Drug Metabolism in Drug Design and Development Basic Concepts and Practice

fasted for 4 h, and rats, dogs, and monkeys are fasted overnight before dose
administration.
In general, a total of six to eight healthy male subjects, aging 15–65 years,
participate in human ADME studies. Healthy subjects are usually not used for
anticancer drugs. For cytotoxic anticancer drugs (mutagenic, carcinogenic, or
teratogenic), patient subjects are needed for the ADME studies. After at least
an 8 h overnight fasting in general, each subject receives a single clinically
relevant dose of [^14 C]-drug containing 50–100mCi of radioactivity. If^3 H-drug
is administered the higher dose of radioactivity (50–1000mCi) is needed to
detect the low energyb-radiation of^3 H (Beumer et al., 2006). All subjects
remain in the clinical facility for at least 7 days, which may be longer depending
on the PK parameters (t1/2,Cmax) of the drug, and are closely monitored for
adverse events throughout the study. In general an oral cathartic dose of milk
of magnesia (30 mL) is administered 2–3 days before the patient discharge, and
additional doses, if required, to ensure defecation prior to release from the
clinical facility. Subjects are discharged from the clinic in the afternoon of the

TABLE 18.2 Species used in toxicological studies.

Species Strain and genders Type of toxicological/pharmacological studies

Mouse CD-1, male and
female

Two-year carcinogenicity study

Rat Sprague–
Dawley male
and female,
Wistar, Fisher

Short term PK, dose selection, 2-year
carcinogenicity studies, teratogenecity
studies, 2-week single dose and/or repeated
dose toxicology studies, 1-month and/or
3-months and 1-year single and/or repeated
dose toxicology studies, embryo-fetal
development study, study of fertility and
early embryonic development, range finding
study in pregnant rats
Rabbit New Zealand White,
SPF, Oryctolagus
cuniculus; female

Reproductive studies including range finding
studies in pregnant rabbits, embryo-fetal
development study, teratogenecity studies
Dog Purebred beagle,
male and/or
female

Short term PK, dose selection, 2-week and
1-month single and/or repeated dose
toxicology studies, 3-months and 1-year
repeated dose toxicology studies
Monkey Cynomolgus
(Macaca fascicularis),
male and/or female

Short term PK, dose selection, range finding
studies, 2-week, 1-month, 1-year toxicological
studies (single and/or repeated doses)
Human NA, male and/or
female

Intended species for efficacy and safety

Note: Depending on the drug program other toxicological/pharmacological studies may be
conducted in addition to the studies listed above.

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