In vivo potency revisited - Keep the target in sight

Area of Science:

• Pharmacology and Drug Discovery
• Biochemical Sciences
• Systems Biology

Background:

• Pharmacological potency is crucial in drug discovery but often relies on in vitro binding affinity (e.g., K_d) which may not translate to in vivo efficacy.
• In vivo potency is a complex interplay of ligand binding, target dynamics, and elimination processes, differing significantly from simplified in vitro models.
• Overlooking the dynamic nature of in vivo systems can lead to inaccurate predictions of efficacious doses and drug exposure.

Purpose of the Study:

• To compare potency measures derived from in vitro (Model A) and various in vivo (Model B, Model C) systems.
• To introduce and validate a new parameter, L₅₀, that integrates target and complex turnover with binding affinity for improved in vivo potency assessment.
• To highlight the limitations of traditional in vitro parameters for predicting in vivo drug performance.

Main Methods:

• Formulated equilibrium (steady-state) equations for three models: closed in vitro system (A), open in vivo with ligand clearance and target turnover (B), and open in vivo with added complex elimination (C).
• Simulated and graphically illustrated the equilibrium relationships between ligand, target, and complex concentrations for each model.
• Derived the L₅₀ parameter, defined as the ligand concentration at half-maximal target and complex concentrations, and compared it with K_d, EC₅₀, and K_m using literature data.

Main Results:

• In vivo systems (Models B and C) exhibit distinct equilibrium relationships compared to in vitro systems (Model A), influenced by target and complex turnover rates.
• The novel L₅₀ parameter, derived from in vivo models, amalgamates target turnover, binding affinity, and complex elimination, providing a more comprehensive measure of potency.
• L₅₀ values can differ significantly from K_d or K_m, depending on the relative rates of target degradation (k_deg) and complex elimination (k_e(RL)), underscoring the inadequacy of in vitro data alone for in vivo predictions.

Conclusions:

• A better understanding of in vivo pharmacological potency necessitates evaluating determinants within an open system framework.
• L₅₀ offers a valuable metric for predicting effective drug concentration ranges, aiding translational research and assessing in vivo target engagement.
• The study emphasizes that compounds with similar in vitro binding affinities can exhibit vastly different in vivo potencies, advocating for the use of L₅₀ over solely in vitro parameters for ranking compounds in vivo.