A novel microdose approach to assess bioavailability...
Transcript of A novel microdose approach to assess bioavailability...
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
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Dos
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Time (h)
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Dos
e (%
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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
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M11 M16 M27 M21+M22 TMC435
1004 50 mg 150 mg
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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
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M11 M16 M18 M27 M21 +M22
TMC435
1004 50 mg Oral 150 mg Oral
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M11 M16 M18 M27 M21 +M22
TMC435
1006 50 mg Oral 150 mg Oral
1004, 1006 = patient number
Dos
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Dos
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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