2.6.5 NONCLINICAL PHARMACOKINETICS …...2.6.5 NONCLINICAL PHARMACOKINETICS TABULATED SUMMARY...

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2.6.5 NONCLINICAL PHARMACOKINETICS TABULATED SUMMARY

Lixisenatide (AVE0010)

Date: xx-xxx-20xx Document Number: -

2.6.5 NONCLINICAL PHARMACOKINETICS TABULATED SUMMARY xx-xxxx-20xx Lixisenatide (AVE0010)

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LIST OF TABLES

TS 2.6.5.1 Pharmacokinetics Tabulated Summary – Overview – Study Program.......................................... 3 TS 2.6.5.2 Pharmacokinetics Tabulated Summary – Pharmacokinetic parameters after a single dose ...... 13 TS 2.6.5.3 Pharmacokinetics Tabulated Summary – Pharmacokinetic parameters after repeated dose .... 16 TS 2.6.5.4 Pharmacokinetics Tabulated Summary – Protein Binding .......................................................... 17 TS 2.6.5.5 Pharmacokinetics Tabulated Summary – Qualitative organ distribution after a single dose ...... 18 TS 2.6.5.6 Pharmacokinetics Tabulated Summary – Quantitative organ distribution after a single dose .... 21 TS 2.6.5.7 Pharmacokinetics Tabulated Summary – Placental transfer ....................................................... 24 TS 2.6.5.8 Pharmacokinetics Tabulated Summary – Placental transfer ....................................................... 25 TS 2.6.5.9 Pharmacokinetics Tabulated Summary – Other distribution study .............................................. 26 TS 2.6.5.10 Pharmacokinetics Tabulated Summary – In vitro metabolism .................................................. 27 TS 2.6.5.11 Pharmacokinetics Tabulated Summary – In vitro metabolism .................................................. 30 TS 2.6.5.12 Pharmacokinetics Tabulated Summary – Excretion after a single dose ................................... 31 TS 2.6.5.13 Pharmacokinetics Tabulated Summary – Excretion into milk ................................................... 32 TS 2.6.5.14 Pharmacokinetics Tabulated Summary – in vitro drug interaction – CYP Inhibition ................. 33 TS 2.6.5.15 Pharmacokinetics Tabulated Summary – in vitro drug interaction – CYP Induction ................. 34

2.6.5 NONCLINICAL PHARMACOKINETICS TABULATED SUMMARY xx-xxxx-20xx Lixisenatide (AVE0010)

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TS 2.6.5.1 Pharmacokinetics Tabulated Summary – Overview – Study Program

Test Article: Lixisenatide

Type of Study Test System Method of Administration Testing Facility Study Number Location

Absorption Mouse (db/db) IP / SC / IV xxxxxxxxxxxxxxxxxxxxxxxxxxxxx

xxxxxxxxx Denmark [00-077] 4.2.2.2-1

Mouse (NMRI) IP / SC / IV xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-085] 4.2.2.2-2

Rat (Sprague Dawley)

SC / IV xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-062] 4.2.2.2-3

Rat (Sprague Dawley)

SC / IV xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-074] 4.2.2.2-4

Rat (Sprague Dawley)

IP xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[01-012] 4.2.2.2-5

Rabbit (Ssc: CPH)

IV xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-032] 4.2.2.2-6

Rabbit (Ssc: CPH)

IV xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-044] 4.2.2.2-7

Rabbit (Ssc: CPH)

SC xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-139] 4.2.2.2-8

Rabbit (NZW) SC xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[02-139] 4.2.2.2-9

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TS 2.6.5.1 Pharmacokinetics Tabulated Summary – Overview – Study Program (continued)

Test Article: Lixisenatide

Type of Study Test System Method of Administration Testing Facility Study Number Location

Absorption (continued) Rabbit (NZW) SC xxxxxxxxxxxxxxxxxxxxxxxxxxxxx

xxxxxxxxx Denmark [03-013] 4.2.2.2-10

Dog (Beagle) SC / IV xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-141] 4.2.2.2-11

Pig (Crossbreed of Danish

country, Duroc and Yorkshire)

SC / IV xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-045] 4.2.2.2-12

Pig (Crossbreed of Danish

country, Duroc and Yorkshire)

SC / IV xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-083] 4.2.2.2-13

Distribution Tissue

distribution Rat (Long Evans) SC / IV Sanofi-Aventis Frankfurt,

Germany [DIS0474] 4.2.2.3-1

Tissue distribution

Rat (Long Evans) SC / IV Sanofi-Aventis Frankfurt, Germany

[DIS0531] 4.2.2.3-2

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TS 2.6.5.1 Pharmacokinetics Tabulated Summary – Overview – Study Program (continued)

Test Article: Lixisenatide

Type of Study Test System Method of Administration Testing Facility Study Number Location

Distribution (continued) Placental transfer

Rat (Long Evans) SC Sanofi-Aventis Frankfurt, Germany

[PLT0236] 4.2.2.3-3

Placental transfer

Rabbit (NZW) SC Sanofi-Aventis Frankfurt, Germany

[PLT0237] 4.2.2.3-4

Plasma Protein Binding

Plasma of Rat and Dog

In vitro Sanofi-Aventis Frankfurt, Germany

[LPR1021] 4.2.2.3-5

Metabolism Metabolic

stability and identification

S9 fraction of liver and kidney (human and

animal species)

In vitro Sanofi-Aventis Frankfurt, Germany

[F20xxKIN0001] 4.2.2.4-1

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TS 2.6.5.1 Pharmacokinetics Tabulated Summary – Overview – Study Program (continued)

Test Article: Lixisenatide

Type of Study Test System Method of Administration Testing Facility Study Number Location

Metabolism (continued) Metabolic stability

Plasma (human and animal

species)

In vitro xxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-039] 4.2.2.4-2

Elimination and Excretion Milk excretion Rat (Long Evans) SC Sanofi-Aventis Frankfurt,

Germany [MIL0066] 4.2.2.5-1

Drug Interactions

No studies conducted Other

No studies conducted

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TS 2.6.5.1 Pharmacokinetics Tabulated Summary – Overview – Study Program (continued) – Methods of Analysis

Test Article: Lixisenatide

Type of Study Test System Method of Administration Testing Facility Study Number Location

Quantitative Assay Sandwich Enzyme Immunoassay Rat NA xxxxxxxxxxx

xxxxxxxxx xxxxxxxxx

Switzerland.

[F20xxKIN0107] (xxx-332910)

4.2.2.1-1

Sandwich Enzyme Immunoassay Rat NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland.

[F20xxKIN0290] (xxx-332910 Amendment)

4.2.2.1-1a

Sandwich Enzyme Immunoassay Rat NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland.

[F20xxKIN0248] (xxx-26642)

4.2.2.1-2

Sandwich Enzyme Immunoassay Rat NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland.

[F20xxKIN0010] (xxx-26642

Amendment)

4.2.2.1-2a

Sandwich Enzyme Immunoassay Mouse NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0145] (xxx-18568)

4.2.2.1-3

NA: Not Applicable

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TS 2.6.5.1 Pharmacokinetics Tabulated Summary – Overview – Study Program (continued) – Methods of Analysis (continued)

Test Article: Lixisenatide

Type of Study Test System Method of Administration Testing Facility Study Number Location

Quantitative Assay Sandwich Enzyme Immunoassay Mouse NA xxxxxxxxxxx

xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0289] (xxx-18568

Amendment)

4.2.2.1-3a

Sandwich Enzyme Immunoassay Mouse NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0284] (xxx-28058)

4.2.2.1-4

Sandwich Enzyme Immunoassay Mouse NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0125] (xxx-28058

Amendment 1)

4.2.2.1-4a

Sandwich Enzyme Immunoassay Dog NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0152] (xxx-19051)

4.2.2.1-5

Sandwich Enzyme Immunoassay Dog NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0306] (xxx-19051

Amendment 1)

4.2.2.1-5a

NA: Not Applicable

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TS 2.6.5.1 Pharmacokinetics Tabulated Summary – Overview – Study Program (continued) – Methods of Analysis (continued)

Test Article: Lixisenatide

Type of Study Test System Method of Administration Testing Facility Study Number Location

Quantitative Assay Sandwich Enzyme Immunoassay Dog NA xxxxxxxxxxx

xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0107] (xxx-19051

Amendment 2)

4.2.2.1-5b

Sandwich Enzyme Immunoassay Dog NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0308] (xxx-26643)

4.2.2.1-6

Sandwich Enzyme Immunoassay Dog NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0011] (xxx-26643

Amendment)

4.2.2.1-6a

Sandwich Enzyme Immunoassay Rabbit NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0019] (xxx19052)

4.2.2.1-7

LC/MS Dog NA xxxxxxx

xxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-107]

4.2.2.1-8

NA: Not Applicable

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TS 2.6.5.1 Pharmacokinetics Tabulated Summary – Overview – Study Program (continued) – Methods of Analysis (continued)

Test Article: Lixisenatide

Type of Study Test System Method of Administration Testing Facility Study Number Location

Quantitative Assay

LC/MS Rat / Plasma NA xxxxxxx

xxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-107]

4.2.2.1-8

LC/MS Pig / Plasma NA xxxxxxx

xxxxxxxxxxxxxxxx xxxxxxxxx Denmark

[00-107]

4.2.2.1-8

NA: Not Applicable

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TS 2.6.5.1 Pharmacokinetics Tabulated Summary – Overview – Study Program (continued) – Methods of Analysis (continued)

Test Article: Lixisenatide

Type of Study Test System Method of Administration Testing Facility Study Number Location

Quantitative Assay Direct ELISA (anti drug antibody) Rat NA xxxxxxxxxxx

xxxxxxxxx xxxxxxxxx

Switzerland.

[F20xxKIN0265] (xxx-17838)

4.2.2.1-9

Direct ELISA (anti drug antibody) Rat NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland.

20xx-0085 (PT05-0014; xxx-26010) and (xxx-17838)

see 2.6.7 [TS 2.6.7.7C]

4.2.3.2-15

Direct ELISA (anti drug antibody) Rat NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland.

[F20xxKIN0246] (xxx-21011)

4.2.2.1-10

Direct ELISA (anti drug antibody) Mouse NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0014] (xxx-27229)

4.2.2.1-11

NA: Not Applicable

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TS 2.6.5.1 Pharmacokinetics Tabulated Summary – Overview – Study Program (continued) – Methods of Analysis (continued)

Test Article: Lixisenatide

Type of Study Test System Method of Administration Testing Facility Study Number Location

Quantitative Assay Direct ELISA (anti drug antibody) Mouse NA xxxxxxxxxxx

xxxxxxxxx xxxxxxxxx

Switzerland

[F20xxKIN0012] (xxx-27229

Amendment 1)

4.2.2.1-11a

Direct ELISA (anti drug antibody) Dog NA xxxxxxxxxxx xxxxxxxxx xxxxxxxxx

Switzerland

20xx-1926 (1859/045) see 2.6.7

[TS 2.6.7.7F]

4.2.3.2-19

Cellular NAB assay – GLP receptor activation assay

Rat NA Sanofi-Aventis Frankfurt, Germany

[DOS1043]

(xxx071716.01)

4.2.2.1-12

NA: Not Applicable

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TS 2.6.5.2 Pharmacokinetics Tabulated Summary – Pharmacokinetic parameters after a single dose

Species (strain) Mouse (db/db) Mouse (NMRI)

Study No. (Location) [00-077] (4.2.2.2-1) [00-085] (4.2.2.2-2) Method of Administration IP SC IV IP SC IV Feeding Conditions Fasted Fasted Fasted Fasted Fasted Fasted Test Article 1 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 Vehicle/Formulation 2 PBS

1 mL/kg PBS

1 mL/kg PBS

1 mL/kg PBS

1 mL/kg PBS

1 mL/kg PBS

1 mL/kg Dose (nmol/kg) 100 1000 100 1000 100 100 100 100 No. of Animals** 9 18 9 17 16 17 18 32 Sample Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Analyte AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 Analytical method SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS Gender Male Male Male Male Male Male Male Male PK Parameters:

tmax (min) 14 51 28 49 0 48.6 14.4 0 Cmax (nM) 94 568 50 332 1069 2.9 39.5 719

AUC (min x µM) 6.9 119 3.75 52.7 10.4 NC 2.08 13.7 t1/2z (min) 40 103 - 69 37 NC 24 83

CL (mL/min/kg) 9.6* 9.6* 9.6* 9.6* 9.6 NC 7.3* 7.3 Vss (mL/kg) NC NC NC NC 132 NC NC 421

F (%) 69 115 36 51 NC*** 15 Additional Information: * Cl corrected for bioavailability **non-serial sampling with 1 or 2 animals per time point ***report estimates a value of 0.4 using Cmax NC: not calculated ;

1 AVE0010 is mentioned in the reports as ZS42-0010 or ZP10 or ZP10A 2 PBS: solution in phosphate buffered saline

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TS 2.6.5.2 Pharmacokinetics Tabulated Summary – Pharmacokinetic parameters after a single dose (continued)

Species (strain) Rat (Sprague Dawley)

Study No. (Location) [00-062] (4.2.2.2-3) [00-074] (4.2.2.2-4) [01-012] (4.2.2.2-5) Method of Administration SC IV SC IV IP Feeding Conditions NA** NA** NA** NA** NA** Test Article 1 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 Vehicle/Formulation isotonic saline

1 mL/kg isotonic saline

1 mL/kg isotonic saline

1 mL/kg isotonic saline

1 mL/kg PBS2

1 mL/kg Dose (nmol/kg) 137 772 1231 1231 1000 100 900 No. of Animals 3 3 2 1 6 5 6 Sample Plasma Plasma Plasma Plasma Plasma Plasma Plasma Analyte AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 Analytical method SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS Gender Male Male Male Male Male Male Male PK Parameters:

tmax (min) 19±7.4 15.5±0.8 19.5±8.0 0 18.1±4.1 0 6.7±2.6 Cmax (nM) NA NA NA 21000 113±41 1663±421 48±12

AUC (min x µM) 0.3659-1.1845 3.4577-6.0815 5.8785/11.8732 270.503 8.335±4.355 17.982±3.901 1.8±0.34 t1/2z (min) 37±3.1 29.1±4.9 36.3±16.5 30.5 30.5±10.5 48.6±10.2 29±7.9

CL (mL/min/kg) 3.3*±0.9 4.8*±1.5 4.5*±2.2 4.6 5.9*±1.4 5.8±1.4 5.7*±1.2 Vss (mL/kg) 174*±34 193*±26 212*±6 62.9 284*±108 98±36 -

F (%) 1.2-3.9 2.0-3.6 2.2/4,4 4.3±1.9 1.1±0.21 Additional Information: * Clcorrected=Clsc*F or Vcorrected=Vsc*F; ** catheterized animals, conscious; NA: no special information given in the report or protocol

1 AVE0010 is mentioned in the reports as ZS42-0010 or ZP10 or ZP10A 2 PBS: solution in phosphate buffered saline

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TS 2.6.5.2 Pharmacokinetics Tabulated Summary – Pharmacokinetic parameters after a single dose (continued)

Species (strain) Rabbit (Ssc:CPH) Rabbit(NZW) Dog (Beagle) Pig (Crossbreed) Study No. (Location)

[00-032] (4.2.2.2-6)

[00-044] (4.2.2.2-7)

[00-139] (4.2.2.2-8)

[02-139] (4.2.2.2-9)

[00-141] (4.2.2.2-11)

[00-045] (4.2.2.2-12)

[00-083] (4.2.2.2-13)

Method of

IV IV SC IV SC SC IV (infusion) SC IV SC IV (infusion)

Feeding Conditions NA** NA** NA** NA** NA** NA NA Fasted*** Fasted*** Fasted**** Fasted****

Test Article 1 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 Vehicle/Formulation 2 IS

1 mL/kg IS

1 mL/kg IS

0.25 mL/kg IS

1 mL/kg Special 1 0.75 mL

PBS 0.5 mL/kg

PBS 5mL/kg

Special 2 Special 3 IS 1 mL/kg

IS 1 mL/min for 30 min

Dose (nmol/kg) 200 137 400 65 2 41 21 61-104 61-130 109 18.0-19.9 No. of Animals 5 12 2 4 3 4/4 4/4 3 3 3 3 Sample Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Analyte AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 AVE0010 Analytical method SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS ELISA SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS SPE/LC/MS Gender Male Male Male Male Female Male Female Male Female Female Female Female Female PK Parameters:

tmax (min) 0 0 160±72 0 84±9 128±26 122±39 30 30 142-225 - 120±23 - Cmax (nM) 4000±1700# 2600±1370# 240±32 840±500 1.853±0.364 40±11 53±27 216±44 226±50 12-22 347-886 39±3 85±6

AUC (min x µM) 42±40# 47.4±12.9# 140±22 26±8.8 0.41±0.06# 27±17 22.7±11 14.6±2.2 14.9±2.3 4.22-6.73 14.4-29.9 15.4±2.1 3.63-4.15 t1/2z (min) 63±16 84±45 275±75 91±41 58±6 342±206 180±57 60±25 57±3 NC 196-392 159±20 53±5

CL (mL/min/kg) 5.3±2 3.0±1.1 2.0*±1.2 2.8±0.9 5.1*±0.9# 2.18*±1.56 1.82*±0.89 1.46±0.20 1.44±0.26 NC 2.9-4.5 5.1*±0.2 5.0±0.6 Vss (mL/kg) 270±260 150±59 1400*±280 200±140 426*±110 790*±230 600*±430 104±45 95±21 2740-4970* 441-736 1650*±360 192±22

F (%) - - 38±5/86## - NC 102±75 84±54 >26 - 71±17 - Additional Information: *Cl/F or V/F in 00-139 and 02-139; Clcorrected=Clsc*F or Vcorrected=Vsc*F in 00-141; apparent distribution volume in 00-045 and 00-083; ** catheterized animals, conscious; *** fasted overnight, non-conscious; **** fasted

NA: no special/specific information given in the report or protocol NC: not calculated # data calculated from values given in the report ## depending on calculation (using AUClast or AUCinf)

1 AVE0010 is mentioned in the reports as ZS42-0010 or ZP10 or ZP10A 2 IS.: isotonic saline solution; PBS: solution in phosphate buffered saline; Special 1: 200 mMsucrose, 50 mM L-histidine, 43.2 mM HCl, pH 5.3

Special 2: isotonic saline / 0.2 mL/kg or phosphate buffer pH 7.4 / 0.1 mL/kg; Special 3: isotonic saline / 0.2 mL/kg or phosphate buffer pH 7.4 / 0.1 or 0.2 mL/kg

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TS 2.6.5.3 Pharmacokinetics Tabulated Summary – Pharmacokinetic parameters after repeated dose

Species (strain) Rabbit (NZW)

Study No. (Location) [03-013] (4.2.2.2-10)

No. of Animals 3 (conscious) Test Article AVE0010

Vehicle/Formulation 120 mM mannitol, 50 mM acetic acid 50 mM phenol, 20 mM methionine, 20 mM asparagine, 5 mM EDTA adjuisted to pH 4.5 with ammonia;

1 µl/h Method of administration SC infusion over 3 days (osmotic pump)

Dose 4 µg/h (0.94 µg/hr{kg} or 71 µg/kg over 3 days

Sample Plasma

Analyte AVE0010

Analytical method ELISA

PK Parameters: Css* (nM) 0.485

AUC (min x µM) 2.22#

t1/2z (min) 396#

CL (mL/min/kg) 7.36#

Vd (mL/kg) 4000

Additional Information: * steady state plasma concentration, # data calculated from values given in the report

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TS 2.6.5.4 Pharmacokinetics Tabulated Summary – Protein Binding

Study System: in vitro Test Article: AVE0010 (Batch xxxxxxxxxxxx) Study Number: [LPR1021] Method: Ultracentrifugation Substance Analyzed: AVE0010 Location: 4.2.2.3-5

Test System: Plasma (EDTA) a Analytical Method: ELISA Assay Concentrations (ng/mL) % Bound

Dog Rat 0.05 36 62 50 69 79 10000 42 46 Mean (range) 49 62 Additional Information: a : Plasma from male animals pooled from at least three individuals

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TS 2.6.5.5 Pharmacokinetics Tabulated Summary – Qualitative organ distribution after a single dose

Species (Strain): Rat (Long Evans) Test Article: AVE0010-[glycin-³H, N-terminal end] Study Number: [DIS0474]

No. per Time Point / Gender: 1 / male Vehicle / Formulation: isotonic saline solution with 43mM sodium citrate (pH 5.3) / 2 mg/g

Location: 4.2.2.3-1

Feeding Conditions: normal fed Method of Administration: SC, IV Sampling Times: IV: 5 min; SC: 15 min, 6 h, 24h, 48h, 72h, 168h, 336h Dose: 1mg/kg Analytical Method/Substance Analyzed: Quantitative whole body autoradiography

Radioactivity Level (µgEq/g) SC IV

Tissue/Organ: 15 min

5 min Adrenal 0.1589 3.3232 Bladder_cont. 0.5748 0.1002 Bladder_wall 0.2561 1.6974 Blood_art. 0.2301 2.6291

Blood_ven 0.2213 2.6610

Mean Blood 0.2257 2.6450 Bone 0.0809 0.9233 Bone_marrow 0.0890 1.1140 Brain 0.0192 0.0618 Brown_Fat 0.0713 0.4244 Cornea 0.1281 0.2232 Fat BLQ 0.0089 Glandular_stomach 0.3831 1.3809 Kidney 0.3171 9.0801

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2.6.5.5 Pharmacokinetics Tabulated Summary – Qualitative organ distribution after a single dose (continued)

Radioactivity Level (µgEq/g) SC IV

Tissue/Organ: 15 min

5 min Lachrymal_gl. 0.2174 0.6523 Large_I._cont. 0.0108 0.0509 Large_I._wall 0.1892 1.6650 Lens BLQ 0.0129 Liquor ND 0.8040 Liver 0.0831 2.6003 Lung 0.3560 2.9344 Myocardium 0.1688 2.1493 Oesoph._cont. BLQ 0.0953 Oesoph._wall 0.1778 1.5241 Pancreas 0.6600 1.8174 Pineal_body 0.5130 2.4963 Pituitary_gl. 0.2140 3.4869 Prostate 0.1234 0.6978 Renal_cortex 0.5316 15.6138 Renal_medulla 0.1398 3.6349 Salivary_gl. 0.4844 3.1460 Skeletal_muscle 0.0859 0.6650 Skin 0.0639 0.4558 Small_I._cont. 0.0278 0.8005 Small_I._wall 0.1730 2.1743 Spinal_cord 0.0107 0.0300

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2.6.5.5 Pharmacokinetics Tabulated Summary – Qualitative organ distribution after a single dose (continued)

Radioactivity Level (µgEq/g) SC IV

Tissue/Organ: 15 min

5 min Spleen 0.1537 2.5061 Stomach_cont. 0.0110 0.0492 Stomach_wall 0.1035 0.5975 Testis 0.0409 0.1443 Thymus 0.1350 0.9263 Thyroid_gl. 0.4054 3.4703 Uvea/Retina 0.2605 1.5218 Additional Information: The unstable labelling position (6 h post-dose the fraction of radioactivity in urine attributed to ³H2O amounted ≈ 50%) forced to focus on the first measurement times (iv. 5 min; sc. 15 min) only. Even at these early time points part of the obtained radioactivity concentrations have to be related to degradation products already. LOQ: 0.0036 µg equivalents/g

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TS 2.6.5.6 Pharmacokinetics Tabulated Summary – Quantitative organ distribution after a single dose

Species (Strain): Rat (Long Evans) Test Article: AVE0010-[39-Lys-, 40-Lys-, 41-Lys-, 42-Lys-14C4]

Study Number: [DIS0531]

No. per Time Point / Gender: 1 / male; 1 month & 3 months postdose: 3 / male

Vehicle / Formulation: isotonic saline solution with 50mM sodium citrate (pH5.3) / 2 mg/mL

Location: 4.2.2.3-2

Feeding Conditions: normal fed Method of Administration: sc, iv Sampling Times: iv: 5min; sc: 5min, 15min, 1.5h, 3h, 6h, 24h, 48h, 72h, 168h, 336h, 1month, 3months

Dose: 1mg/kg (iv & sc)

Analytical Method/Substance Analyzed: Quantitative whole body autoradiography

Radioactivity Level (µgEq/g) SC SC IV

Tissue/Organ: 5 min 15 min

5min Adrenal 0.17 0.39 2.50 Adrenal_cortex 0.16 0.42 2.29 Adrenal_medulla 0.19 0.33 2.96 Bladder_cont. 0.01 0.02 0.04 Bladder_wall 0.04 0.13 1.06 Blood_art. 0.16 0.31 2.36 Blood_ven. 0.13 0.31 2.33 Bone 0.05 0.21 1.79 Bone_marrow 0.06 0.18 1.37 Brain BLQ 0.02 0.05 Brown_fat 0.10 0.14 1.03 Choroid_plexus 0.03 0.19 1.17 Cornea BLD BLD 0.20 Fat BLQ 0.01 0.03 Kidney 0.36 1.58 16.62

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TS 2.6.5.6 Pharmacokinetics Tabulated Summary – Quantitative organ distribution after a single dose (continued)

Radioactivity Level (µgEq/g) SC SC IV

Tissue/Organ: 5 min 15 min

5min Lachrymal_gl. 0.06 0.16 1.15 Large_I._cont. BLD BLD 0.01 Large_I._wall 0.05 0.17 1.52 Lens BLD BLD 0.02 Liquor BLD BLD BLD Liver 0.12 0.27 2.97 Lung 0.13 0.32 2.21 Myocardium 0.11 0.21 1.69 Oesoph._cont. 0.01 0.01 0.08 Oesoph._wall 0.05 0.18 1.03 Pancreas 0.10 0.34 1.14 Pineal_body 0.11 0.26 0.85 Pituitary_gl. 0.18 0.25 3.11 Prostate 0.04 0.09 0.65 Renal_cortex 0.68 3.31 36.99 Renal_medulla 0.08 0.27 2.65 Salivary_gl. 0.11 0.26 2.32 Seminal vesicle BLQ 0.02 0.03 Skeletal_muscle 0.03 0.07 0.44 Skin 0.04 0.13 0.99 Small_I._cont. 0.02 0.03 0.11 Small_I._wall 0.05 0.16 1.72 Spinal_cord BLQ 0.02 0.05

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TS 2.6.5.6 Pharmacokinetics Tabulated Summary – Quantitative organ distribution after a single dose (continued)

Radioactivity Level (µgEq/g) SC SC IV

Tissue/Organ: 5 min 15 min

5min Spleen 0.07 0.20 1.81 Stomach_cont. BLD BLD BLD Stomach_glandular 0.14 0.29 1.98 Stomach_wall 0.03 0.11 0.79 Testis BLQ 0.03 0.16 Thymus 0.04 0.12 0.62 Thyroid_gl. 0.12 0.28 2.47 Uvea/Retina 0.05 0.07 1.33 Vitreous_body BLD BLD 0.06 Additional Information: Also the 14C-label emerges as unstable (24 h after administration 43% of the administered radioactivity was obtained as volatile radioactivity!) The unstable labelling position forced to focus on the first measurement times (iv. 5 min; sc. 5 min and 15 min) at which results are comparable to the radioactivity concentrations observed with a ³H-labelled drug compound (see DIS0474). Even at these early time points parts of the obtained radioactivity concentrations have to be related to degradation products already. LOQ: 0.0068 µg equivalents/g An additional investigation of lixisenatide concentrations in brain by a sensitive ELISA revealed that in mean 2.4% of the lixisenatide concentration in plasma was found in the brain indicating no significant difference to the part expected from the amount of plasma in brain.

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TS 2.6.5.7 Pharmacokinetics Tabulated Summary – Placental transfer

Species (Strain) Rat (Sprague Dawley) Study No. (Location) [PLT0236] (4.2.2.3-3)

Gestation Day 17 17 No. per Time Point 2 4 Feeding Conditions normal fed normal fed Test Article AVE0010-[39-Lys-. 40-Lys-. 41-Lys-. 42-Lys-14C4] AVE0010 Vehicle/Formulation isotonic saline solution with 50mM sodium citrate (pH5.3) / 2 mg/mL isotonic saline solution with 50mM sodium citrate (pH5.3) / 2 mg/mL Method of Administration sc sc Dose (active moiety) 1mg/kg 1mg/kg Treatment Duration 24h 24h Analyte Radioactivity AVE0010 Analytical Method Quantitative whole body autoradiography ELISA

Concentration (µgEq/g ) Concentration (ng/mL plasma ) 0.25 h 24 h 0.25 h 24 h

Tissue / Organ Fetus Dam Ratio Fetus Dam Ratio Fetus Dam Ratio Fetus Dam Ratio Fetus / maternal blood resp. plasma 0.07 0.51 0.145 1.864 1.22 1.533 0.507 355 0.0014 BLQ 35.8 -

Fetus / placenta 0.39 0.31 0.236 2.15 1.80 0.867 Brain - 0.04 - 0.41 Lung - 0.70 - 0.66 Liver - 0.56 - 2.09

Kidney - 5.34 - 2.68 Myocardium - 0.39 - 1.28

% dose in total fetal tissue 0.11 4.3 Additional Information: Most of the observed transfer of radioactivity is due to the instability of the drug/radiolabel. The more sensitive, specific method for lixisenatide determination

to investigate fetal plasma (ELISA) revealed a very low placenta permeation. No lixisenatide was detected in the amniotic fluid (LLOQ = 12 pg/mL)

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TS 2.6.5.8 Pharmacokinetics Tabulated Summary – Placental transfer

Species (Strain) Rabbit (New Zealand White) Study No. (Location) [PLT0237] (4.2.2.3-4) Gestation Day 18 18 No. per Time Point 1 4 Feeding Conditions normal fed normal fed Test Article AVE0010-[39-Lys-. 40-Lys-. 41-Lys-. 42-Lys-14C4] AVE0010 Vehicle/Formulation isotonic saline solution with 50mM sodium citrate (pH5.3) / 5 mg/mL isotonic saline solution with 50mM sodium citrate (pH5.3) / 5 mg/mL Method of Administration sc sc Dose (active moiety) 0.5mg/kg 0.5mg/kg Treatment Duration 24h 24h Analyte Radioactivity AVE0010 Analytical Method Quantitative whole body autoradiography ELISA

Concentration (µgEq/g ) Concentration (pg/mL plasma ) 3 h 24 h 3 h 24 h

Tissue / Organ Fetus Dam Ratio Fetus Dam Ratio Fetus Dam Ratio Fetus Dam Ratio Fetus / maternal blood resp.

0.25 0.29 0.87 0.99 0.78 1.26 <12 to 197 66000 to 138667 <0.0001 to 0.003 BLQ 445 to 1057 -

Fetus / placenta 0.25 0.57 0.44 0.99 2.02 0.49 Brain 0.17 - 0.90 - Lung - - - - Liver 0.67 - 3.41 -

Kidney - - - - Myocardium - - - -

% dose in total fetal tissue 0.15 0.49 Additional Information: Most of the observed transfer of radioactivity is due to the instability of the drug/radiolabel. The more sensitive, specific method for lixisenatide determination to investigate fetal plasma (ELISA, LLOQ = 12 pg/mL) revealed a very low placenta permeation.

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TS 2.6.5.9 Pharmacokinetics Tabulated Summary – Other distribution study

Not applicable, because no other distribution studies were conducted.

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TS 2.6.5.10 Pharmacokinetics Tabulated Summary – In vitro metabolism

Test System: Supernatant 9000 g (S9) fraction of liver and kidney

Study Number: [F20xxKIN0001]

Test Article: AVE0010 (Batch xxxxxxx) Location: 4.2.2.4-1 Concentration (µM): 5 Time: 2-10-60 min Analytical Method: LC-MS/MS S9 Proteins: 2 mg/mL Species (Strain. Sex) Mouse

(CD1. male) Rat

(Sprague Dawley. male)

Rabbit (New Zealand White. male)

Dog (Beagle. male)

Human (female/male)

S9 Fraction liver kidney liver kidney liver kidney liver kidney liver kidney

Biotransformation (%) (60 min incubation) 20 81 55 91 89 74 86 66 92 89

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TS 2.6.5.10 Pharmacokinetics Tabulated Summary – In vitro metabolism (continued)

Test System: Supernatant 9000 g (S9) fraction of liver and kidney

Study Number: [F20xxKIN0001] (continued)

Test Article: AVE0010 (Batch xxxxxxx) Location: 4.2.2.4-1 Formation of 28 biodegradation products, elucidated in human S9 fractions

S9-Liver Fraction:

HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPSKK KKKK 2min

10min

60min

S9-Kidney Fraction:

HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPSKK KKKK 2min

10min

60min

S9-Liver Fraction:

HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPSKK KKKK 2min

10min

60min

S9-Liver Fraction:

HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPSKK KKKK 2min

10min

60min

HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPSKK KKKK HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPSKK KKKK 2min

10min

60min

2min

10min

60min

S9-Kidney Fraction:

HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPSKK KKKK 2min

10min

60min

S9-Kidney Fraction:

HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPSKK KKKK 2min

10min

60min

HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPSKK KKKK HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPSKK KKKK 2min

10min

60min

2min

10min

60min

Inc.-Time

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TS 2.6.5.10 Pharmacokinetics Tabulated Summary – In vitro metabolism (continued)

Test System: Supernatant 9000 g (S9) fraction of liver and kidney

Study Number: [F20xxKIN0001] (continued)

Test Article: AVE0010 (Batch xxxxxxx) Location: 4.2.2.4-1 Formation of 28 biodegradation products, elucidated in human S9 fractions, Metabolic identification of AVE0010 in S9-fractions of human (tabular presentation)

Metabolite: Proposed sequences: MW(Da)

Liver 2min

Liver 10min

Liver 60min

Kidney 2min

Kidney 10min

Kidney 60min

P1 FIEWLKNGGPSSGAPPSKKKKKK(-) 2511.4564 xP2 IEWLKNGGPSSGAPPSKKKKKK(-) 2364.3880 x x x x xP3 EWLKNGGPSSGAPPSKKKKKK(-) 2251.3039 x xP4 WLKNGGPSSGAPPSKKKKKK(-) 2122.2613 x xP5 LKNGGPSSGAPPSKKKKKK(-) 1936.1820 xP6 KNGGPSSGAPPSKKKKKK(-) 1823.0979 xP7 NGGPSSGAPPSKKKKKK(-) 1695.0030 x xP8 PPSKKKKKK(-) 1067.7417 x x x x xP9 PSKKKKKK(-) 970.6889 x x

P10 EWLKNGGPSSGAPPSKKKKK(K) 2123.2089 xP11 GAPPSKKKKK(K) 1067.7053 x x x xP12 (-)HGEGTFTSDLSKQMEEEA 1994.8766 x x xP13 (-)HGEGTFTSDLSKQMEEE 1923.8394 x xP14 (-)HGEGTFTSDLSKQMEE 1794.7969 xP15 (-)HGEGTFTSDLSKQM 1536.7117 x x xP16 (-)HGEGTFTSDLSKQ 1405.6712 xP17 (-)HGEGTFTSDLSK 1277.6126 xP18 (-)HGEGTFTSDL 1062.4856 xP19 GTFTSDLSKQMEE 1471.6739 xP20 GTFTSDLSKQM 1213.5887 xP21 LSKQMEEEAVRL 1431.7630 xP22 LSKQMEEEAVR 1319.6629 xP23 LSKQMEEEA 1063.5094 x x x xP24 TSDLSKQM 908.4511 x xP25 TSDLSKQME 1037.4937 xP26 TSDLSKQMEE 1166.5363 x xP27 TSDLSKQMEEEA 1366.6160 x x x xP29 FTSDLSKQMEEEA 1513.6844 x

cleavage product close to C-terminal end M methionin, putative position for radioactive labelingcleavage product close to N-terminal end MW: Molecular Weightinternal cleavage product

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TS 2.6.5.11 Pharmacokinetics Tabulated Summary – In vitro metabolism

Test System: Plasma Study Number: [00-039]

Test Article: ZS42-0010 (AVE0010). (Batch xxxxxxxxxxx) Location: 4.2.2.4-2

Concentration (µM): 1.002

Time: 45 min (rodents) or 90 min (other species) intervals

Analytical Method: LC-MS/MS

Species (Strain) / Parameter (Mean ± SD)

Mouse (mixed)

Mouse (db/db)

Rat (Sprague Dawley)

Rabbit (mixed)

Dog (Beagle)

Pig (DSS) Human

Plasma half-lives (min) 476 ± 60 212 ± 1 224 ± 19 521 ± 66 322 ± 3 564 ± 44 2094 ± 598

Additional Information: Study on stability of lixisenatide in heparin stabilized plasma

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TS 2.6.5.12 Pharmacokinetics Tabulated Summary – Excretion after a single dose

Not applicable.

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TS 2.6.5.13 Pharmacokinetics Tabulated Summary – Excretion into milk

Species (Strain): Rat / Sprague Dawley Test Article: AVE0010-[39-Lys-. 40-Lys-. 41-Lys-. 42-Lys-14C4] Study Number: [MIL0066] No. per Time Point: 3 dams with 4 pups each Vehicle / Formulation: isotonic saline solution with 50mM sodium

citrate (pH5.3) / 2 mg/mL Location: 4.2.2.5-1

Feeding Conditions: normal fed Method of Administration: SC

Sampling Times: 2h. 4h. 24h Dose (active moiety): 1mg/kg Analytical Method/Substance Analyzed: QWBA / HPLC. Radioactivity

Concentration (µgEq/g ) Tissue/Organ: 2 h 4 h 24 h

Blood (dam) 0.880 1.261 0.858 Plasma (dam) 1.405 2.022 1.111

Stomach content (pup) 0.003 0.041 3.560 Ratio milk1 / plasma <0.002 0.020 3.200

% dose excreted via milk (0-24h) 9.4 Additional Information: Most of the observed transfer of radioactivity into milk is due to the instability of the drug/radiolabel. Using a more sensitive, specific method for lixisenatide determination (ELISA) to investigate the stomach content of the pups revealed that only 0.0004% of the unchanged lixisenatide administered to the dam was found in gastric content of the pups 24h postdose.

1 Ratio of stomach content of the pups as surrogate for the milk and plasma of the dam

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TS 2.6.5.14 Pharmacokinetics Tabulated Summary – in vitro drug interaction – CYP Inhibition

Not applicable, because no animal drug-drug-interaction studies were conducted

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TS 2.6.5.15 Pharmacokinetics Tabulated Summary – in vitro drug interaction – CYP Induction

Not applicable, because no animal drug-drug-interaction studies were conducted (eg, on nonclinical models of disease (eg, renally impaired animals)).