Background
Methods
Synthesis of AFM tartrate
Toxicity studies
Animals
Preparation of dose formulation
Verification of formulation
Dosage calculation
Male
|
Female
| ||||||
---|---|---|---|---|---|---|---|
Vehicle
|
1,000× human dosage
a
|
100× human dosage
a
|
Vehicle
|
1,000× human dosage
a
|
100× human dosage
a
| ||
No. of animals | 10 | 10 | 10 | 10 | 10 | 10 | |
Dose per day | By surface area (μg/m2) | 0 | 5,920 | 592 | 0 | 5,920 | 592 |
By body weight (μg/kg) | 0 | 987 | 98.7 | 0 | 987 | 98.7 | |
No. dosages | 1 | 1 | 1/5 | 1 | 1 | 1/5 | |
Total dosage (μg/kg) | 0 | 987 | 98.7/493.5 | 0 | 987 | 98.7/493.5 | |
Dosage volume (mL/kg) | 7.58 | 7.58 | 7.58/7.58 | 7.58 | 7.58 | 7.58/7.58 | |
Rats killedb
| |||||||
Interim | Day | 3 | 3 | 3/7 | 3 | 3 | 3/7 |
No. of killed | 5 | 5 | 5/5 | 5 | 5 | 5/5 | |
Terminal | Day | 15 | 15 | 15/19 | 15 | 15 | 15/19 |
No. of killed | 5 | 5 | 5/5 | 5 | 5 | 5/5 |
Dosing procedure
Observation protocol
Clinical pathology
Gross necropsy
Histopathologic examination
Statistical analyses
Dosimetry studies of [18 F]AFM in monkeys
Synthesis of [18 F]AFM
Animals
PET imaging protocol
Image analysis
Residence times and absorbed dose calculations
Results
Toxicity studies of AFM in rats
Biodistribution of [18 F]AFM in monkeys
%ID/organ
| |||||||||
---|---|---|---|---|---|---|---|---|---|
Brain
|
Lungs
|
Heart
|
Liver
|
Spleen
|
Kidneys
|
Bone
|
Red marrow
|
Bladder
| |
Time (min) post-injection | |||||||||
15 | 2.24 ± 0.69 | 19.26 ± 4.98 | 1.77 ± 0.27 | 3.94 ± 0.87 | 0.17 ± 0.05 | 2.09 ± 0.53 | 7.53 ± 2.71 | 3.40 ± 0.51 | 0.07 ± 0.04 |
55 | 1.98 ± 0.43 | 5.43 ± 1.42 | 0.79 ± 0.16 | 3.03 ± 0.46 | 0.07 ± 0.02 | 1.26 ± 0.46 | 11.17 ± 4.35 | 7.48 ± 1.46 | 0.62 ± 0.92 |
95 | 1.36 ± 0.30 | 2.73 ± 0.54 | 0.43 ± 0.07 | 2.21 ± 0.43 | 0.04 ± 0.02 | 0.74 ± 0.33 | 9.08 ± 4.36 | 8.03 ± 2.13 | 0.78 ± 1.04 |
110 | 1.18 ± 0.27 | 2.21 ± 0.39 | 0.36 ± 0.05 | 1.98 ± 0.42 | 0.03 ± 0.01 | 0.63 ± 0.30 | 8.70 ± 3.97 | 7.89 ± 2.20 | 0.82 ± 1.13 |
155 | 0.81 ± 0.20 | 1.35 ± 0.22 | 0.22 ± 0.03 | 1.30 ± 0.48 | 0.02 ± 0.01 | 0.41 ± 0.22 | 7.21 ± 3.23 | 6.69 ± 2.15 | 0.67 ± 1.05 |
170 | 0.72 ± 0.17 | 1.18 ± 0.17 | 0.19 ± 0.02 | 1.17 ± 0.46 | 0.02 ± 0.01 | 0.35 ± 0.20 | 6.34 ± 3.12 | 6.34 ± 2.13 | 0.66 ± 1.10 |
215 | 0.44 ± 0.21 | 0.72 ± 0.29 | 0.11 ± 0.05 | 0.79 ± 0.36 | 0.01 ± 0.01 | 0.20 ± 0.15 | 4.47 ± 2.44 | 5.16 ± 1.49 | 0.47 ± 0.68 |
230 | 0.39 ± 0.19 | 0.64 ± 0.25 | 0.10 ± 0.04 | 0.70 ± 0.34 | 0.01 ± 0.01 | 0.17 ± 0.13 | 4.09 ± 2.42 | 4.51 ± 1.19 | 0.42 ± 0.61 |
Residence time (h) | 0.051 ± 0.013 | 0.153 ± 0.045 | 0.034 ± 0.011 | 0.069 ± 0.025 | 0.035 ± 0.002 | 0.019 ± 0.002 | 0.069 ± 0.031b
| 0.325 ± 0.080 | 0.018 ± 0.024d
|
0.277 ± 0.125c
|
Absorbed radiation dose estimates
Male
|
Female
|
Total
| |
---|---|---|---|
Target organ | |||
Adrenalsa
| 14.0 ± 0.1 | 16.8 ± 0.4 | 15.1 ± 1.4 |
Braina
| 12.8 ± 2.2 | 12.4 ± 1.2 | 12.7 ± 1.8 |
Breastsa
| 9.0 ± 0.5 | 10.5 ± 0.5 | 9.5 ± 0.9 |
Gallbladdera
| 12.6 ± 0.3 | 13.9 ± 0.8 | 13.1 ± 0.8 |
LLI walla
| 12.4 ± 0.8 | 15.2 ± 0.8 | 13.5 ± 1.6 |
Small intestinea
| 12.4 ± 0.6 | 14.0 ± 0.8 | 13.0 ± 1.0 |
Stomacha
| 11.3 ± 0.6 | 13.7 ± 0.8 | 12.2 ± 1.4 |
ULI walla
| 11.9 ± 0.6 | 14.5 ± 0.8 | 12.9 ± 1.4 |
Heart walla
| 21.0 ± 1.6 | 19.3 ± 1.0 | 20.3 ± 1.6 |
Kidneysa
| 18.9 ± 1.3 | 21.8 ± 0.8 | 20.0 ± 1.9 |
Livera
| 15.7 ± 2.7 | 14.7 ± 1.8 | 15.3 ± 2.3 |
Lungsa
| 36.6 ± 6.3 | 32.6 ± 4.6 | 35.1 ± 5.8 |
Musclea
| 10.0 ± 0.4 | 12.4 ± 0.5 | 10.9 ± 1.3 |
Ovariesa
| 12.8 ± 0.8 | 15.2 ± 0.8 | 13.7 ± 1.4 |
Pancreasea
| 13.1 ± 0.3 | 15.4 ± 0.7 | 14.0 ± 1.2 |
Red marrowa
| 35.8 ± 4.8 | 34.7 ± 6.5 | 35.4 ± 5.1 |
Osteogenic cellsa
| 32.8 ± 4.8 | 49.5 ± 5.7 | 39.1 ± 9.8 |
Skina
| 7.6 ± 0.3 | 9.5 ± 0.4 | 8.3 ± 1.0 |
Spleena
| 11.0 ± 1.9 | 12.0 ± 0.6 | 11.4 ± 1.6 |
Testesa
| 9.0 ± 0.8 | - | 9.0 ± 0.8 |
Thymusa
| 11.5 ± 0.5 | 13.5 ± 0.6 | 12.3 ± 1.1 |
Thyroida
| 10.3 ± 0.5 | 12.1 ± 0.5 | 11.0 ± 1.0 |
Urinary bladdera
| 23.1 ± 12.9 | 11.1 ± 0.7 | 18.6 ± 11.6 |
Uterusa
| 12.6 ± 1.3 | 14.3 ± 0.8 | 13.3 ± 1.4 |
Total bodya
| 12.2 ± 0.1 | 15.3 ± 0.0 | 13.4 ± 1.6 |
Effective dose equivalent (EDE)b
| 20.2 ± 0.5 | 20.6 ± 0.5 | 20.3 ± 0.5 |
Effective dose (ED)b
| 18.0 ± 0.5 | 18.3 ± 0.4 | 18.2 ± 0.5 |