AMS-ENABLED HUMAN ADME STUDY OF THE FGFR INHIBITOR DERAZANTINIB
Karine Litherland1, Elwin R. Verheij2, Mathias Wind1, Franziska von Siebenthal1, Gerda Mawududzi Assaba Sanvee1, Agnes Kaelin Aebi1, Rianne A. F. de Ligt2, Esther van Duijn2, Wouter H.J. Vaes2, Marc Engelhardt1, Ray Cooked3, Nand Singh41Basilea Pharmaceutica International Ltd, Allschwil, CH. 2TNO, Zeist, NL. 3Pharmaron UK Ltd, Rushden, UK. 4Quotient Sciences Ltd, Nottingham, UK.

Background: Derazantinib (DZB) is an oral FGFR inhibitor under clinical development for patients with intrahepatic cholangiocarcinoma (iCCA), urothelial, and gastric cancer. As part of the development program of derazantinib,
an innovative open-label, parallel group clinical study design was conducted to assess the absorption and disposition of derazantinib after intravenous (IV) and oral administrations. Accelerator mass spectrometry (AMS)-enabledand LC-MS/MS analysis were performed for mass balance, routes of excretion and elimination, absolute oral bioavailability, and metabolism of derazantinib in healthy male subjects.
Total radioactivity recovery in urine and feces

Study design––

Part 1, microtracer study: 6
healthy subjects, single oral
dose of 300 mg DZB, followed 8hours later by an IV microdoseof 100 μg [14C]-DZB (250 nCi,9.25 kBq).
Part 2: 6 healthy subjects,
single oral dose of 300 mg [14C]DZB (53 µCi, 1.9 MBq).

Part 1 (IV-microtracer)
Mean (%)
Percentage of administered dose (%)± SD
Subject # 101 102 103 104 105 106

Part 2 (Oral)
Mean (%)
Percentage of administered dose (%)± SD
Subject # 201 202 203 204 205 206

Urine0-1176h

6.85 ±0.905Urine 01176h

7.05

5.38

11.6

5.88

4.13

5.64

90.1 ±
8.96
97.0 ±
8.49

Feces0-1176h

85.5

72.8

72.0

74.1

79.9

74.8

Total

92.5

78.1

83.6

79.9

84.0

80.4

6.15

7.74

7.81

5.73

6.28

7.41

Feces
0-1176h

90.5

96

82.8

97.5

97.9

76

Total

96.7

104

90.6

103

104

83.4

–

6.62 ±
2.63
76.5 ±
5.20
83.1 ±
5.14

The majority of total radioactivity following oral and IV administrationof [14C]-DZB was recovered in feces indicating that hepatic
excretion was the main route of elimination.

Material and Methods–––

Blood, urine, and feces samples were collected throughout the
study for assessment of total radioactivity, DZB, its acid metabolite
M-13, and metabolite profiling.
AMS was used to determine total radioactivity in plasma, urine andfeces and [14C]-DZB concentrations in plasma. For thequantification and characterization of metabolites in acidified
plasma and feces, samples were fractionated using an ultraperformance liquid chromatography (UPLC) system that wascoupled to a high-resolution mass spectrometer (hrMS).
Due to the low [14C] levels in the Part 1 plasma pools, a large
volume of injection (80 μL) was required to load an adequate
amount of [14C] on the column and a 2D UPLC setup wasdeveloped to profile plasma pool sample at approximately 1 mBq
total radioactivity on column.

Part 1

Part 2

Total radioactivity, DZB, and acid metabolite (M-13) Plasma PK

Part 1

Part 2

T1/2(h)Cmax(ng/mL)Tmax(h)

AUC0-72h(ng.h/mL)

AUCinf(ng.h/mL)

CL(mL/min)

Vss(L)[14C]-DZB

172

0.85

0.325

4.53

17.0

96.8

1480

Total Radioactivity2900.83

0.283

6.38

38.4

NC

NC

[14C]-DZB

243

154

7.99

8070

40200

116

2440

Total Radioactivity

346

297

7.00

17100

97600

NC

NC

Acid metabolite (M-13)

292

53.3

10.0

2490

5990

NC

NC

NC: Not calculated–––

Metabolite profiling and identification
Unchanged DZB was the major circulating component in plasma after
oral and IV dosing, representing 48 and 62% of the [14C]radiochromatogram respectively. M-13 and M-24 (glucuronide
conjugate of M-6) were the only other circulating components
contributing to more than 10% of total radioactivity (11% and 13%,respectively) after oral dosing. M-13 was the most abundantcomponent in plasma after IV dosing (16%).
Unchanged DZB and M-6 (hydroxylated metabolite of DZB) were themain components in feces after oral and IV dosing: respectively, 46%
and 21% (oral) / 15% and 36% (IV) of the radiochromatogram withno other metabolites contributing to >10% of radioactivity.

PlasmaPart 1

Feces
Part 1

PlasmaPart 2Feces
Part 2Distribution and elimination

The minimum fraction absorbed was above 60% and the oral
bioavailability of DZB was 56% based on AUCinf.

Part 1
Part 2Conclusion: A new and innovative approach combining 2D UPLC and AMS analysis was used successfully to profile low level of [14C] in plasma pool samples. Following a 300 mg oral dose administration, derazantinib was wellabsorbed with an absolute bioavailability of 56%. Hepatic excretion was the main route of elimination following IV and oral dosing of [14C]-derazantinib. DZB was well tolerated in healthy male subjects.