Poster Session I (PI 1-106)Displayed 8:00 am – 3:00 ... - Nature

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is not labeled for the use under discussion, or the product is still investigational;
Company/ Drug; Tofacitinib (CP-690,550). C.W. Alvey:
1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am
a paid consultant/employee for; Company/Drug; Pfizer Inc. 5. I am a
significant stockholder for; Company/Drug; Pfizer Inc as part of my
employee 401 (K) benefit. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product
is still investigational; Company/Drug; Tofacitinib (CP-690,550).
W. Petit: 1. This research was sponsored by; Company/Drug; Pfizer
Inc. 2. I am a paid consultant/employee for; Company/Drug; Pfizer
Inc. 5. I am a significant stockholder for; Company/Drug; Pfizer Inc,
not significant. 6. I will be discussing the following product, which is
not labeled for the use under discussion, or the product is still investigational;
Company/Drug; Tofacitinib (CP-690,550). S. Krishnaswami:
1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am
a paid consultant/employee for; Company/Drug; Pfizer Inc. 5. I am
a significant stockholder for; Company/Drug; Pfizer Inc. 6. I will be
discussing the following product, which is not labeled for the use under
discussion, or the product is still investigational; Company/Drug;
Tofacitinib (CP-690,550).
BACKGROUND: Tofacitinib (CP-690,550) is an oral Janus Kinase
(JAK) inhibitor currently in development for the treatment of several
inflammatory diseases including rheumatoid arthritis and psoriasis.
The objective of this study was to demonstrate a lack of an inhibitive or
inductive effect of tofacitinib on the pharmacokinetics (PK) of the oral
contraceptives (OCs), ethinyl estradiol (EE) and levonorgestrel (LN).
METHODS: This was a randomized, open-label, 2-sequence,
2-period crossover study (A3921071; NCT01137708) of the effect of
30 mg twice-daily (BID) tofacitinib for 11 days on the single-dose PK
of OCs (administered as a single Microgynon 30 ® tablet) in 19 healthy
female subjects. Blood samples for EE and for LN PK were collected
prior to and up to 48 hours post-dose. PK parameters were calculated
using noncompartmental analysis. Treatment comparisons were made
using analysis of variance to calculate adjusted geometric mean ratios
for test/reference and associated 90% confidence intervals for the mean
ratios. The test and reference treatments were OC treatments with and
without coadministration of tofacitinib, respectively.
RESULTS: The 90% CIs for the ratios of the adjusted geometric
means (Test/Reference) for AUC inf and C max were entirely within the
predefined acceptance region (80.00%, 125.00%) for both EE and LN
when single oral doses of the combination OCs were administered with
multiple-dose tofacitinib relative to the OCs administered alone, indicating
that tofacitinib had no net inhibitive or inductive effect on the
PK of EE and LN. For both agents, t 1/2 and T max values were similar
with and without coadministration of tofacitinib.
CONCLUSION: Tofacitinib does not influence the PK of oral contraceptives,
ethinyl estradiol and levonorgestrel.
PI-72
EFFECTS OF QUINIDINE ON PHARMACOKINETICS (PK)
OF ORAL (PO) AND INTRAVENOUSLY (IV) ADMINISTERED
EDOXABAN. N. Matsushima, 1 J. Mendell, 1 H. Zahir, 1 F. Lee, 2
T. Sato, 1 J. Jin, 1 D. Weiss 2 ; 1 Daiichi Sankyo, Co, Ltd, Parsippany, NJ,
2 Celerion, Inc, Neptune, NJ. N. Matsushima: 1. This research was
sponsored by; Company/Drug; Daiichi Sankyo, Inc. 2. I am a paid
consultant/employee for; Company/Drug; Daiichi Sankyo Co., Ltd.
6. I will be discussing the following product, which is not labeled for
the use under discussion, or the product is still investigational; Company/Drug;
Edoxaban [still investigational]. J. Mendell: 1. This
research was sponsored by; Company/Drug; Daiichi Sankyo, Inc. 2.
I am a paid consultant/employee for; Company/Drug; Daiichi Sankyo
Co., Ltd. 6. I will be discussing the following product, which is not
labeled for the use under discussion, or the product is still investigational;
Company/Drug; Edoxaban [still investigational]. H. Zahir:
1. This research was sponsored by; Company/Drug; Daiichi Sankyo,
Inc. 2. I am a paid consultant/employee for; Company/Drug; Daiichi
Sankyo Co., Ltd. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product is still
investigational; Company/Drug; Edoxaban [still investigational].
F. Lee: 1. This research was sponsored by; Company/Drug; Daiichi
Sankyo, Inc. 2. I am a paid consultant/employee for; Company/Drug;
Celerion, Inc. 6. I will be discussing the following product, which is
not labeled for the use under discussion, or the product is still investigational;
Company/Drug; Edoxaban [still investigational]. T. Sato:
1. This research was sponsored by; Company/Drug; Daiichi Sankyo,
Inc. 2. I am a paid consultant/employee for; Company/Drug; Daiichi
Sankyo Co., Ltd. 6. I will be discussing the following product, which
is not labeled for the use under discussion, or the product is still investigational;
Company/Drug; Edoxaban [still investigational]. J. Jin:
1. This research was sponsored by; Company/Drug; Daiichi Sankyo,
Inc. 2. I am a paid consultant/employee for; Company/Drug; Daiichi
Sankyo Co., Ltd. 5. I am a significant stockholder for; Company/
Drug; Daiichi Sankyo, Inc. 6. I will be discussing the following product,
which is not labeled for the use under discussion, or the product is
still investigational; Company/Drug; Edoxaban [still investigational].
D. Weiss: 1. This research was sponsored by; Company/Drug; Daiichi
Sankyo, Inc. 2. I am a paid consultant/employee for; Company/Drug;
Celerion, Inc. 6. I will be discussing the following product, which is
not labeled for the use under discussion, or the product is still investigational;
Company/Drug; Edoxaban [still investigational].
BACKGROUND: Edoxaban is a selective, oral direct factor Xa
inhibitor currently in phase 3 clinical development for stroke prevention
in atrial fibrillation and the treatment and secondary prevention of
venous thromboembolism. Edoxaban is a substrate of P-glycoprotein
(P-gp), therefore, the effect of quinidine, a potent P-gp inhibitor, on
the absorption and elimination of edoxaban was evaluated in 2 clinical
studies in healthy subjects.
METHODS: The effects of oral quinidine (300 mg, tid) on the
PK of edoxaban were assessed in 2 randomized, open label, crossover
studies: a) Study 1 edoxaban PO 60 mg (n = 42) and b) Study 2
edoxaban IV 30 mg infused over 30 min (n = 36). Blood samples for
PK assessment were collected up to 24 hours and 72 hours post-dose
in the PO and IV dose studies, respectively. The plasma concentrations
of edoxaban and its metabolite, M4, were determined by validated
LC-MS/MS methods. Edoxaban PK was compared by treatments;
edoxaban coadministered with quinidine vs edoxaban alone using a
mixed-effect model.
RESULTS: Based on the geometric LSM ratio values, co-administration
of quinidine increased the total exposure (AUC) of edoxaban by
77% and 35% following PO and IV administration, respectively.
CONCLUSION: Quinidine increases total exposure of PO or IV
edoxaban. These results suggest that P-gp inhibition influences both
the absorption and elimination of edoxaban.
Parameter a
AUC last ,
ng·hr/mL
Geometric
LSM ratio
(90% CI), %
Study 1 (oral edoxaban) Study 2 (IV edoxaban)
Edoxaban
60 mg PO
(n=35)
Edoxaban 60 mg
PO + Quinidine
(n=33)
Edoxaban
30 mg IV
(n=35)
Edoxaban 30 mg
IV + Quinidine
(n=28)
1443 ± 329.7 2484 ± 402.4 1305 ± 189.6 1758 ± 318.1
- 177 (165-189) - 135 (128-143)
C max , ng/mL 223 ± 74.9 390 ± 93.4 424 ± 114.8 456 ± 132.5
Geometric
LSM ratio
(90% CI), %
- 185 (165-208) - 107 (96-120)
T max , h b 1.5 (0.5, 6.0) 1.5 (0.5, 2.5) 0.5 (0.3, 2.0) 0.5 (0.5, 1.0)
t 1/2 , h 6.4 ± 1.59 5.0 ± 0.62 6.7 ± 2.54 11.3 ± 7.82
a Parameters arithmetic mean (± SD) unless indicated; b Median (min, max)
s34 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt