Changes

Toxicology

12,316 bytes added, 17:32, 21 November 2009

/* Summary */

*[http://ctd.mdibl.org/ Comparative Toxicogenomics database]

==Sample ~~Report~~Example== Cyclopropavir (CPV,ZSM-I-62,MBX400)has been shown to be potent against beta-and gamma-herpes virusesHere is the study conducted to test the toxicology and pharmacokinetics of this active on rat

{|border="2" cellspacing="0" cellpadding="4" width="100%"

|align = "center" bgcolor = "#~~FCD5B4~~339966"~~|'''S.No'''|align~~ colspan = "~~center" bgcolor = "#FCD5B4~~7"|'''~~Database~~Summary of Primary Pharmacokinetic, Toxicokineticand Toxicology Studies'''~~|align = "center" bgcolor = "#FCD5B4"|'''Compound/Substance Name'''|align = "center" bgcolor = "#FCD5B4"|'''Information Available'''~~

|align = "center" bgcolor = "#~~FCD5B4~~33CCCC" rowspan = "2"|'''1Species (Strain)'''|align = "center" bgcolor = "#33CCCC" rowspan = "2"|~~[http:~~rowspan = "2"|'''Route'''|align = "center" bgcolor = "#33CCCC" rowspan = "2"|'''Dose (mg/~~/toxnet.nlm.nih.gov/ Toxicology Data Network]~~kg)'''|align = "center" bgcolor = "#33CCCC" colspan = "2"|~~Paracetamol~~'''No. of Animals per Sex'''|align = "center" bgcolor = "#33CCCC" rowspan = "2"|~~Chemical, Toxicological, and Environmental Health Data~~'''GLP?'''

|align = "center" bgcolor = "#~~FCD5B4~~33CCCC"|'''2M'''|align = "center"~~|[http://potency.berkeley.edu/ The Carcinogenic Potency Database]~~|~~align = "center"|Dimethadione~~'''F'''~~|align = "center"|Rats and Mice: Cancer Test Summary ,Criteria for inclusion of experiments ,Standardization of average daily dose levels ,TD50 estimation for a standard lifespan etc.,~~

|align = "center" ~~bgcolor~~ |Rat (Sprague Dawley)|align = "~~#FCD5B4~~center"|~~'''3'''~~Single Dose Pharmacokinetic|align = "center"|~~[http://ecb.jrc.ec.europa.eu/esis/ European chemical substances information system]~~| 10 |align = "center"|~~Ibuprofen~~9 |align = "center"|General Information,Biocidal Products Directive (Directive 98/8/EC) Information,Classification and Labelling Information,Export and Import of Dangerous Chemicals (Regulation (EC) No 689/2008) Information,HPV-~~LPV (High and Low Production Volume) Information,IUCLID & OECD Chemical Data Sheets and Export Files Information etc.,~~|align = "center"| No

|align = "center"| 

|align = "center"|oral

|align = "center"|1

|align = "center"| 9

|align = "center"| -

|align = "center"| 

|align = "center"| 5

|align = "center"| 9

|align = "center"| -

|align = "center"| 

|align = "center"| 10

|align = "center"| 9

|align = "center"| -

|align = "center"| 

|align = "center"| Single Dose Acute Toxicity

|align = "center"| Oral

|align = "center"| 0

|align = "center"| 5

|align = "center"| Yes

|align = "center"| 

|align = "center"| 50

|align = "center"| 5

|align = "center"| 

|align = "center"| 100

|align = "center"| 5

|align = "center"| 

|align = "center"| 300

|align = "center"| 5

|align = "center"| 

|align = "center"| 14-Day Toxicity/Toxicokinetic

|align = "center"| Oral

|align = "center"| 0

|align = "center"| 15 <nowiki>+</nowiki> 9 TK

|align = "center"| Yes

|align = "center"| 

|align = "center"| 10

|align = "center"| 10 <nowiki>+</nowiki> 9 TK

|align = "center"| 

|align = "center"| 50

|align = "center"| 10 <nowiki>+</nowiki> 9 TK

|align = "center"| 

|align = "center"| 100

|align = "center"| 15 <nowiki>+</nowiki> 9 TK

|align = "center"| 

{|border="2" cellspacing="0" cellpadding="4" width="100%"

|align = "center" bgcolor = "#339966" colspan = "11"|'''Single-Dose Pharmacokinetic and ToxicokineticParameters'''

|align = "center" bgcolor = "#33CCCC" rowspan = "2"|''' Species (Strain) '''

|align = "center" bgcolor = "#33CCCC" rowspan = "2"|''' Study '''

|align = "center" bgcolor = "#33CCCC" rowspan = "2"|''' Route '''

|align = "center" bgcolor = "#33CCCC" rowspan = "2"|''' Dose (mg/kg) '''

|align = "center" bgcolor = "#33CCCC" colspan = "2"|''' No. of Animals '''

|align = "center" bgcolor = "#33CCCC" rowspan = "2"|''' AUC0-∞(ng∙hr/mL) '''

|align = "center" bgcolor = "#33CCCC" rowspan = "2"|''' t1/2(hr) '''

|align = "center" bgcolor = "#33CCCC" rowspan = "2"|''' Cmax(ng/mL) '''

|align = "center" bgcolor = "#33CCCC" rowspan = "2"|''' Tmax(hr) '''

|align = "center" bgcolor = "#33CCCC" rowspan = "2"|''' F (%) '''

|align = "center" bgcolor = "#33CCCC"|'''M'''

|align = "center" bgcolor = "#33CCCC"|'''F'''

|align = "center"| Rat (Sprague Dawley)

|align = "center"| Single Dose PK

|align = "center"| i.v.

|align = "center"| 10

|align = "center"| 9

|align = "center"| -

|align = "center"| 10735

|align = "center"| 2.34

|align = "center"| 14500

|align = "center"| 0.083

|align = "center"| -

|align = "center"| 

|align = "center"| Oral

|align = "center"| 1

|align = "center"| 9

|align = "center"| -

|align = "center"| 494

|align = "center"| 1.09

|align = "center"| 262

|align = "center"| 0.5

|align = "center"| 46.0

|align = "center"| 

|align = "center"| 5

|align = "center"| 9

|align = "center"| -

|align = "center"| 1638

|align = "center"| 1.23

|align = "center"| 590

|align = "center"| 0.5

|align = "center"| 30.5

|align = "center"| 

|align = "center"| 10

|align = "center"| 9

|align = "center"| -

|align = "center"| 2435

|align = "center"| 1.12

|align = "center"| 739

|align = "center"| 0.5

|align = "center"| 22.7

|align = "center"| 

|align = "center"| 14-Day Toxicity/TK

|align = "center"| Oral

|align = "center"| 10

|align = "center"| 9

|align = "center"| -

|align = "center"| 2413

|align = "center"| 1.51

|align = "center"| 612

|align = "center"| 1.00

|align = "center"| -

|align = "center"| 

|align = "center"| -

|align = "center"| 9

|align = "center"| 1843

|align = "center"| 3.74

|align = "center"| 682

|align = "center"| 0.50

|align = "center"| -

|align = "center"| 

|align = "center"| 50

|align = "center"| 9

|align = "center"| -

|align = "center"| 7671a

|align = "center"| ND

|align = "center"| 1517

|align = "center"| 2.00

|align = "center"| -

|align = "center"| 

|align = "center"| -

|align = "center"| 9

|align = "center"| 7055

|align = "center"| 3.08

|align = "center"| 1131

|align = "center"| 2.00

|align = "center"| -

|align = "center"| 

|align = "center"| 100

|align = "center"| 9

|align = "center"| -

|align = "center"| 11749

|align = "center"| 3.30

|align = "center"| 1763

|align = "center"| 1.00

|align = "center"| -

|align = "center"| 

|align = "center"| -

|align = "center"| 9

|align = "center"| 9129a

|align = "center"| ND

|align = "center"| 1175

|align = "center"| 4.00

|align = "center"| -

{|border="2" cellspacing="0" cellpadding="4" width="100%"

|align = "center" bgcolor = "#339966" colspan = "14"|'''Selected Hematology Data from Rat Single-Dose -Escalating Toxicology Studies'''

|bgcolor = "#33CCCC"|''' Species (Strain) '''

|bgcolor = "#33CCCC"|''' Sex '''

|bgcolor = "#33CCCC"|''' Dose (mg/kg)a '''

|bgcolor = "#33CCCC"|''' Red Blood Cell Count(1x106/μL) '''

|bgcolor = "#33CCCC"|''' Hemoglobin (g/dL) '''

|bgcolor = "#33CCCC"|''' Hematocrit(%) '''

|bgcolor = "#33CCCC"|''' Mean Corpuscular Volume (femtoliter) '''

|bgcolor = "#33CCCC"|''' Mean Corpuscular Hemoglobin (pg) '''

|bgcolor = "#33CCCC"|''' Mean Corpuscular Hemoglobin Conc. (g/dL) '''

|bgcolor = "#33CCCC"|''' Reticulocytes(1x103/μL) '''

|bgcolor = "#33CCCC"|''' Platelets (1x103/μL) '''

|bgcolor = "#33CCCC"|''' White Blood Cell Count (1x103/μL) '''

|bgcolor = "#33CCCC"|''' Neutrophils (1x103/μL) '''

|bgcolor = "#33CCCC"|''' Lymphocytes(1x103/μL) '''

| Rat (Sprague Dawley)b

| M

| 0

| 6.94±0.221

| 14.3 ±0.48

| 44.5 ±1.89

| 64.1 ±1.52

| 20.6 ±0.36

| 32.2 ±0.33

| 544.5 ±30.82

| 1448 ±288.8

| 7.15 ±0.885

| 0.71±0.214

| 6.19 ±0.984

| 300

| 7.27 ±0.537

| 14.7 ±0.70

| 48.0 ±3.02

| 63.4 ±2.37

| 20.2 ±0.81

| 31.9 ±0.80

| 503.3 ±67.80

| 1228 ±201.6

| 6.42 ±1.189

| 0.79 ±0.338

| 5.32 ±1.153

| F

| 0

| 7.29 ±0.150

| 14.8 ±0.23

| 44.7 ±0.58

| 61.2 ±0.58

| 20.3 ±0.25

| 33.2 ±0.24

| 353.2 ±10.97

| 1328 ±104.2

| 6.24 ±1.442

| 0.75 ±0.233

| 5.15 ±1.443

| 300

| 7.55 ±0.185

| 15.2 ±0.28

| 45.6 ±1.11

| 60.4 ±4.41

| 20.1 ±0.52

| 33.3 ±0.38

| 333.0 ±52.44

| 1245 ±166.6

| 7.66 ±1.944

| 0.63 ±0.374

| 6.70 ±1.693

{|border="2" cellspacing="0" cellpadding="4" width="100%"

|align = "center" bgcolor = "#339966" colspan = "8"|'''Safety Pharmacology Studies'''

|align = "center" bgcolor = "#33CCCC" rowspan = "2"| Species (Strain)

|align = "center" bgcolor = "#33CCCC" rowspan = "2"| Study Type

|align = "center" bgcolor = "#33CCCC" rowspan = "2"| Route

|align = "center" bgcolor = "#33CCCC" rowspan = "2"| Dose (mg/kg)

|align = "center" bgcolor = "#33CCCC" colspan = "2"| No. of Animals

|align = "center" bgcolor = "#33CCCC" rowspan = "2"| GLP?

|align = "center" bgcolor = "#33CCCC" rowspan = "2"| Results

|align = "center" bgcolor = "#33CCCC"| M

|align = "center" bgcolor = "#33CCCC"| F

|align = "center"| Rat (Sprague Dawley)

|align = "center"| Central Nervous System

|align = "center"| Oral

|align = "center"| 0

|align = "center"| 6

|align = "center"| Yes

|align = "center"| Cyclopropavirhad no effect on clinical signs, body weight or Irwintest results

|align = "center"| 

|align = "center"|10

|align = "center"| 6

|align = "center"| 

|align = "center"| 50

|align = "center"| 6

|align = "center"| 

|align = "center"| 100

|align = "center"| 6

|align = "center"| 

{|border="2" cellspacing="0" cellpadding="4" width="100%"

|align = "center" bgcolor = "#339966" colspan = "13"|'''Selected Clinical Chemistry Data from Rat Single-Dose Escalating Toxicology Studies'''

|align = "center" bgcolor = "#33CCCC"|''' Species (Strain) '''

|align = "center" bgcolor = "#33CCCC"|''' Sex '''

|align = "center" bgcolor = "#33CCCC"|''' Dose (mg/kg) '''

|align = "center" bgcolor = "#33CCCC"|''' Urea Nitrogen (mg/dL) '''

|align = "center" bgcolor = "#33CCCC"|''' Creatinine(mg/dL) '''

|align = "center" bgcolor = "#33CCCC"|''' Total Protein (g/dL) '''

|align = "center" bgcolor = "#33CCCC"|''' Albumin (g/dL) '''

|align = "center" bgcolor = "#33CCCC"|''' Globulin (g/dL) '''

|align = "center" bgcolor = "#33CCCC"|''' Albumin Globulin Ratio '''

|align = "center" bgcolor = "#33CCCC"|''' Calcium (mg/dL) '''

|align = "center" bgcolor = "#33CCCC"|''' Phosphorus (mg/dL) '''

|align = "center" bgcolor = "#33CCCC"|''' Sodium (mmol/L) '''

|align = "center" bgcolor = "#33CCCC"|''' Potassium(mmol/L) '''

|align = "center"| Rat (Sprague Dawley)a,b

|align = "center"| M

|align = "center"| 0

|align = "center"| 14 ±1.1

|align = "center"| 0.5±0.00

|align = "center"| 5.7 ±0.24

|align = "center"| 4.0 ±0.12

|align = "center"| 1.7 ±0.05

|align = "center"| 2.4 ±0.09

|align = "center"| 10.8 ±0.11

|align = "center"| 11.0 ±0.51

|align = "center"| 147 ±1.3

|align = "center"| 5.8 ±0.31

|align = "center"| 

|align = "center"| 300

|align = "center"| 13 ±1.3

|align = "center"| 0.5 ±0.00

|align = "center"| 5.8 ±0.43

|align = "center"| 4.1 ±0.12

|align = "center"| 1.7 ±0.11

|align = "center"| 2.4 ±0.13

|align = "center"| 10.9 ±0.28

|align = "center"| 10.6 ±0.27

|align = "center"| 148 ±1.6

|align = "center"| 5.8 ±0.37

|align = "center"| 

|align = "center"| F

|align = "center"| 0

|align = "center"| 15 ±1.3

|align = "center"| 0.6 ±0.05

|align = "center"| 6.0 ±0.18

|align = "center"| 4.4 ±0.05

|align = "center"| 1.7 ±0.18

|align = "center"| 2.7 ±0.31

|align = "center"| 11.1 ±0.30

|align = "center"| 9.5 ±0.40

|align = "center"| 147 ±1.0

|align = "center"| 5.4 ±0.4

|align = "center"| 

|align = "center"| 300

|align = "center"| 15 ±2.3

|align = "center"| 0.5 ±0.04

|align = "center"| 6.1 ±0.18

|align = "center"| 4.6 ±0.08

|align = "center"| 1.6 ±0.17

|align = "center"| 3.0 ±0.35

|align = "center"| 11.3 ±0.11

|align = "center"| 9.7 ±0.72

|align = "center"| 147 ±2.3

|align = "center"| 5.5 ±0.5

===Summary===

'''Pharmacokinetic data (plasma)'''

*In the single dose rat PK study, exposure was less than dose proportional

*Orally bioavailable

*Rat 10 mg/kg oral Cmax: 739 ng/mL(2.8 μM)

*Rat 10 mg/kg intravenous Cmax: 14,500 ng/mL(55 μM)

'''Toxicokineticdata (plasma)'''

*Exposure generally increased with increasing doses

*Plasma concentrations were generally higher after the first dose than after the fourteenth daily dose

*Cmaxvalues in the rat were 1175 and 977 ng/mLin females (4.5 and 3.9 μM) and 1763 and 1026 ng/mLin males (6.7 and 3.7 μM) at 100 mg/kg after 1 day and 14 days of dosing, respectively

'''Toxicology studies'''

*Maximum tolerated dose 300 mg/kg (oral; rat)

*Few toxic signs in expected therapeutic range

*Toxicology studies established target organ(s)which are similar to other drugs in class: kidney and possibly hematologic system

*Toxicology studies paired with pharmacology data show acceptable margin of safety

Lakshmikantg

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Toxicology

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