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

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PI-97
POPULATION PHARMACOKINETIC ANALYSIS OF RUX-
OLITINIB IN SUBJECTS WITH MYELOFIBROSIS. X. Chen, X.
Liu, S. Peng, W. V. Williams, V. Sandor, S. Yeleswaram; Incyte Corp.,
Wilmington, DE. X. Chen: None. X. Liu: None. S. Peng: None.
W.V. Williams: None. V. Sandor: None. S. Yeleswaram: None.
BACKGROUND: A population PK model was developed to characterize
the PK of ruxolitinib, a selective inhibitor of Janus kinase
(JAK) 1 and 2, and a Class 1 compound in the Biopharmaceutical Classification
System (BCS), in development for treatment of myeloproliferative
neoplasms.
METHODS: Data from a Phase 2 and a Phase 3 study were used as
the modeling dataset. Data from a second Phase 3 study was used for
validation. Demographics, disease state, clinical laboratory values and
concomitant medications were explored as predictors of PK variability.
Stepwise regression was used to include and eliminate covariates. The
visual predictive check (VPC) and external data validation was used to
assess the overall predictive performance of the final model.
RESULTS: The modeling dataset included 2187 concentrations
from 272 subjects. The external validation dataset contained 1067 concentrations
from 142 subjects. The PK of ruxolitinib was adequately
described by a 2-compartment disposition model with first-order
absorption and linear elimination. All model parameters were estimated
with good precision (≤ 20.3 %SEM and ≤ 43.7% SEM for fixed
and random effect parameters, respectively). Gender and body weight
were identified as covariates for CL and Vc/F, respectively. Apparent
oral clearance was 22.1 L/h and 17.7 L/h for a typical male and female
subject, respectively, with 39.1% unexplained inter-individual variability
(IIV). The typical V c /F for a subject with a median weight of 72.9
kg was estimated to be 58.6 L, with 28% unexplained IIV. The VPC
showed that 89.9% of the observed data fell within the 5th and 95th
percentiles of the simulated data. The model predictive performance
was validated by the external data.
CONCLUSION: Although gender and body weight were statistically
significant predictors of ruxolitinib PK, the geometric mean ratios
for both parameters fell within interval of .5 to 2 and were therefore not
clinically significant.
PI-98
POPULATION PK/PD ANALYSIS OF SPLEEN VOLUME IN
SUBJECTS WITH MYELOFIBROSIS (MF) ADMINISTERED
WITH RUXOLITINIB. X. Chen, X. Liu, S. Peng, W. V. Williams,
V. Sandor, S. Yeleswaram; Incyte Corp., Wilmington, DE. X. Chen:
None. X. Liu: None. S. Peng: None. W.V. Williams: None. V. Sandor:
None. S. Yeleswaram: None.
BACKGROUND: A population PK/PD model was developed to
characterize the time course of spleen volume in MF patients treated
with ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2.
METHODS: Data from a Phase 2 and a Phase 3 study were used
as the modeling dataset. Data from a second Phase 3 study was used
for validation. Population PK/PD analysis was conducted sequentially.
The average daily steady-state plasma concentrations (Cave) derived
from the population PK model were used as an exposure measure.
An indirect response (IDR) model was used to characterize the time
course of spleen volume. An inhibitory E max function was applied to
the formation rate constant for response. Covariates evaluated included
age, gender, weight, race, JAK2V617F mutation, MDRD GFR, total
bilirubin, MF duration etc.
RESULTS: The modeling dataset included 919 spleen volume
measurements from 253 subjects. The external validation dataset
contained 592 spleen volume measurements from 128 subjects. The
structural PK/PD model was parameterized in terms of k in and k out
describing the increase and decrease in spleen volume, respectively.
An E plc of 0.0505 describes the small increment in spleen volume over
time in the absence of drug. Gender and JAK2V617F mutation status
were significant predictors of the IC 50 for spleen volume reduction.
The typical I max was a decrease of 0.765 the typical IC 50 was estimated
at 414 nM and 206 nM for males who are negative and positive for
the JAK2V617F mutation, respectively, and 244 nM and 122 nM for
females who are negative and positive for the JAK2V617F mutation,
respectively. The typical Cave for 15 mg BID was 202 nM. Visual predictive
check and external validation showed that the exposure-spleen
volume relationship was adequately described by the model.
CONCLUSION: Gender and JAK2V617F mutation status were
statistically significant predictors of the IC 50 for spleen volume reduction
by ruxolitinib in MF patients.
PI-99
POPULATION PK/PD ANALYSIS OF TOTAL SYMPTOM
SCORE (MFSAF) IN SUBJECTS WITH MYELOFIBROSIS (MF)
TREATED WITH RUXOLITINIB. X. Chen, X. Liu, S. Peng, W. V.
Williams, V. Sandor, S. Yeleswaram; Incyte Corp., Wilmington, DE.
X. Chen: None. X. Liu: None. S. Peng: None. W.V. Williams: None.
V. Sandor: None. S. Yeleswaram: None.
BACKGROUND: A population PK/PD model was developed to
characterize the time course of MFSAF in MF patients treated with
ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2.
METHODS: Data from a Phase 3 study was used as the modeling
dataset; no external validation dataset was available. The MFSAF was
collected daily from 7 days prior to the first dose through week 24 and
included symptoms of night sweats, itching, abdominal discomfort,
pain under ribs on left, feeling of fullness (early satiety), and muscle/
bone pain. Population PK/PD analysis was conducted sequentially.
The average daily steady-state plasma concentrations derived from
the population PK model was selected as an exposure measure. The
MFSAF was modeled with a modified indirect response (IDR) model,
in which a logit transformation was implemented to constrain model
predictions between scores of 0 and 60; the drug effect was characterized
via an inhibitory E max function applied to the first-order equilibration
rate constant (k out ).
RESULTS: The dataset contained 1,566 data points from 242
subjects. The mean population estimate of I max was 58 and the IC 50
was 233 nM, indicating a substantial reduction in MFSAF at average
ruxolitinib plasma concentrations achieved with ≥10 mg BID dosing
regimens. A placebo effect on the production of response was included
in the model by incorporating an E plc fixed effect term describing a
proportional shift in k out . Baseline MFSAF and blood transfusion
status were each statistically significant predictors of E plc . No statistically
significant covariates were identified for MFSAF change induced
by ruxolitinib. The visual predictive check showed that MFSAF was
described adequately by the model.
CONCLUSION: The time course of MFSAF could be adequately
described by a modified IDR model and no subpopulations with altered
MFSAF in the presence of ruxolitinib were identified.
PI-100
TOLVAPTAN PHARMACOKINETICS (PK) AND PHARMACO-
DYNAMICS (PD) IN HEALTHY CAUCASIAN AND JAPANESE
MEN FOLLOWING 30 MG IN EITHER THE FASTED STATE
OR FOLLOWING A HIGH FAT MEAL OR JAPANESE STAND-
ARD MEAL. S. E. Shoaf, 1 S. Kim, 2 P. Bricmont, 1 S. Mallikaarjun 1 ;
1 Otsuka Pharmaceutical Development & Commercialization, Inc,
Rockville, MD, 2 Otsuka Pharmaceutical Co., Ltd., Osaka, Japan.
S.E. Shoaf: 2. I am a paid consultant/employee for; Company/Drug;
OPDC. S. Kim: 2. I am a paid consultant/employee for; Company/
Drug; OPC-J. P. Bricmont: 2. I am a paid consultant/employee for;
Company/Drug; OPDC. S. Mallikaarjun: 2. I am a paid consultant/
employee for; Company/Drug; OPDC.
BACKGROUND: Tolvaptan (TLV) is a selective vasopressin receptor
(V 2 ) antagonist approved in the US and Europe for hyponatremia
and in Japan for volume overload in heart failure when adequate
response is not obtained with other diuretics. A combined race and
comparative food effect trial was conducted for bridging purposes.
s44 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt