The Toxicologist - Society of Toxicology

lood cell mass and decrease in urine volume in animals given 30% Solutol/70%
PEG 400 at a dose volume of 5 mL/kg/day was likely due to dehydration and hemoconcetration
associated with the loose/watery feces. Neither 10% Solutol/90%
PEG 400 or 30% Solutol/70% PEG 400 at either dose volume produced overt toxicity
after 28 days of dosing, however using the lower dose volume of 2 mL/kg/day
minimized the incidence of loose/watery feces and potential dehydration.
782 TOXICITY OF MDL72, 527 ADMINISTERED ORALLY
TO RATS AND DOGS.
S. D. Grimes 1 , R. W. Watkins 1 , J.F.Mann 1 , H. S. Basu 2 , I. M. Kapetanovic 3
and C. D. Hebert 1 . 1 Southern Research Institute, Birmingham, AL, 2 Colby
Pharmaceutical Company, Menlo Park, CA and 3 National Cancer Institute,
Bethesda, MD.
MDL72,527 is a polyamine oxidase inhibitor that is being developed as a potential
chemotherapeutic agent for prostate cancer. The toxicity of MDL72,527 was evaluated
in Sprague Dawley rats and beagle dogs. Rats were given MDL72,527 via
gavage at doses of 0, 25, 75, 250, or 1000 mg/kg/day daily for up to 14 days or at
doses of 0, 25, 50, 100, or 200 mg/kg/day MDL72,527 once every 14 days for 71
days. Initially, dogs were to be given daily doses of MDL72,527 via capsules at
doses of 0, 50, 200, or 1000 mg/kg/day for 14 consecutive days. However, because
of intolerance to MDL72,527 at higher doses, dogs in the 200 and 1000
mg/kg/day dose groups were dosed for only 7 and 5 days, respectively. Dogs in the
50 mg/kg/day dose group received this dose on Days 1-7, with an increase to 100
mg/kg/day on Days 8-14. Adverse effects associated with giving MDL72,527 daily
to rats and dogs included unscheduled mortality, clinical signs of toxicity, decreases
in body weight and food consumption, clinical pathology abnormalities, and extensive
microscopic lesions. Excluding a thin carcass in one dog, no test article-related
gross lesions were observed in rats and dogs given MDL72,527. Microscopic
lesions in dogs and rats receiving MDL72,527 daily were multisystemic, consisting
of cytoplasmic vacuolization of numerous tissues, particularly the vasculature.
Animals given MDL72,527 once every 14 days had minimal test article-related
clinical signs, clinical pathology abnormalities, and microscopic lesions (apoptosis).
Extreme toxicity was associated with daily oral administration of MDL72,527.
Administration of the drug every 14 days for 71 days appeared to mitigate adverse
effects of the drug at doses where the drug is active in preventing cancer progression
in a mouse spontaneous prostate cancer model. A no-observed-adverse effect level
was not established for rats or dogs on the dosing schedules used in these studies.
Funded with federal funds from National Cancer Institute Contract
HHSN26120043307C
783 SAFETY ASSESSMENT OF PHOSPHO-IBUPROFEN AS A
POTENTIAL CANCER CHEMOPREVENTIVE AGENT.
R. W. Watkins 1 , J. F. Mann 1 , S. D. Grimes 1 , R. Fulton 2 , C. V. Rao 3 , I. M.
Kapetanovic 4 and C. D. Hebert 1 . 1 Southern Research Institute, Birmingham, AL,
2 FVClinPath Consulting, Birmingham, AL, 3 University of Oklahoma Health Sciences
Center, Oklahoma City, OK and 4 National Cancer Institute, Bethesda, MD.
Phospho-ibuprofen (pIB) is being evaluated for use as a cancer chemopreventive
agent, and is believed to have lower toxicity and greater chemopreventive potency
than ibuprofen itself. To assess the toxicity and pharmacokinetic behavior of pIB in
rats, two studies were performed in which Sprague Dawley rats received daily oral
gavage doses of pIB at 0, 25, 50, 150, or 450 mg/kg/day for 14 days or 0, 20, 100,
or 500 mg/kg/day for 28 days. One rat died in the high dose group of each study.
Administration of 150 or 450 mg/kg/day produced minimal clinical signs and minimal
changes in neutrophil, globulin, and albumin values. In the 14-day study, a
no-observed-adverse-effect level (NOAEL) dose was not identified. pIB metabolites
in plasma included R- and S-ibuprofen, hydroxyphospho-ibuprofen, 1- and 2-hydroxyibuprofen,
and ibuprofen glucuronide. In the 28-day study, there were no
clinical signs of toxicity attributed to pIB administration. Rats in the two highest
dose groups had minimal (≤10%) deficits in body weight gain and food consumption
compared to controls. Clinical pathology alterations in leukocytes (high leukocytes,
neutrophils, and monocytes), serum protein (low total protein, albumin, and
albumin/globulin) and/or high fibrinogen values observed for rats in the two highest
dose groups were consistent with inflammatory and necrotic effects observed in
various tissues of animals in this study, as well as with the known toxic effects of
ibuprofen. Microscopic lesions consistent with ibuprofen toxicity were observed in
the glandular stomach, forestomach, large intestine, kidney, and liver of pIB-treated
rats. Based on microscopic changes observed in the gastrointestinal tract and kidney
at the 20 mg/kg/day dose level, a NOAEL dose was not identified for rats dosed
with pIB daily for 28 days.
Funded wholly with federal funds from National Cancer Institute Contract
HHSN26120043307C
784 EARLY SAFETY ASSESSMENT CONSIDERATIONS AND
STRATEGIES IN DRUG DISCOVERY.
S. Mohr 1 , A. J. Olaharski 2 , F. Crameri 1 , T. Singer 1 and T. Weiser 1 . 1 Nonclinical
Safety, F. Hoffmann-La Roche, Basel, Switzerland and 2 Nonclinical Safety, F.
Hoffmann-La Roche, Nutley, NJ.
The likelihood that a new chemical entity progresses through the pre-clinical stages
to market is very low. While there are many factors that contribute to the failure of
developing novel pharmaceuticals, one of the largest has historically been due to
safety. Because drug failures are tremendously expensive, both in terms of time and
money, a number of strategies have been developed to reduce attrition.
Traditionally, non clinical safety representation within Roche began once a clinical
lead had been selected and safety studies to support entry into human were
planned. This process resulted in a large number of unexpected toxicities observed
during the first repeat dose safety studies and a high attrition rate. Approximately 5
years ago, an early safety representative (ESR) group was formed to provide active
safety support to project teams during all the early drug discovery phases (from target
assessment to clinical lead selection). One area of focus has been in the form of
a thorough early safety target assessment which provides a non-clinical safety
(NCS) functional opinion on the potential safety liabilities, strategies to adress
these liabilities and an assessment of whether the putative target should be pursued.
Additionally, a number of in silico, in vitro and in vivo mechanistic/ranking approaches
are specifically applied to better select drug candidates. This philosophy is
conceptually very simple; reduce compound attrition through proactive and collaborative
safety representation at earlier phases of drug discovery, identifying potential
target-related safety liabilities during target assessment and the generation of more
predictive safety data during the lead optimization phase prior to clinical lead selection.
Specific examples of how this approach has been applied within Roche will be
provided. Using this approach, Roche was able to markedly reduce the safety-related
attrition of the selected clinical leads .
785 ASSESSMENT OF HEMATOLOGICAL TOXICITY
ASSOCIATED WITH COMBINING CLASSICAL
CHEMOTHERAPEUTIC AND TARGETED CANCER
DRUGS.
S. Khoh-Reiter, D. Lee and B. Jessen. Pfizer Inc., San Diego, CA.
In the past standard treatment for cancer was chemotherapy. While effective in
combating cancer, there are often undesirable side-effects with hematological adverse
effects being the most common. In an attempt to decrease the toxicity profile
of the treatments, rationally designed drugs or targeted therapies are being developed,
such as kinase inhibitors. Another approach undertaken by oncologists is
combining more than one drug to treat the cancers, aptly called combination therapy.
The purpose of this study is to propose a predictive method for determining
the adverse effects of combining classical chemotherapy and a targeted therapy on
bone marrow cells. The ability to know whether the effects of combining drugs will
produce a synergistic, additive or similar toxicity profile as the monotherapies will
provide invaluable data for patient treatment plans. Five compounds, three of
which are kinase inhibitors, Sorafenib, Imatinib and a CHK-1 compound; a taxane,
Paclitaxel; and a classical nucleoside analog, Gemcitabine were tested using differentiated
in vitro human bone marrow mononuclear cells, which can give rise to
various hematopoietic lineages. Dose-dependent decrease in cell viability in the
progenitor population was determined using cellular ATP as the biomarker. A synergistic
response was obtained through the combination of Gemcitabine and the
CHK-1 compound. In the Sorafenib-Paclitaxel combination, an additive decrease
in the cell viability was observed compared to the treatments of the single therapies
alone. To a much lesser extend, Gemcitabine combined with Sorafenib or Imatinib
did not produce an additive response. In summary, these results demonstrate the
feasibility of using human bone marrow mononuclear cells to test different combination
therapies for oncology and can subsequently be used as a research tool for
predicting neutropenia for various single or combination therapies for either developing
compounds or established therapies.
786 HUMAN NON-RELEVANCE OF MOTILIN AGONIST
INDUCED ANAPHYLACTOID REACTIONS IN
BEAGLE DOGS.
P. Chowdhury and C. Powell. Safety Assessment, GlaxoSmithKline, Ware, United
Kingdom.
Background: Toxicities in animals must be assessed for human relevance.
GSK962040 & GSK1322888 (MW 461 & 434, respectively) are motilin receptor
agonists, in development as gastric prokinetics. Methods: Single oral doses of
GSK962040 were given to beagle dogs or Göttingen minipigs. Daily oral doses of
SOT 2011 ANNUAL MEETING 169