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Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

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Page 1: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Drug Metabolism and Pharmacokinetics Core

Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Page 2: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Services:

• Pharmacokinetic studies: Quantify drug levels in serum/plasma, tissue or cells

• Evaluation of Organ Toxicity: Blood chemistry analysis for liver, kidney and bone marrow toxicity

• Hematology: Measure complete blood counts• Measure GSH/GSSG• Redox analysis: Detection of protein thiol

status in cells, tissue, serum and plasma.• Education and training

Page 3: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

H2N

COOH

O

NH

O

NH

S

S

O

NHNH

O

COOH

H2N

COONa

COONa

. [Pt(NH3)2Cl2]

NOV-002, a myeloproliferative agent

Phase II: Neo-adjuvant breast cancer trial at MUSC

Page 4: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Pharmacokinetic Analysis

Page 5: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

B.

A.

0.1

1.0

10.0

100.0

0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50

Time

Observed

Predicted

0.01

0.10

1.00

10.00

0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50

Time

Observed

Predicted

ug/

mL

GS

SG

ug/

mL

GS

H

Page 6: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Estimated pharmacokinetic parameters for NOV-002 (GSSG) and its primary metabolite (GSH)

PK Parameter GSH GSSG

Co (ug/mL) 4.10 0.65

Cmax (ug/mL) 18.30 2.16

Tmax (hr) 0.16 0.15

Volume of distribution, V/F (L/kg) 42.61

K01 (absorption rate constant), hr-1 6.42

K10 (elimination rate constant), hr-1 5.81 6.40

AUC 0-30min (ug.h/mL) 6.37 1.18

Clearance, CL/F (L/hr/kg) 273.15

Page 7: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Evaluation of Organ Toxicity

Page 8: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Table 2. Mortality and Nephrotoxicity of Cisplatin in Mice

Elevated AbnormalMortality Creatinine Renal Histology

Saline 0/6* 0/6 0/6NOV-002 0/6 0/6 0/6Cisplatin 1/8§ 6/7§ 7/7§Cisplatin + NOV-002 0/9 3/9 3/9

•Data are the number of mice who died, had elevated plasma creatinine (>0.2 mg/dL) or abnormal renal histology over the number of mice treated.§ Statistically significant differences between treatment groups were detected with a Fisher Exact Test, P<0.01.

Page 9: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Saline NOV-002

Cisplatin Cisplatin + NOV-002

Page 10: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Hematology:

Page 11: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Cisplatin Induced Bone Marrow ToxicityWhite Blood Cells

HM2 Hematology System (Abaxis)

Female Male

x 1

09 c

ells

/mL

Normal 6 x 109 Female +/+

Cisplatin + + NOV-002 - +

Page 12: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Measure GSH/GSSGRedox Potential

Eh (

mV

)

Page 13: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Redox analysis:

-S- TGTM -SH

NOV-002

+ TGTM

+

-S-SG

% F

ree

Su

lfhyd

ryls

**

*

*

Page 14: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

A B

C

D

Kda150100

75 50

37

NOV-002 (25 mg/kg, iv) 0 ¼ ½ 1 4 24 h

WB: PSSG

WB: actin

Identification of Plasma Markers following NOV-002 treatment

Page 15: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Cost Recovery System:

• Assay Development $1,500 + Column• PK Modeling $50/ hr• Plasma / Serum Assay $50 / sample• Organ toxicity analysis $35 / sample• Hematology (CBC) $20 / sample• GSH/GSSG levels $25 / sample• Protein Thiol Analysis $35 / sample• Breeze HPLC

– User Operated Training $ 50 / hour– User Operation fee $ 25 / hour– Over-night / weekend fee $18 / hour

Page 16: Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

Drug Metabolism and Pharmacokinetics Core

Drug Discovery Building 420843-876-2391

Danyelle Townsend, Ph.D., Director Yefim Manevich, Ph.D., Drug Discovery Building 420 [email protected]@musc.edu

Joachim Uys, Ph.D. PK project [email protected]