RESEARCH ARTICLE : Pharmacokinetics, Pharmacodynamics and Drug Transport and MetabolismA Paradigm Shift in Pharmacokinetic–Pharmacodynamic (PKPD) Modeling: Rule of Thumb for Estimating Free Drug Level in Tissue Compared with Plasma to Guide Drug Design
Section snippets
INTRODUCTION
In preclinical and clinical studies, total drug concentrations in plasma or tissue are often correlated with pharmacodynamics (PD). However, the use of total tissue levels (e.g., tissue concentrations derived from homogenates) or biopsies to draw direct conclusions on drug activity is unwarranted and/or unreliable.1., 2., 3., 4. This is in contrast with the unbound (free) drug concentration at the target site, which should be more pharmacologically relevant.1., 2., 3., 4. Related to this,
METHOD
Theoretical PBPK modeling simulations in humans were made for diverse scenarios to compare the resulting free drug concentration in plasma and tissue. As said, the dissimilarities in the binding and ionization on both sides of the membrane were investigated first. Hence, for passively permeable compounds either ionized or not at the physiological pH, the maximal dissimilarity between the interstitial and intracellular (free) drug concentrations were quantified.
RESULTS
A total of 14 simulation scenarios were evaluated in the present study for the comparison of the simulated Cmax and AUClast for the unbound drug (used as a measured of free drug concentrations in plasma and heart cells in humans). The comparative assessment is presented in Table 1, Table 2. As expected, the results indicate that free drug concentrations in plasma and tissue cells are not equal as observed by the dissimilarities in the simulated values of Cmax and AUClast for the unbound drug.
DISCUSSION
Data from in vitro plasma protein-binding experiments that determine the fraction of protein-bound drug are frequently used in drug discovery to guide structure design and to prioritize compounds for in vivo studies.2 Therefore, this old paradigm (using only fup derived from an in vitro static environment) is usually misleading, because this practice yields no enhancement of the in vivo free drug concentration in a dynamic system. Hence, in vivo efficacy should be determined by the free drug
CONCLUSION
This present study is a first step toward the comparison of free drug concentration in tissue and plasma under dynamic in vivo condition either after nonsteady-state and steady-state intravenous administrations in humans for passively permeable drugs that can be ionized at the physiological pH. Therefore, these observations provide much more relevant information compared with the traditional approach based only upon in vitro fup value. In other words, the current PBPK model simulations indicate
ACKNOWLEGMENTS
This work represents an initiative undertaken as a part of Dr Poulin’s research program. The author wishes to thank Conrad Housand at Aegies Technologies Inc. in Orlando, Florida, for the simulation software ADME Workbench® (www.admewb.com) that has facilitated the conduct of this study.
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2016, Journal of Pharmaceutical SciencesCitation Excerpt :For example, a low bioavailability effect after oral administration will reduce drug exposure, and, hence, will reduce Cfreecells and Cfreeinterstitial compared with a higher bioavailability effect.5 The same is true for a low or high CL effect2. And as the ionization state of both the drug and the target binding site potentially change as a function of pH, this would necessitate knowing the necessary pH value.