A novel microdose approach to assess bioavailability, intestinal absorption,

gut metabolism, and hepatic clearance of simeprevir in healthy volunteers

Sivi Ouwerkerk-Mahadevan,1 Jan Snoeys,1 Alex Simion,2 Ellen Scheers,1 Maria Beumont-Mauviel2

1Janssen Research & Development, Beerse, Belgium; 2Janssen Infectious Diseases BVBA, Beerse, Belgium

Sivi Ouwerkerk-Mahadevan Employee of Janssen Research & Development, Beerse, Belgium

Presenter’s disclosure information

Simeprevir (SMV/TMC435)

Once-daily capsule, HCV NS3/4A protease inhibitor

Approved in Japan, Canada, the USA, Russia and Europe

Antiviral activity in patients infected with HCV GT 1, 2, 4, 5, and 6

Phase III trials of SMV+PR in HCV GT 1- and GT 4-infected treatment-naïves and relapsers showed SVR12 rates ~80%1–4

In a Phase II trial (COSMOS) of SMV + sofosbuvir ± ribavirin in HCV GT 1-infected treatment-naïves and prior null responders, the overall SVR12 rate was 92.2%5,6

Safe and well tolerated (~3800 patients treated in clinical trials to date)

In development as part of IFN-free combinations

GT, genotype; IFN, interferon; PR, peginterferon-α-2a/-2b + ribavirin; SVR12, sustained virologic response 12 weeks after end of treatment

1. Jacobson I et al. Lancet In press; 2. Manns M et al. Lancet In press; 3. Forns X et al. Gastroenterology Mar 3 [Epub ahead of print];

4. Moreno C et al. HepDART 2013; 5. Lawitz E et al. EASL 2014; 6. Sukowski MS et al. EASL 2014.

NS3 protease SMV

NS4A co-factor

Design Study in healthy male volunteers (N=6) Single oral dose of 200 mg 14C-SMV (50 µCi) Unchanged SMV was determined in plasma and blood Total radioactivity and metabolic profiles were determined

in plasma, urine, and feces Results that were used in the design of C118 Blood / plasma ratio of SMV = 0.69 LC-MS/MS response factor of metabolites in feces

Initial Conventional Mass Balance Study TMC435-TiDP16-C103

LC-MS, liquid chromatography–mass spectrometry

Objectives TMC435-TiDP16-C118

A Phase I, open-label, sequential, single-dose study in healthy volunteers (N = 6, all completed)

Primary objective – To evaluate the absolute bioavailability (Fabs) and pharmacokinetics (PK) of

SMV after administration of a single oral dose of 50 mg or 150 mg, followed by a single iv dose of 100 μg [3H]-SMV

Note:150 mg is the therapeutic dose, 50 mg was added to investigate mechanism of non-linear PK

Secondary objectives – To evaluate the proportion of the iv dose excreted in urine

and feces

– Safety and tolerability

Treatment TMC435-TiDP16-C118

Oral dose of SMV followed by an iv dose of [3H ]-SMV – 10 min iv infusion at tmax of oral dose (5 hr) – Two dosing periods – Plasma, urine, and feces collected

Oral 50 mg SMV

iv 100 µg [3H]-SMV (10 mins)

Wash-out period (7–14 days)

SMV and [3H]-SMV plasma PK profiles, and total plasma radioactivity were determined for both treatments 0–72 hours after oral SMV administration

Urine per 24-hour interval and feces were collected for at least 96 hours after oral SMV administration

→ 5 hr → → 5 hr →

Treatment period 1 Treatment period 2

Oral 150 mg SMV

iv 100 µg [3H]-SMV (10 mins)

Concept of iv micro-radiotracer design

Parent compound concentration from oral dose measured by LC-MS/MS

Parent compound concentration from iv dose measured by radioactivity detection with/without HPLC

Plas

ma

Con

cent

ratio

n

Oral dose iv infusion Time (h)

Simultaneous generation of oral and iv PK profiles

Plasma PK parameters TMC435-TiDP16-C118

Parameters

SMV 50 mg oral + 100 μg iv (Treatment period 1)

SMV 150 mg oral + 100 μg iv

(Treatment period 2)

iv dose, mean ± SD (tmax: median [range])

Cmax, ng/mL 12.07 ± 2.21 12.64 ± 2.78

AUC∞, ng.h/mL 17.1 ± 4.58 23.3 ± 8.28

t1/2term, h 10.8 ± 1.64 11.5 ± 2.11

CL, L/h 6.23 ± 1.77 4.75 ± 1.56

Vd, L 94.4 ± 15.4 75.3 ± 15.9

Oral dose, mean ± SD (tmax: median [range])

Cmax, ng/mL 262 ± 60.5 1503 ± 550

tmax, h 4.99 (2.50–5.00) 5.00 (4.99–6.00)

AUC∞, ng.h/mL 3976 ± 1257 21676 ± 7805

t1/2term, h 11.6 ± 1.75 12.0 ± 1.39

Fabs, % 45.98 ± 2.56 62.12 ± 5.65

0

20

40

60

80

100

0 100 200 300

Dos

e (%

)

Time (h)

0

20

40

60

80

100

0 100 200 300

Dos

e (%

)

Time (h)

Urine 1001

Urine 1002

Urine 1003

Urine 1004

Urine 1005

Urine 1006

Feces 1001

Feces 1002

Feces 1003

Feces 1004

Feces 1005

Feces 1006

Cumulative excretion in urine and feces TMC435-TiDP16-C118

Total recovery , % (mean ± SD)

SMV 50 mg oral + 100 μg iv (Treatment period 1)

SMV 150 mg oral + 100 μg iv

(Treatment period 2) Urine 1.85 ± 0.68 2.22 ± 0.59

Feces 85.68 ± 2.80 84.10 ± 1.91

Urine + feces 87.53 ± 2.48 86.32 ± 2.28

50 mg 150 mg

Metabolite profiling in feces could distinguish between oral and intravenous doses

0

10

20

30

40

50

M11 M16 M27 M21+M22 TMC435

1004 50 mg 150 mg

0

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30

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50

M11 M16 M27 M21+M22 TMC435

1006 50 mg 150 mg

Radiochromatograms for metabolism after iv dose

LC-MS/MS for metabolism after oral dose

0

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60

M11 M16 M18 M27 M21 +M22

TMC435

1004 50 mg Oral 150 mg Oral

0

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M11 M16 M18 M27 M21 +M22

TMC435

1006 50 mg Oral 150 mg Oral

1004, 1006 = patient number

Dos

e (%

) D

ose

(%)

Dos

e (%

) D

ose

(%)

SMV SMV

SMV SMV

Intravenous dose: 100 µg 3H-SMV

Dose 100µg 3H-SMV

Fh =(1-ClB)/Q 0.95

ClB = Cl/(blood/plasma ratio); Q=liver blood flow

Gut metabolism Hepatic metabolism

Biliary excretion

Bioavailability

To feces 3H-SMV in feces 33% of dose via biliary excretion

Oral dose: unlabelled SMV 150mg

F = FaxFgxFh = 0.64

Fh 0.95

Bioavailability

Liver

Absorption

33%x100mg = 33mg

Dose 150mg SMV

Gut wall

Metabolism To feces SMV in feces = 57.7 mg Unabsorbed SMV in feces = 57.5 mg - 33 mg = 24.7 mg Fa = 1 - (24.7 mg / 150 mg) = 0.84

Metabolism

SMV from bile = 33%

Fg=0.8

Portal vein

FgxFa= F/Fh=0.67 100mg

Parameters influencing bioavailability TMC435-TiDP16-C118

Absolute bioavailability

(Fabs)

Fraction absorbed

(Fa)

Fraction escaping

liver extraction

(Fh)

Fraction escaping gut-

wall elimination

(Fg) 50 mg oral +100 μg iv (Treatment period 1) 46.0 ± 2.6 0.75 ± 0.07 0.90 ± 0.03 0.69 ± 0.07

150 mg oral +100 μg iv (Treatment period 2) 62.1 ± 5.6 0.83 ± 0.06 0.92 ± 0.03 0.81 ± 0.03

Effect on saturation of intestinal efflux by P-gp saturation of 3A4 in intestine saturation of uptake in hepatocytes

Conclusions

The absolute bioavailability of orally administered SMV was dose-dependent; 46% at 50 mg and 62% at 150 mg

Intestinal absorption, metabolism, and hepatic uptake were saturable, with a greater fraction absorbed and lower fraction metabolized at the higher dose

Both treatments were generally well tolerated in healthy male volunteers

Acknowledgements TMC435-TiDP16-C118

The authors would like to thank the volunteers

Medical writing support was provided by Martin Goulding on behalf of Complete Medical Communications, funded by Janssen