Characterization of hADME and pharmacokinetics ofinhaled Velsecorat: alternative use of IV dosing and AMS
Marta Pelay-Gimenoa, Ann Aurell Holmbergb, Lars Weidolfb, Sofia Necanderb, Peter Boldb, Sharan Sidhuc, Rianne A.F. de Ligta,
Elwin R. Verheija, Alexandra Jauhiainenb, Ioannis Psallidasb and Susanne Prothonb
aTNO, Leiden, The Netherlands; bAstraZeneca, Gothenburg, Sweden; cQuotient Sciences, Nottingham, United Kingdom

INTRODUCTION

Velsecorat is a potent non-steroidal glucocorticoid receptor modulator
investigated as a potential treatment for asthma. In general, inhaled
drugs suffer from additional complications during characterization ofhuman absorption, distribution, metabolism and excretion (hADME), aswell as pharmacokinetics (PK). Main challenges are: preparation of theright particle size for the 14C-compound, quantification of actual inhaled
dose, and unknown long-term toxicity of inhaled 14C accumulated in thelungs. Thus, intravenous (IV) dosing is used as a surrogate route forinhaled administration.

STUDY DESIGN AND MASS BALANCE RESULTS
ADoseScreeningDay -28 to -2BTechniques like accelerator mass spectrometry (AMS) have changed oneof the main paradigms of the hADME strategy and are shaping a more
flexible and sustainable drug development process. AMS’ high sensitivity
for 14C analysis has enabled the implementation of 14C-microtracer
studies by reducing the radioactive dose, thereby enabling the conductof hADME studies earlier in development. In addition, this completelyeliminates the need for 14C-radiolabelled studies in animals.

Admissions
Day -1

720 µg inhaled Velsecorat
and 30 µg IV 14C-Velsecorat(6.7 kBq, 180 nCi)
Day 1

Discharge
Day 8Figure 1. (A) A total of 6
subjects, healthy male andnon-pregnant, non-lactating
female, were dosed according
to this scheme.
(B) Total radioactivity (TRA)
analysis results: an averageof 76.0% of the administeredradioactivity was recoveredat 168h after dosing, fromwhich a 24.4% was recoveredin urine and a 51.6% in feces.

PHARMACOKINETIC RESULTS
Cmax[pmol/L]

Tmax
[h]

T1/2
[h]

509

0.88

26.9

10600

107-543

1.00

1.99

671

70.7

113

565

1.00

18.4

3380

13.6

276

Velsecorat(inhaled)
14C-Velsecorat(IV)
TRA

AUC0-t CL/F or CL[ng.h/mL][L/h]Vss[L]

Figure 2. The difference between the t1/2 in plasma estimated for inhaled Velsecorat(27h) and for intravenous 14C-Velsecorat (2h) confirmed its elimination is absorptionrate-limited from the lungs. Thus, a long pulmonary residence time is ensured
supporting a once-daily administration.

14C Activity [µBq]

METABOLISM RESULTS
0-12h Pool
A 30002000

C Activity [µBq]
14C1000

PLASMA

500
0.00

9000
8000
7000
6000
5000
4000
3000
2000
1000
05.00

C Activity [µBq]

10.00

M1

15.00
Time [min]20.00

M220.00

5.00

4000

2000
1000
010.0015.00
Time [min]

20.00

0.00

5.00

10.00

15.00
Time [min]

20.00

30.00

25.00

M44, M8
M31, M32 or M46
M23
M33, M34
M47, M9,M24
M35 M10, M11

3000

30.00

25.00

URINE
M2

5000

14

D

M1

1500

0

B

24h Pool

2500

Velsecorat

FECES
25.00

30.00

Figure 3. AMS metabolic profiles in human (A) plasma (AUC0-12h (blue) and 24h (orange) pools); B) urine (0-72h pool); (C) feces (0-96h pool); and (D) Proposed metabolic
scheme for Velsecorat in humans. Urine and extracts of plasma and feces were fractionated using an ultra-performance liquid chromatography (UPLC) system coupled to ahigh-resolution mass spectrometer (HRMS, e.g. Q-Exactive). Post-column, the eluent was split between the Q-Exactive (for on-line generation of high-resolution MS and MS2data) and the fraction collector (for off-line 14C determination in the fractions by AMS). Potential sites of metabolism are highlighted using the Markush coloring system.

CONCLUSIONS

 Velsecorat showed a high clearance, volume of distribution and bioavailability, and a confirmed absorption-rate limited elimination following
inhalation. It is substantially metabolized via three major routes: O-dealkylation of the indazole ether (M2); ring opening of the 1,4-dioxane ring(M46) and ring opening of the oxolane ring (M47).
 The use of an IV 14C-microtracer enabled the determination of the mass balance, excretion routes and levels of circulating metabolites in humans
with a radiation exposure similar to natural background levels. Additionally, high resolution metabolite profiles were obtained for all matrices, andmetabolite identification was performed for all major metabolites and a number of minor metabolites.

REFERENCES
Aurell et al, Drug Metabolism & Disposition 50 (2022) 150-7; Young et al, Clinical Pharmacology & Therapeutics (2022).