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

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PI-75
A PHARMACOKINETIC STUDY OF ORAL PACLITAXEL IN
COMBINATION WITH HM30181 IN SOLID CANCER PATIENTS.
S. E. Kim, N. Gu, D. Shin, S. H. Yoon, J. Y. Cho, S. G. Shin,
K. S. Yu, I. J. Jang; Department of Clinical Pharmacology and Therapeutics,
Seoul National University College of Medicine and Hospital,
Seoul, Republic of Korea. S.E. Kim: 1. This research was sponsored
by; Company/Drug; Hanmi Pharmaceutical Co., Ltd. (Seoul, Korea).
None of the authors have any conflict of interest. N. Gu: 1. This
research was sponsored by; Company/Drug; Hanmi Pharmaceutical
Co., Ltd. (Seoul, Korea). None of the authors have any conflict of
interest. D. Shin: 1. This research was sponsored by; Company/Drug;
Hanmi Pharmaceutical Co., Ltd. (Seoul, Korea). None of the authors
have any conflict of interest. S.H. Yoon: 1. This research was sponsored
by; Company/Drug; Hanmi Pharmaceutical Co., Ltd. (Seoul,
Korea). None of the authors have any conflict of interest. J.Y. Cho:
1. This research was sponsored by; Company/Drug; Hanmi Pharmaceutical
Co., Ltd. (Seoul, Korea). None of the authors have any conflict
of interest. S.G. Shin: 1. This research was sponsored by; Company/
Drug; Hanmi Pharmaceutical Co., Ltd. (Seoul, Korea). None of the
authors have any conflict of interest. K.S. Yu: 1. This research was
sponsored by; Company/Drug; Hanmi Pharmaceutical Co., Ltd.
(Seoul, Korea). None of the authors have any conflict of interest.
I.J. Jang: 1. This research was sponsored by; Company/Drug; Hanmi
Pharmaceutical Co., Ltd. (Seoul, Korea). None of the authors have any
conflict of interest.
BACKGROUND: As a selective inhibitor of multi-drug resistance
1, HM30181 have a potential to provide an increase in oral bioavailability
of paclitaxel, a chemotherapeutic agent. The aim of this study was
to explore the pharmacokinetics (PKs) of paclitaxel after oral administrations
of capsule formulations in combination with HM30181AK
tablet in patients with solid cancer.
METHODS: Paclitaxel of 180 mg/m 2 and 240 mg/m 2 was administered
in combination with a HM30181AK 15 mg tablet on day
1 and was administered alone on day 2. Paclitaxel of 300 mg/m 2
was co-administered with a HM30181AK 15 mg tablet on day 1 and
day 2. Blood and urine samples for PK analysis were collected up to
48 hours after the first dose on day 1 in 3 patients per 3 dose groups.
Paclitaxel concentrations were determined by liquid chromatographytandem
mass spectrometry and PK parameters were estimated by noncompartmental
analysis.
RESULTS: The mean (standard deviation) AUC last of paclitaxel on
day 1 was 462.8 (343.9), 993.7 (76.9), and 846.3 (283.1) μg*hr/L and
that on day 2 was 527.2 (431.1), 456.3 (120.4), and 1157.1 (409.7)
μg*hr/L following administration of paclitaxel (180, 240, and 300 mg/
m 2 , respectively); the mean (minimum-maximum) time of paclitaxel
concentrations above 0.01 μM were 17.7 (1.3 - 32.8), 43.2 (33.8 -
48.1), and 47.5 (47.0 - 47.7) hours, respectively. The fraction excreted
unchanged in urine was 1.13, 2.30, and 1.90% on day 1 and that was
1.36, 1.22, and 2.07% on day 2 after administration of 180, 240, and
300 mg/m 2 paclitaxel, respectively.
CONCLUSION: The systemic exposures of paclitaxel were not
proportional to increases in the dose. Among three paclitaxel dose
groups, 300 mg/m 2 group represented the highest sum of AUC last on
day 1 and day 2 and its mean time of paclitaxel concentrations above
0.01 μM was 47.5 hours.
PI-76
DIFFERENCES IN ACUTE PAIN, HYPERALGESIA, ALLODY-
NIA AND NEUROGENIC FLARE IN RESPONSE TO TOPICAL
AND INTRADERMAL CAPSAICIN. K. Francke, 1 E. Neuhoff, 1
W. Heber, 2 J. Lambert, 1 M. Grossmann 3 ; 1 PAREXEL, London, United
Kingdom, 2 PAREXEL, Baltimore, MD, 3 PAREXEL, Berlin, Germany.
K. Francke: None. E. Neuhoff: None. W. Heber: None. J. Lambert:
None. M. Grossmann: None.
BACKGROUND: Experimental human pain models are widely used
to explore nociceptive mechanisms and to study the efficacy of novel
analgesic drugs. We previously used topical capsaicin cream to induce
pain, neuronal sensitization and neurogenic flare. However, the sensitivity
of the method was limited mainly due to inconsistent dermal absorption.
This study investigated the test-retest correlation and inter subject
variability of sensitization after intradermal capsaicin injection.
METHODS: In a 2-way crossover design, 28 healthy male volunteers
received intradermal injections of 90 μg Capsaicin (GMP grade;
30 μl, 0.3% solution in 7.5% Tween 80) to the volar forearm. The acute
pain, mechanical allodynia, pinprick hyperalgesia and neurogenic flare
reaction were assessed at several timepoints up to 60 min post injection.
The experiment was repeated 5 days later in exactly the same fashion.
RESULTS: Subjects perceived pain and developed neuronal sensitization
and neurogenic flare following capsaicin injection. Mean
values at 15 min post and correlation coefficients of test/retest were:
pain (NRS 11) 4.6±0.3, r= 0.81; mechanical allodynia 13.1±2.3 cm^2,
r= 0.82; pinprick hyperalgesia 18.1±2.4 cm^2, r= 0.73; flare 37.8±3.3
cm^2, r= 0.63.
CONCLUSION: Intradermal capsaicin injection is a suitable pain
model that can be utilized in early clinical drug development. The sensory
endpoints acute pain, allodynia and hyperalgesia showed acceptable
test-retest repeatability, but less correlation for neurogenic flare.
In general there was a trend towards lower responses in the second test
session. Intersubject comparisons showed considerable differences
in the extent of the induced sensory components, with some subjects
developing only small areas of hyperalgesia. This makes distinction
between primary and secondary sensitization difficult and limits the
dynamic range of the endpoint. Pre-screening is therefore recommended
to identify sensitive responders.
PI-77
PROPOFOL PHARMACOKINETICS IN CHILDREN IN EGYP-
TIEN POPULATION. A. A. Guemei, 1 R. S. Saleh, 2 A. M. El-Attar, 3
O. T. Fahmy 4 ; 1 Faculty of Medicine at King Fahad Medical City,
Riyadh, Saudi Arabia, 2 Faculty of Medicine, Alexandria University,
Alexandria, Egypt, 3 Faculty of Medicine, Alexandria University,
Alexandria, Egypt, 4 Faculty of Pharmacy, Alexandria University, Alexandria,
Egypt. A.A. Guemei: None. R.S. Saleh: None. A.M. El-Attar:
None. O.T. Fahmy: None.
BACKGROUND: Propofol has gained popularity as an agent for
both induction and maintenance of anesthesia for adults and children.
This is primarily because of its rapid onset, short duration of action and
minimal side effects. Pharmacokinetics of children is different from
adults. There had been a lack of pharmacokinetic studies in Egyptian
children less than 3 years of age.
METHODS: Forty eight pediatric patients (2-24 months) were randomly
assigned into 4 groups, each group had 12 patients. They were
scheduled to undergo superficial body surgery of 1 hour expected duration.
Venous blood samples were collected and analyzed using high
performance liquid chromatography (HPLC). Non linear mixed effects
modeling (NONMEN) software program was used to analyze the pharmacokinetic
data.
RESULTS: The pharmacokinetic of propofol in pediatric patients
followed a two compartment model with systemic clearance (Cl) 29.77
± 9.46 ml kg -1 min -1 , central volume of distribution (Vc) 0.62 ±0.24
kg -1 , and volume at steady state (Vss) 1.67 ± 0.26 kg -1 . The half life
(HL) was 0.24 ± 0.02h.
CONCLUSION: It was found that the children of this age have a larger
volume of distribution and a higher clearance of propofol than adults.
Therefore, the induction and maintenance doses should be increased in this
young age group using population based pharmacokinetic parameters.
PI-78
POPULATION MODELING OF THE PHARMACOKINETICS
AND PHARMACODYNAMICS OF PONESIMOD, A SELECTIVE
S1P1 RECEPTOR AGONIST. A. Krause, P. Brossard, D. D’Ambrosio,
J. Dingemanse; Actelion Pharmaceuticals, Allschwil, Switzerland.
A. Krause: 1. This research was sponsored by; Company/Drug;
Actelion Pharmaceuticals Ltd. 2. I am a paid consultant/employee
s36 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt