Cellular effect and efficacy of carfilzomib depends on cellular net concentration gradient

Schäfer, Julia; Welti, Lukas; Seckinger, Anja; Burhenne, Jürgen; Theile, Dirk; Weiß, Johanna

doi:10.1007/s00280-017-3335-4

Cited by 5 publications

(8 citation statements)

References 21 publications

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“…Therefore, this binding site must be at the extracellular site in a location only accessible when the channel is in the open state. CFZ-mediated inhibition of I K(DR) or I K(M) presented here is direct and independent of its possible actions on the activity of cytosolic proteasomes or on any changes in intracellular peptide levels (Dasgupta et al, 2014; Schäfer et al, 2017). On the other hand, it would be interesting to explore whether the suppression by CFZ of proteasome activity would secondarily ascribes from its blocking of membranous I K(DR) to some extent in different types of neoplastic cells.…”

Section: Discussionmentioning

confidence: 76%

“…The main action of CFZ on I K(DR) is thought to be principally through a state-dependent, open-channel block mechanism. Apart from its inhibitory effect on cytosolic proteasome or on changes in intracellular peptides (Dasgupta et al, 2014; Schäfer et al, 2017), block of CFZ of I K(DR) presented herein is of peculiar importance, since it may have characteristics making it significant from both pathophysiological, therapeutic, or toxicological point of view.…”

Section: Discussionmentioning

confidence: 99%

“…PSI, the structure of which is shared by CFZ, is another inhibitor of proteasome activity. The IC 50 value for CFZ-induced suppression of cell viability in RPMI-8226 myeloma cells obtained during one-hour exposure was around 40 nM (Schäfer et al, 2017). Therefore, its effective concentration required for the inhibition of I K(DR) in different types of neoplastic cells probably overlaps with that for the suppression of proteasome activity (Yu et al, 2002; Schäfer et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…The IC 50 value for CFZ-induced suppression of cell viability in RPMI-8226 myeloma cells obtained during one-hour exposure was around 40 nM (Schäfer et al, 2017). Therefore, its effective concentration required for the inhibition of I K(DR) in different types of neoplastic cells probably overlaps with that for the suppression of proteasome activity (Yu et al, 2002; Schäfer et al, 2017). Because the maximal plasma concentration of CFZ reached in the blood in vivo was reported to be around 1000–2000 ng/ml (i.e., 1.4–2.8 µM) (Maruyama et al, 2018), such unanticipated modifications of I K(DR) amplitude and gating are expected to occur at a concentration achievable in humans.…”

Section: Discussionmentioning

confidence: 99%

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High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

Liu

Lee

et al. 2019

Front. Pharmacol.

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Carfilzomib (CFZ, Kyprolis®) is widely recognized as an irreversible inhibitor of proteasome activity; however, its actions on ion currents in electrically excitable cells are largely unresolved. The possible actions of CFZ on ionic currents and membrane potential in pituitary GH3, A7r5 vascular smooth muscle, and heart-derived H9c2 cells were extensively investigated in this study. The presence of CFZ suppressed the amplitude of delayed-rectifier K+ current (I K(DR)) in a time-, state-, and concentration-dependent manner in pituitary GH3 cells. Based on minimal reaction scheme, the value of dissociation constant for CFZ-induced open-channel block of I K(DR) in these cells was 0.33 µM, which is similar to the IC50 value (0.32 µM) used for its efficacy on inhibition of I K(DR) amplitude. Recovery from I K(DR) block by CFZ (0.3 µM and 1 µM) could be well fitted by single exponential with 447 and 645 ms, respectively. The M-type K+ current, another type of K+ current elicited by low-threshold potential, was slightly suppressed by CFZ (1 µM). Under current-clamp condition, addition of CFZ depolarized GH3 cells, broadened the duration of action potentials as well as raised the firing frequency. In A7r5 vascular smooth muscle cells or H9c2 cardiac cells, the CFZ-induced inhibition of I K(DR) remained efficacious. Therefore, our study led us to reflect that CFZ or other structurally similar compounds should somehow act on the activity of membrane KV channels through which they influence the functional activities in different types of electrically excitable cells such as endocrine, neuroendocrine cells, smooth muscle cells, or heart cells, if similar in vivo findings occur.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

Liu

Lee

et al. 2019

Front. Pharmacol.

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“…Chemical interaction between the drug and its molecular site of action. The mechanisms of interaction between drugs and their molecular targets are numerous 60 and interactions with high affinity binding sites can modify both cellular 53 and systemic PK. 61 To establish appropriate quantification methods for drugs at their targets, it matters whether and how target binding occurs.…”

Section: Expression and Activity Of Transporters At The Cellular Sitementioning

confidence: 99%

Approaching sites of action of drugs in clinical pharmacology: New analytical options and their challenges

Longuespée

Theile

Fresnais

et al. 2020

Brit J Clinical Pharma

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Clinical pharmacology is an important discipline for drug development aiming to define pharmacokinetics (PK), pharmacodynamics (PD) and optimum exposure to drugs, i.e. the concentration-response relationship and its modulators. For this purpose, information on drug concentrations at the anatomical, cellular and molecular sites of action is particularly valuable. In pharmacological assays, the limited accessibility of target cells in readily available samples (i.e. blood) often hampers mass spectrometry-based monitoring of the absolute quantity of a compound and the determination of its molecular action at the cellular level. Recently, new sample collection methods have been developed for the specific capture of rare circulating cells, especially for the diagnosis of circulating tumour cells. In parallel, new advances and developments in mass spectrometric instrumentation now allow analyses to be scaled down to the cellular level. Together, these developments may permit the monitoring of minute drug quantities and show their effect at the cellular level. In turn, such PK/PD associations on a cellular level would not only enrich our pharmacological knowledge of a given compound but also expand the basis for PK/PD simulations. In this review, we describe novel concepts supporting clinical pharmacology at the anatomical, cellular and molecular sites of action, and highlight the new challenges in mass spectrometry-based monitoring. Moreover, we present methods to tackle these challenges and define future needs. K E Y W O R D S clinical pharmacology, mass spectrometry, personalized medicine, review, sites of action 1 | INTRODUCTION Clinical pharmacology studies the relevant parameters of drug fate (pharmacokinetics, PK) and efficacy (pharmacodynamics, PD) in humans in order to establish the dose-response and concentrationresponse relationship. It also defines intraindividual and interindividual modulators of these relationships, leading to different effectiveness, safety and dose requirements. Monitoring drug concentrations and effects is therefore of considerable importance during drug development, starting with the very first clinical trials. 1 Clinical pharmacology clarifies mechanisms of both beneficial and adverse drug effects in order to get closer to drug effectiveness monitoring. A drug's site of action can be defined at different scales: anatomical (the compartment the drug has to reach, e.g. tissues), cellular (the

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Mechanistic Pharmacokinetic/Pharmacodynamic Modeling in Support of a Patient-Convenient, Longer Dosing Interval for Carfilzomib, a Covalent Inhibitor of the Proteasome

et al. 2023

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Background Carfilzomib is an irreversible second-generation proteasome inhibitor that has a short elimination half-life but much longer pharmacodynamic (PD) effect based on its irreversible mechanism of action, making it amenable to longer dosing intervals. A mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was built using a bottom-up approach, based on the mechanism of action of carfilzomib and the biology of the proteasome, to provide further evidence of the comparability of once-weekly and twice-weekly dosing. Methods The model was qualified using clinical data from the phase III ENDEAVOR study, where the safety and efficacy of bortezomib (a reversible proteasome inhibitor) and carfilzomib were compared. Simulations were performed to compare the average proteasome inhibition across five cycles of treatment for the 20/70 mg/m 2 once-weekly (70 QW) and 20/56 mg/ m 2 twice-weekly (56 BIW) regimens. Results Results indicated that while 70 QW had a higher maximum concentration (C max ) and lower steady-state area under the concentration-time curve (AUC) than 56 BIW, the average proteasome inhibition after five cycles of treatment between the regimens was comparable. Presumably, the higher C max of carfilzomib from 70 QW compensates for the lower overall AUC compared with 56 BIW, and hence 70 QW is expected to have comparable proteasome inhibition, and therefore comparable efficacy, to 56 BIW. The comparable model-predicted proteasome inhibition between 70 QW and 56 BIW also translated to comparable clinical response, in terms of overall response rate and progression-free survival. Conclusion This work provides a framework for which mechanistic PK/PD modeling can be used to guide optimization of dosing intervals for therapeutics with significantly longer PD effects than PK, and help further justify patient-convenient, longer dosing intervals.

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Cellular effect and efficacy of carfilzomib depends on cellular net concentration gradient

Cited by 5 publications

References 21 publications

High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

Approaching sites of action of drugs in clinical pharmacology: New analytical options and their challenges

Mechanistic Pharmacokinetic/Pharmacodynamic Modeling in Support of a Patient-Convenient, Longer Dosing Interval for Carfilzomib, a Covalent Inhibitor of the Proteasome

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