Does In Vitro Potency Predict Clinically Efficacious Concentrations?

Abstract

The in vitro affinity of a compound for its target is an important feature in drug discovery, but what remains is how predictive in vitro properties are of in vivo therapeutic drug exposure. We assessed the relationship between in vitro potency and clinically efficacious concentrations for marketed small molecule drugs (n = 164) and how they may differ depending on therapeutic indication, mode of action, receptor type, target localization, and function. Approximately 70% of compounds had a therapeutic unbound plasma exposure lower than in vitro potency; the median ratio of exposure in relation to in vitro potency was 0.32, and 80% had ratios within the range of 0.007 to 8.7. We identified differences in the in vivo-to-in vitro potency ratio between indications, mode of action, target type, and matrix localization, and whether or not the drugs had active metabolites. The in vitro-assay variability contributions appeared to be the smallest; within the same drug target and mode of action the within-variability was slightly broader; but both were substantially less compared with the overall distribution of ratios. These data suggest that in vitro potency conditions, estimated in vivo potency, required level of receptor occupancy, and target turnover are key components for further understanding the link between clinical drug exposure and in vitro potency.

Time-Dependent Distribution of Hydroxychloroquine in Cynomolgus Macaques Using Population Pharmacokinetic Modeling Method

“…It appeared that the free plasma concentration of HCQ was lower than extracellular EC 50 in vitro (submitted data). However, it is quite complicated to extrapolate efficacy from in vitro to humans just based on this simple comparison, as pointed out by Jansson-Löfmark et al (2020) . Moreover, HCQ has specific affinity with pigmented tissues, lysosomes, and golgi ( Hoekenga, 1954 ; Fox, 1993 ; Schroeder and Gerber, 2014 ).…”

Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects

“…A recent study found that in vitro drug potency does not necessarily predict in vivo benefit, discussing that the source of this in vitro-in vivo discrepancy in PDs appeared to be in vivo biology, such as wide variability of target kinetic. 27 One important biology missing here, in the case of enterocyte-targeting drugs, is turnover of enterocytes. Despite its rapid turnover rate comparable to t 1/2,target and drug-target binding rates, [13][14][15][16][18][19][20] the impact of enterocyte turnover, as well as its IIV, on PDs of enterocyte-targeting drugs has not been focused solely because it slipped off from our attention without justification.…”

“…A recent study found that in vitro drug potency does not necessarily predict in vivo benefit, discussing that the source of this in vitro‐in vivo discrepancy in PDs appeared to be in vivo biology, such as wide variability of target kinetic 27 . One important biology missing here, in the case of enterocyte‐targeting drugs, is turnover of enterocytes.…”

Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions

“…Antibody-target binding parameters including k on , k off , and K D are usually measured using in vitro binding assays such as surface plasmon resonance in static environments [ 67 , 197 ]. Amounting evidence has indicated that these in vitro methods lack in vivo correlation due to the static non-native in vitro binding conditions not revealing the physiological factors [ 198 , 199 , 200 , 201 , 202 ], such as pressure and shear force in the living tissues [ 203 ]. The modeling approaches can be a complementary and powerful tool for identifying the in vivo binding parameters and exploring the underlying mechanisms that affect antibody-receptor binding in the living system [ 204 ].…”