Lost in translation: What's in an EC50? Innovative PK/PD reasoning in the drug development context

• Translation across species and from in vitro to in vivo is a central tenet in drug discovery pharmacology. Successful implementation requires proper assessment of both in vivo potency and efficacy. This notwithstanding, in vivo data is typically defined mostly in terms of ligand-to-target binding affinity, similar to in vitro studies. As in vivo potency and efficacy involve a combination not only of drug, but also partitioning, target, and drug-target-complex events and processes, ignoring some of the central differences between in vivo and in vitro may result in serious miscalculations of in vivo efficacious exposure for translational predictions. We compare potency measures derived from two basic pharmacodynamic model situations: A 'closed' in vitro system defining target binding of a ligand when both concentrations remain essentially static, and an 'open' in vivo system where target turnover dynamics and elimination of the drug-target complex are also included. Corresponding equilibrium (steady-state) expressions in the central pharmacokinetic compartment are derived and presented. Three representative variants of 'open' in vivo systems are discussed, showing relationships for ligand-target complex and ligand for each of the systems and graphically illustrating corresponding shapes. The examples include i) two ligands competing for one target, ii) two targets competing for one ligand (/drug), and iii) target-ligand (/drug) interactions in a peripheral PK compartment. The expanded in vivo potency EC50 expression emphasises the contribution from target-related biology parameters that need accounting for, and particularly that 'closed' system (in vitro) properties should not be first choice when ranking compounds in vivo ('open' system).

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

Nyckelord

Potency

Target turnover

Variability

In vitro-in vivo extrapolation

Inter-species scaling

Translation

disposition

target

body

Pharmacology & Pharmacy

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)