-700
Oxazolidinone classLimited water solubilityPhosphate ester prodrug (TR-701)Rapid conversion to active drug
N O
O
HN
O
F
N
O
Linezolid
N O
OH
O
F
N
NN
N
N
N O
O
F
N
NN
N
N
OP
O
ONa
ONaIn VivoPhosphatases
TR-700
TR-701
TR-700TR-700
Oxazolidinone classIndication complicated skin and skin
structure infections (cSSSI)In vitro activity against:
S. aureus (MS and MR), Linezolid-resistant MRSA carrying binding-
site mutations, cfr geneS. pneumoniae (PS, PR), S. pyogenes, S.
agalactiae, Enterococci (inc.. VRE)
Rennie et al. (2003), Im et al. (2007), Jones et al. (2009), Shaw et al. (2007), Schaadt et al. (2009)
RationaleRationale
Plasma concentrations linked to PK/PD indices
Free drug in tissue more relevantDrug molecules need to reach tissue
Total Plasma, Muscle Tissue, Adipose Tissue, --- Free Plasma
Barbour et al. (2009), Deghanyar et al. (2005)
Mean Ceftobiprole Concentrations After Single 500 mg i.v. Dose
C(tissue) < fc(plasma) C(tissue) > fc(plasma)
Mean Linezolid Concentrations After Single 600 mg i.v. Dose
RationaleRationale
Biopsy, skin blisters, imaging techniques AUC of Moxifloxacin after 400 mg p.o single
dose:
Measure unbound PK parameter in tissue using microdialysis
Mueller et al. (1999)
Plasma Muscle
Tissue
Subcutaneous Tissue
Saliva Capillary Blood
Blister
AUC [µg*h/m
L]19.8 8.5 8.0 17.6 18.7 12.3
Microdialysis PrincipleMicrodialysis Principle
Diffusion through a semipermeable membrane
“Mimics” blood vesselSampling tool Assess free drug directly
Courtesy of CMA
RecoveryRecoveryProbe is continuously perfused → no
equilibriumcdialysate < cmedium
Recovery defined as ratio cdialysate/cmediumDialysate: liquid recovered from probeMedium: tissue or solution containing
compound of interestFactors influencing recovery:
Temperature, Membrane length, Flow-rate, Molecular size, Membrane properties, Tissue properties
Probe calibration → recovery factor
RetrodialysisRetrodialysis
Perfusate contains known concentration of compound
Dialysate concentration measuredCalculated recovery used to
adjust drug concentrations from experiment
100*100]Recovery[%perfusate
dialysate
c
c
Courtesy of CMA
Study DesignStudy DesignTR-700 measured in plasma, s. c. adipose and
muscle tissue15 healthy volunteers Pilot (n = 3) and Main Study (n = 12)
Two microdialysis probes implantedRetrodialysis to calibrate probeWashout period
Main StudySingle dose of study drug, 600 mg p.o.Dialysate samples every 20 minutes for 12 h,
blood samples for 24 h after dosingProtein binding samples 0, 2, 12h post dose
CMA 60 probe, Courtesy of CMA, Sweden)
Main Study: ResultsMain Study: ResultsProtein Binding 87 % (1.3%)
TR-700 Levels in Plasma (Total and Unbound), Adipose and Muscle Tissues
Time [h]
0 4 8 12 16 20 24
Co
nce
ntr
atio
n [n
g/m
L]
0
1000
2000
3000
4000
5000
6000
7000
Adipose Tissue Muscle Tissue Total Plasma fPlasma
TR-700 Levels in Plasma (Unbound), Adipose and Muscle Tissues
Time [h]
0 4 8 12 16 20 24
Co
nce
ntr
atio
n [n
g/m
L]
0
200
400
600
800 Adipose Tissue Muscle Tissue fPlasma
Mean PK Parameters (SD)Mean PK Parameters (SD)
Parameter Unit Plasma fPlasmaAdipose Tissue
Muscle Tissue
Cmax (µg/mL) 5.37 (1.51) 0.70 (0.27) 0.66 (0.16) 0.74 (0.15)
Tmax§ (hr) 2 (1-4) 2 (1-4)
3.33 (2.33-10.3)
3.67 (1.67-7)
AUC0-12(µg*h/mL)
38.8 (7.55) 4.96 (1.09) 5.27 (1.28) 5.95 (1.11)
AUC0-24(µg*h/mL)
57.1 (14.7) 7.28 (1.91) - -
AUC∞(µg*h/mL)
70.0 (24.8) 8.89 (3.06) 16.6 (15.8) 14.6 (10.5)
t½§ (hr)
8.13 (5.94-12.8)
8.13 (5.94-12.8)
9.22 (5.98-85.9)
9.59 (6.15-48.2)
CL/F (L/hr) 9.46 (2.91) * * *Vz/F (L) 113 (19.3) * * *
fAUC0-12, tissue/fAUC0-12, plasma
1.08 (0.22) 1.22 (0.18)
Protein Binding % 87.2 (1.3) * * ** Not applicable; § Median (Range); λz: terminal elimination rate constant
ConclusionConclusion
TR-700 conc. in observed tissues similar to unbound plasma concentrations
No significant difference between AUC0-12 for unbound plasma, adipose and muscle tissues
Drug and microdialysis well tolerated
AcknowledgementsAcknowledgements
Prof. Hartmut DerendorfMaria Grant, MD and Christoph Seubert,
MD, PhDSreedharan Sabarinath, PhDGeneral Clinical Research Center at the
University of FloridaPhilippe Prokocimer, MDTrius Therapeutics, Inc.
Individual Adipose Concentrations
Time [min]
0 60 120 180 240 300 360 420 480 540 600 660 720 780
Con
cent
ratio
ns [
ng/m
L]
0
100
200
300
400
500
600
700
800
900
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