be acceptable. Radiopurity of the radiolabeled drug should be checked before
dose preparation and stability (radiopurity) of the radiolabeled drug under
conditions of administration should also be checked at predose and postdose.
18.2.2 Preparation of Animals and Human Subjects
Two animal species, one rodent (rat or mouse) and one nonrodent (dog or
monkey) are normally chosen for ADME studies. A summary of typical study
design is presented in Table 18.1. Selection of animals will be based on the
animal species used in the toxicological studies. The strain and source of
animals should match those used in the toxicological studies. A list of animals
used in toxicity studies is presented in Table 18.2. Although male animals are
normally used for metabolism studies, female animals should also be used if
PK/metabolism difference is known between males and females since both
genders are used in toxicological studies. If the drug is being developed for
Japanese registration, both male and female animals should be used in mass
balance studies. In addition, the dispositional studies may be conducted in
other species such as rabbits used for reproduction, teratogenicity, and
carcinogenicity studies.
Dogs and monkeys are normally nonnaive animals. Animals usually
completes at least 14 days of quarantine or conditioning before dose
administration. In general, a certified canine or primate diet such as
LabChowTMor LabDietTM (Purina Mills Inc) is fed to dogs and monkeys
and a certified rodent diet such as LabDiet (Purina Mills Inc) is given to rats
and micead libitumdaily. Tap water is provided to animalsad libitum. Mice are
TABLE 18.1 ADME study designs.
Species Na Gender Age Weight Doseb(mCi/subject)
Mouse 5/3 (+12)c M/F 7–12 weeks 25–40 g 5–15
Ratd 3 (+12)c M/F 7–12 weeks 150–300 g 25–50
Rabbit 3 F/pregnant 3–5 months 2–4 kg 50–100
Dogd 3 M/F 6–10 months 8–13 kg 100–200
Monkeyd 3 M/F 2–5 years 2.5–4 kg 100–200
Humand 6–8 M/F 15–65 yearse 65 kg 100
Note: Dose level (mg/kg), dose volume (mL/kg), dose concentration (mg/mL), dose radioactivity
(mCi/kg), vehicle, dosing regimen/route depends on the drug program and should be provided in
the study protocol before the start date. Specific activity of the radiolabeled drug may be adjusted
(isotopicvally diluted) to yield the desired radioactive dose level.
aN: number of animals or subjects.
bFor a (^14) C-labeled drug.
cThe numbers in parenthesis are the additional animals that are dosed for blood collection for the
biotransformation studies (at least four time points; three animals/time point).
dAdditional studies with bile cannulated animals or humans may be conducted if needed.
eOld population may be needed for special experiments. The normal age range is 18–45 years.
576 ADME STUDIES IN ANIMALS AND HUMANS