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PHARMACOKINETICS

Comparison of Maximum Drug Concentration and Area Under the Time-Concentration Curve Between Humans and Animals for Oral and Intravenous Investigational Drugs

Tomoe Fujita, MD, PhD, Yoshiaki Matsumoto, PhD, Machiko Ozaki, MD, Masataka Majima, MD, PhD, Yuji Kumagai, MD, PhD and Yoshio Ohtani, MD, PhD

From the Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan (Dr Fujita, Dr Majima, Dr Kumagai); the Clinical Investigation Center, Kitasato University East Hospital, Sagamihara, Kanagawa, Japan (Dr Fujita, Dr Ozaki, Dr Kumagai, Dr Ohtani); the Department of Clinical Pharmacokinetics, College of Pharmacy, Nihon University, Funabashi, Chiba, Japan (Dr Matsumoto); and the Department of Health Science, Kitasato University School of Allied Health Sciences, Sagamihara, Kanagawa, Japan (Dr Ohtani).

The study compared maximum drug concentration (Cmax) and area under the time-concentration curve (AUC) after normalization of doses to body weight and to body surface area and developed relationships for Cmax and AUC between humans and animals for 75 oral and 10 intravenous investigational drugs. For the oral drugs, animal-human ratios of Cmax were different among animals in both normalizations. Surface area-normalized AUC ratios were not different, whereas weight-normalized ones were different. For both normalizations for intravenous drugs, AUC ratios were not different. Drugs exhibiting 1/10 or smaller ratios tended to have low bioavailability. Regression of the relationships for dose-normalized Cmax and AUC transformed logarithmically between humans and animals were significant for the drugs with relatively high bioavailability. As approaches for predicting human Cmax and AUC from animals, surface area normalization seems to surpass weight normalization, and the equation obtained can be applied to drugs with high bioavailability.

Key Words: Phase I study • body surface area normalization • area under the time-concentration curve (AUC) • maximum drug concentration (Cmax) • linear regression analysis

Address for reprints: Tomoe Fujita, Clinical Investigation Center, Kitasato East Hospital, Asamizodai 2-1-1, Sagamihara, Kanagawa 228-8520, Japan; e-mail: tomoe{at}kitasato-u.ac.jp.


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