In vivo potency revisited – Keep the target in sight

Gabrielsson, Johan; Peletier, L. A.; Stephan, Holger

doi:10.1016/j.pharmthera.2017.10.011

Cited by 25 publications

(25 citation statements)

References 33 publications

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“…This is similar to the closed ( in vitro ) system in case of a standard monoclonal antibody TMDD model and can be for the BsAb model equivalently formulated in stationary form by Eqs. 20–22 and 26–30 (see Supplementary Material – ).…”

Section: Methodsmentioning

confidence: 98%

“…23 can be used in Eqs. [15][16][17][18][19][20][21][22]. On the other hand, an equivalent model can be constructed consisting of one differential equation for free BsAb:…”

Section: Tmdd Model For Bsabsmentioning

confidence: 99%

“…15 and 17, see Supplementary Material S1-S10 for derivation. The number of parameters now reduces to 10: This is similar to the closed (in vitro) system in case of a standard monoclonal antibody TMDD model [20][21][22] and can be for the BsAb model equivalently formulated in stationary form by Eqs. 20-22 and 26-30 (see Supplementary Material S1-S10).…”

Section: Tmdd Model For Bsabsmentioning

confidence: 99%

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Target‐Mediated Drug Disposition Model for Bispecific Antibodies: Properties, Approximation, and Optimal Dosing Strategy

Schropp

Khot

Shah

et al. 2019

CPT Pharmacom & Syst Pharma

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Bispecific antibodies (BsAbs) bind to two different targets, and create two binary and one ternary complex ( TC ). These molecules have shown promise as immuno‐oncology drugs, and the TC is considered the pharmacologically active species that drives their pharmacodynamic effect. Here, we have presented a general target‐mediated drug disposition (TMDD) model for these BsAbs, which bind to two different targets on different cell membranes. The model includes four different binding events for BsAbs, turnover of the targets, and internalization of the complexes. In addition, a quasi‐equilibrium (QE) approximation with decreased number of binding parameters and, if necessary, reduced internalization parameters is presented. The model is further used to investigate the kinetics of BsAb and TC concentrations. Our analysis shows that larger doses of BsAbs may delay the build‐up of the TC . Consequently, a method to compute the optimal dosing strategy of BsAbs, which will immediately create and maintain maximal possible TC concentration, is presented.

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Section: Methodsmentioning

confidence: 98%

“…23 can be used in Eqs. [15][16][17][18][19][20][21][22]. On the other hand, an equivalent model can be constructed consisting of one differential equation for free BsAb:…”

Section: Tmdd Model For Bsabsmentioning

confidence: 99%

Section: Tmdd Model For Bsabsmentioning

confidence: 99%

See 1 more Smart Citation

Target‐Mediated Drug Disposition Model for Bispecific Antibodies: Properties, Approximation, and Optimal Dosing Strategy

Schropp

Khot

Shah

et al. 2019

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

show abstract

“…Indeed, an extended expression of in vivo potency EC 50 was recently derived, which incorporates both binding affinity (K d = k off /k on , where k on and k off denote the second-order on and first order rate of ligand-receptor binding), ligand-target binding rates, and target turnover properties. 31 The in vitro drug potency measure primarily assesses binding affinities (e.g., the K d parameter) but typically neglects ligand-target kinetics and target turnover. Highly variable Ratios across compounds and targets are therefore not surprising.…”

Section: In Vivo Potency Vs Target Turnovermentioning

confidence: 99%

“…Highly variable Ratios across compounds and targets are therefore not surprising. 31,32 A clear in vitro-to-in vivo correlation is not to be expected unless target-to-complex kinetics are constant or close to unity, and ligand-target removal is relatively slow (ligand-target complex elimination rate << ligand-target off-rate). 31,32 Failure to take target turnover and target-ligand complex characteristics into account is therefore likely to result in less predictable in vivo properties from in vitro potency readouts.…”

Section: In Vivo Potency Vs Target Turnovermentioning

confidence: 99%

Does In Vitro Potency Predict Clinically Efficacious Concentrations?

Jansson‐Löfmark

Stephan

Gabrielsson

2020

Clin Pharma and Therapeutics

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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.

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Integration of Pharmacokinetic and Pharmacodynamic Reasoning and Its Importance in Drug Discovery

Gabrielsson

Stephan

2018

Early Drug Development

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In vivo potency revisited – Keep the target in sight

Cited by 25 publications

References 33 publications

Target‐Mediated Drug Disposition Model for Bispecific Antibodies: Properties, Approximation, and Optimal Dosing Strategy

Target‐Mediated Drug Disposition Model for Bispecific Antibodies: Properties, Approximation, and Optimal Dosing Strategy

Does In Vitro Potency Predict Clinically Efficacious Concentrations?

Integration of Pharmacokinetic and Pharmacodynamic Reasoning and Its Importance in Drug Discovery

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