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1.
Drug Discov Today ; 24(12): 2286-2298, 2019 12.
Article in English | MEDLINE | ID: mdl-31518641

ABSTRACT

Synergistic drug combinations are commonly sought to overcome monotherapy resistance in cancer treatment. To identify such combinations, high-throughput cancer cell line combination screens are performed; and synergy is quantified using competing models based on fundamentally different assumptions. Here, we compare the behaviour of four synergy models, namely Loewe additivity, Bliss independence, highest single agent and zero interaction potency, using the Merck oncology combination screen. We evaluate agreements and disagreements between the models and investigate putative artefacts of each model's assumptions. Despite at least moderate concordance between scores (Pearson's r >0.32, Spearman's ρ>0.34), multiple instances of strong disagreement were observed. Those disagreements are driven by, among others, large differences in tested concentrations, maximum response values and median effective concentrations.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Models, Biological , Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Line, Tumor , Drug Resistance, Neoplasm , Drug Synergism , High-Throughput Screening Assays/methods , Humans
2.
AAPS J ; 20(1): 11, 2017 12 04.
Article in English | MEDLINE | ID: mdl-29204742

ABSTRACT

Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D) and the target dissociation rate constant on target and tissue selectivity. The K D values of CB1 ligands in the ChEMBL database are predicted by QSAR random forest (RF) modeling for the CB1 receptor and known off-targets (TRPV1, mGlu5, 5-HT1a). Of these CB1 ligands, rimonabant, CP-55940, and Δ8-tetrahydrocanabinol, one of the active ingredients of cannabis, were selected for simulations of target occupancy for CB1, TRPV1, mGlu5, and 5-HT1a in three brain regions, to illustrate the principles of the combined PBPK-QSAR modeling. Our combined PBPK and target binding modeling demonstrated that the optimal values of the K D and k off for target and tissue selectivity were dependent on target concentration and tissue distribution kinetics. Interestingly, if the target concentration is high and the perfusion of the target site is low, the optimal K D value is often not the lowest K D value, suggesting that optimization towards high drug-target affinity can decrease the benefit-risk ratio. The presented integrative structure-pharmacokinetic-pharmacodynamic modeling provides an improved understanding of tissue and target selectivity.


Subject(s)
Models, Biological , Pharmacokinetics , Quantitative Structure-Activity Relationship , Humans , Organ Specificity , Receptor, Cannabinoid, CB1/metabolism
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