Page 181 - 2014 Printable Abstract Book
P. 181
transfusions or growth factors. rHuIL-12 also reduced the incidence of severe neutropenia, severe
thrombocytopenia, systemic infection and internal organ hemorrhage. To further investigate the
TM
mechanism of action of HemaMax , we evaluated three different bone marrow samples (femur, sternum
and rib) from control and HemaMax (250ng/kg) treated animals (5 animals / group) that succumbed to
radiation at Days 14 and 15, timepoints associated with the highest mortality and hematological nadirs.
TM
Morphometric analysis of area of regeneration of bone marrow from femurs showed that HemaMax
significantly increased total area of regeneration in comparison to the vehicle-treated control.
TM
HemaMax -treated animals also displayed significantly higher bone marrow cellularity in the sternum
TM
and rib compared to vehicle-control group. In addition, all three bones of HemaMax -treated NHPs
showed higher numbers of megakaryocytes, indicating a role in facilitating platelet regeneration.
Histological analysis of Tartrate-resistant acid phosphatase (TRAP), an osteoclast marker showed
significantly higher number of TRAP expressing osteoclasts in vehicle-control group compared to
TM
TM
HemaMax -treated group (250ng/kg) for all bones assessed, indicating a potential role for HemaMax
in alleviating bone loss or osteoporosis resulting from radiation injury. The safety and tolerability of
TM
HemaMax (s.c.) in 92 human healthy volunteers was established at unit dose levels up to 12μg
TM
(~170ng/kg for a 70 kg adult), indicating that HemaMax is safe in the dose range efficacious for
TM
mitigation of HSARS in humans. To summarize, a single dose of HemaMax (250 ng/kg) administered 24
hours post TBI increases bone marrow hematopoietic recovery and potentially inhibits increase in
osteoclasts post radiation.
(PS2-78) Preclinical development of the radionuclide decorporation agent 3, 4, 3-LI (1, 2-HOPO): Oral
1
1
availability enhancement and dosing regimen optimization. Rebecca J. Abergel ; Taylor A. Choi ; Dahlia
2
2
1
1
D. An ; Deborah I. Bunin ; and Polly Y. Chang, Lawrence Berkeley National Laboratory, Berkeley, CA
2
and SRI International, Menlo Park, CA
The threat of a major radiological contamination presents a danger of not only large-scale external
radiation exposure of the population but also internal contamination with radionuclides. While major
components of such contamination are likely to be actinides and lanthanide fission products, current
therapies for the treatment of f-element incorporation are still limited. Over the past three decades, the
Lawrence Berkeley National Laboratory has dedicated a research program to the discovery of oral
therapeutics for actinide decorporation, leading to the emergence of the active pharmaceutical ingredient
(API) 3,4,3-LI(1,2-HOPO) as an exceptional candidate for actinide sequestration. This synthetic
hydroxypyridinonate chelator is currently undergoing preclinical development for the treatment of
individuals with known or suspected internal contamination with actinides such as plutonium (Pu),
americium (Am), curium (Cm), uranium (U) or neptunium (Np) to increase the rates of elimination of these
radionuclides. In order to seek regulatory approval for this new agent, a number of efficacy and safety
studies must respond to the selective criteria of the Animal Efficacy Rule from the U.S. Food and Drug
Administration (FDA). Recent studies that have been performed with orally-formulated 3, 4, 3-LI (1, 2-
HOPO) for consideration by the FDA as an Investigational New Drug will be presented.
A formulation development program testing more than 75 excipients in vitro led to the selection of API-
containing formulation prototypes with enhanced oral bioavailability properties. The biodistribution of
the API and formulation prototypes were characterized in Swiss-Webster mice and Sprague-Dawley rats
using C-14 as a radiotracer. A final oral formulation was then established and used for Pu and Am
decorporation efficacy studies as well as safety/pharmacology studies in mice, rats and Beagle dogs,
179 | P a g e
thrombocytopenia, systemic infection and internal organ hemorrhage. To further investigate the
TM
mechanism of action of HemaMax , we evaluated three different bone marrow samples (femur, sternum
and rib) from control and HemaMax (250ng/kg) treated animals (5 animals / group) that succumbed to
radiation at Days 14 and 15, timepoints associated with the highest mortality and hematological nadirs.
TM
Morphometric analysis of area of regeneration of bone marrow from femurs showed that HemaMax
significantly increased total area of regeneration in comparison to the vehicle-treated control.
TM
HemaMax -treated animals also displayed significantly higher bone marrow cellularity in the sternum
TM
and rib compared to vehicle-control group. In addition, all three bones of HemaMax -treated NHPs
showed higher numbers of megakaryocytes, indicating a role in facilitating platelet regeneration.
Histological analysis of Tartrate-resistant acid phosphatase (TRAP), an osteoclast marker showed
significantly higher number of TRAP expressing osteoclasts in vehicle-control group compared to
TM
TM
HemaMax -treated group (250ng/kg) for all bones assessed, indicating a potential role for HemaMax
in alleviating bone loss or osteoporosis resulting from radiation injury. The safety and tolerability of
TM
HemaMax (s.c.) in 92 human healthy volunteers was established at unit dose levels up to 12μg
TM
(~170ng/kg for a 70 kg adult), indicating that HemaMax is safe in the dose range efficacious for
TM
mitigation of HSARS in humans. To summarize, a single dose of HemaMax (250 ng/kg) administered 24
hours post TBI increases bone marrow hematopoietic recovery and potentially inhibits increase in
osteoclasts post radiation.
(PS2-78) Preclinical development of the radionuclide decorporation agent 3, 4, 3-LI (1, 2-HOPO): Oral
1
1
availability enhancement and dosing regimen optimization. Rebecca J. Abergel ; Taylor A. Choi ; Dahlia
2
2
1
1
D. An ; Deborah I. Bunin ; and Polly Y. Chang, Lawrence Berkeley National Laboratory, Berkeley, CA
2
and SRI International, Menlo Park, CA
The threat of a major radiological contamination presents a danger of not only large-scale external
radiation exposure of the population but also internal contamination with radionuclides. While major
components of such contamination are likely to be actinides and lanthanide fission products, current
therapies for the treatment of f-element incorporation are still limited. Over the past three decades, the
Lawrence Berkeley National Laboratory has dedicated a research program to the discovery of oral
therapeutics for actinide decorporation, leading to the emergence of the active pharmaceutical ingredient
(API) 3,4,3-LI(1,2-HOPO) as an exceptional candidate for actinide sequestration. This synthetic
hydroxypyridinonate chelator is currently undergoing preclinical development for the treatment of
individuals with known or suspected internal contamination with actinides such as plutonium (Pu),
americium (Am), curium (Cm), uranium (U) or neptunium (Np) to increase the rates of elimination of these
radionuclides. In order to seek regulatory approval for this new agent, a number of efficacy and safety
studies must respond to the selective criteria of the Animal Efficacy Rule from the U.S. Food and Drug
Administration (FDA). Recent studies that have been performed with orally-formulated 3, 4, 3-LI (1, 2-
HOPO) for consideration by the FDA as an Investigational New Drug will be presented.
A formulation development program testing more than 75 excipients in vitro led to the selection of API-
containing formulation prototypes with enhanced oral bioavailability properties. The biodistribution of
the API and formulation prototypes were characterized in Swiss-Webster mice and Sprague-Dawley rats
using C-14 as a radiotracer. A final oral formulation was then established and used for Pu and Am
decorporation efficacy studies as well as safety/pharmacology studies in mice, rats and Beagle dogs,
179 | P a g e
