Category: Preclinical Development
Purpose: The volume of distribution is one of key determinants of predicting plasma concentration profiles and effective half-lives of prospective drugs. The effectiveness of many approaches for predicting volumes of distribution have been assessed only on the distribution volume at steady state (Vss). Predictions of Vss alone are not sufficient to predict plasma concentration profiles because many drugs exhibit multiphasic eliminations. Physiologically based pharmacokinetic (PBPK) models can predict plasma concentration profiles, however it is difficult to establish the relative utility because one method cannot predict the distribution volumes of all compounds accurately.
The aim of this study was to evaluate the accuracy of distribution volumes predicted using PBPK models and compare with the values predicted from other conventional approaches. Assessments were conducted on distribution volumes just after intravenous administration (V1), at steady state (Vss), and in the elimination phase (Vβ).
Methods: Ten marketed compounds exhibiting plasma concentration profiles with two-phase elimination after intravenous administration in humans were evaluated. The Simcyp simulator (version 16, Simcyp, Sheffield, UK) was used to perform PBPK modeling. Human PBPK models of 10 compounds were developed in accordance with the insights from rat, dog, and monkey PBPK model developments, regarding the same optimized compounds’ lipophilicity input (e.g. logP) and method for calculating partition coefficients in tissues (Kp) gained in order to fit to plasma concentration profiles for intravenous doses in all three preclinical animals in common. Observed intravenous plasma clearances in animals and humans were used as in vivo clearances in PBPK models.
Results: The accuracy of V1, Vss, and Vβ values predicted using human PBPK models developed in accordance with prior animal PBPK models was superior to those predicted using conventional approaches, such as allometric scaling, especially for V1 and Vβ. By conventional approaches, V1 and Vβ values of 4–5 out of 10 compounds were predicted within 3-fold error of observed values whereas Vss values for their majority were predicted as such. PBPK models predicted V1, Vss, and Vβ values for almost all compounds within 3-fold errors, resulting in better predictions of plasma concentration profiles than allometric scaling. The distribution volumes predicted using human PBPK models based on prior animal PBPK modeling were more accurate than those predicted without reference to animal models.
Conclusion: It was demonstrated that human PBPK models developed with consideration of animal PBPK models could accurately predict distribution volumes in various elimination phases among two-phase eliminations of compounds, and plasma concentration profiles. This, in turn, should contribute to improved clinical study designs with sufficient duration and to the postulated effective doses in respect of maintenance of drug concentrations by estimating half-lives accurately in humans prior to first-in-human studies.
Kosuke Yoshida– Chuo-ku, Tokyo, Japan
Tomohisa Nakada– Chuo-ku, Tokyo, Japan
Koki Kojima– Chuo-ku, Tokyo, Japan
Akihito Ogasawara– Chuo-ku, Tokyo, Japan
Yoshinobu Nakamaru– Chuo-ku, Tokyo, Japan
Hiroshi Yamazaki– Chuo-ku, Tokyo, Japan