Biomedical Engineering Reference
In-Depth Information
4.5.6.2
Rat Study
Male and female Sprague-Dawley rats (
N
20/sex/group) were administered APF
530 as a single total subcutaneous dose of 0.25 or 1.0 mL/animal. The 1-mL dose
was administered at four sites at 0.25 mL/site. For rats, a 0.25-mL dose/site was
the maximum feasible dose for the polymer formulation based on leakage from
the injection site. The total mass of granisetron administered in the APF 530
formulation was approximately 5 and 20 mg/animal. The 5-mg dose was approxi-
mately 14-19 and 21-28 mg/kg of granisetron in males and females, respectively.
The 20-mg dose was approximately 57-77 and 85-113 mg/kg of granisetron in
male and females, respectively.
Additional animals (
N
=
20/sex/group) were administered 1 mL/animal of
saline control divided equally into four sites, or aqueous granisetron at an intra-
venous dose of 9 mL/kg, or an subcutaneous dose of 1 mL/animal (0.25 mL/site).
Saline control and test formulations were administered through a 16-gage needle.
Five rats/sex/group were sacrifi ced on days 4, 8, 15, and 29.
Administration of APF 530 was well tolerated both locally and systemically.
Histopathological evaluation of the APF 530 injection sites revealed several revers-
ible changes consistent with the injection of a biodegradable polymer. By day 29,
the response to the polymer had resolved without any residual or untoward effects.
=
4.5.6.3
Dog Study
A study in beagle dogs was also conducted to further characterize the systemic
and local toxicity profi le of APF 530. Male and female beagle dogs (
N
6/sex/
group) were administered APF 530 at a single total subcutaneous dose volume of
1.0 or 4 mL/animal. For beagle dogs, a 1-mL/site is the maximum feasible dose
for the polymer formulation based on leakage from the injection site. For the 1-mL
dose, two sites received 0.25 mL and one site received 0.5 mL. For the 4-mL dose
volume, 1-mL was administered at four separate sites. The total mass dose of
granisetron administered in the APF 530 formulation was approximately 20 and
80 mg/animal, or approximately 1.5 - 2.5 and 6 - 10 mg/kg of granisetron, respec-
tively. Additional animals (
N
=
6/sex/group) were administered aqueous graniset-
ron at an intravenous dose of 3 mL/kg or a subcutaneous dose of 4 mg/animal
(1 mL/site), or 2.75 mL/animal of saline control divided into four sites (0.25 and
0.5 mL in one site. 1 mL in two sites). The total mass dose of aqueous granisetron
administered subcutaneously translated to approximately 0.3- 0.5 mg/kg. Saline
control and test formulations were administered through a 16-gage needle.
Administration of APF 530 was well tolerated both locally and systemically.
Histopathological evaluation of the APF 530 injection sites revealed several revers-
ible changes consistent with the injection of a biodegradable polymer. All effects
appeared to be resolving by day 15.
=
4.5.6.4
Phase II and Phase III Clinical Trials
Phase II and Phase III clinical trials have been completed.
In a Phase II clinical trial, the safety, tolerability, and pharmacokinetics in cancer
patients were evaluated. In addition, effi cacy end-points were evaluated relating to
emetic events and the use of additional medication.
