" Given lenalidomide’s mechanism of action, it is intriguing that IMiDs and proteasome inhibitors are synergistic in the treatment of multiple myeloma.(24) Recent evidence suggests that this synergy may result from the pharmacokinetic properties and dosing schedules of these drugs. Although treatment with proteasome inhibitors can block lenalidomide induced degradation of IKZF1 and IKZF3 in vitro,(14) this effect depends on both the order of administration and the dose. When the drugs are administered at the same time, lenalidomide-induced degradation occurs before the onset of proteasomal blockade. (25) " excerpt from [1] below.
[1] BLOOD SPOTLIGHT| NOVEMBER 19, 2015
The novel mechanism of lenalidomide activity
https://ashpublications.org/blood/article/126/21/2366/34644/The-novel-mechanism-of-lenalidomide-activity
Blood (2015) 126 (21): 2366–2369.
" In this article, we review the recently recognized mechanisms of action of lenalidomide and discuss the most recent clinical data regarding its use in patients with both 5q− MDS as well as non-5q− MDS. " excerpt from [2] below.
First published: 13 February 2017
[2] Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications
Article Lenalidomide use in myelodysplastic syndromes: Insights into...
Maximilian Stahl MD,Amer M. Zeidan MBBS, MHS
[3]Jacob Keevan & William D Figg (2014) Article New mechanism of lenalidomide activity
, Cancer Biology & Therapy, 15:8, 968-969, DOI: 10.4161/cbt.29189Updated Dec 26th 2021 as I know have some publications of relevance to Lenalidomide. Top of my list are [1] and [2] at the moment they are most recent publications I have found. [3] added Jan 24 2023 - still need to review but it pre-dates [1] and [2]
Some additional references for background.
Article A Randomized Feasibility Study Evaluating Temozolomide Circa...
Damato AR, Katumba RGN, Luo J, Atluri H, Talcott GR, Govindan A, Slat EA, Weilbaecher KN, Tao Y, Huang J, Butt OH, Ansstas G, Johanns TM, Chheda MG, Herzog ED, Rubin JB, Campian JL. A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma. Neurooncol Pract. 2022 Jan 31;9(3):193-200. doi: 10.1093/nop/npac003. PMID: 35601970; PMCID: PMC9113320.
Core Concept: Emerging science of chronotherapy offers big opportunities to optimize drug delivery https://lnkd.in/gpAz-28v
Optimizing circadian drug infusion schedules towards personalized cancer chronotherapy
Hill RJW, Innominato PF, Le´vi F, Ballesta A (2020) PLoS Comput Biol 16(1): e1007218. https://lnkd.in/gnCAAzk5 https://lnkd.in/g4sY-NDv
Temporal regulation of tumor growth in nocturnal mammals: In vivo studies and chemotherapeutical potential
The FASEB Journal. 2021;35:e21231.First published: 11 January 2021 https://lnkd.in/gm9mr6z
Paula M. Wagner,César G. Prucca,Fabiola N. Velazquez,Lucas G. Sosa Alderete,Beatriz L. Caputto,Mario E. Guido
Harnessing the predictive power of preclinical models for oncology drug development.
Honkala, A., Malhotra, S.V., Kummar, S. et al. Nat Rev Drug Discov (2021). https://lnkd.in/gYnT7VtF
Updated Aug 22nd 2022: Chronotherapy Clinical Trial with a different Drug which is a good background resource.
Temozolomide Chronotherapy for High Grade Glioma
https://clinicaltrials.gov/ct2/show/NCT02781792
Updated Jan 12th 2023: Wang, Chen, et al. "The circadian immune system." Science Immunology 7.72 (2022): eabm2465. Another good background resource.
Article The circadian immune system
I have treated 600 cancer patients with thalidomide and celecoxib, using thalidomide 200mg before sleep, because it has the activity to let the patients somnolent. Celecoxib was able to give an effective therapeutic effect at 400 mg twice a day. As a result, the usage would have been effective.
I expect thalidomide and celecoxib to be marketed worldwide as anti-cancer agents and as a useful drug for the treatment of COVID-19 infections.
Thank you for your feedback/answer Hada-sensei. Will definitely check more.
As mentioned in my questions, "I am trying to understand if there is a theoretical best time to take lenalidomide to improve on efficacy and reduce on toxicity." This company is working on low dose continuous infusion of LEN. See here. https://www.startontx.com/
I also got the following feedback.
"From my reading, the exact targets of lenalidomide remain unknown. Given that, I would try it at two times of day, after waking and before sleep, and see what you see." which fits your feedback.
I have never used lenalidomide, in case of thalidomide, side effect and effect of the thalidomide molecule are caused by celebron+ E3 ubiquitin ligase complex. I think it is important to use thalidomide with combination of the drug which suppress activted NF-kB to get potent anti-cancer effect.
Thank you very much for your answer.
Also got answer from another researcher regarding best time to dose.
" Since being at Children’s, one thing I’ve learned is that there’s no substitute for testing in the clinic. These PK studies don’t need to be large, just large enough to detect a signal. AM PM, that’s it. "
This answer is from a researcher. Will be checking to see if I can reference him directly or not for his quote below.
" Since being at Children’s, one thing I’ve learned is that there’s no substitute for testing in the clinic. These PK studies don’t need to be large, just large enough to detect a signal. AM PM, that’s it. "
Dear Zte Tsung Tan, I am new on this platform and not being sure whether your question addresses any special disease?
Thank you for your question Csongor. Multiple myeloma is the disease. See here for a company planning continuous rather than just once a day https://www.startontx.com/2022/01/10/starton-therapeutics-receives-clinical-trial-authorization-in-europe-to-initiate-phase-1-clinical-trial-of-star-lld-continuous-delivery-lenalidomide/
While not directly related to Lenalidomide, thought this would be a good example of chronotherapeutic effect in the clinic.
Dae Wook Kim et al. " The sex-specific chronotherapeutic effects can be explained by the larger daily fluctuation of circulating leukocytes and neutrophils in females than in males. " " CONCLUSIONS. In female DLBCL patients, R-CHOP treatment in the afternoon can reduce the toxicity while it improves the efficacy and the survival outcome. " Chemotherapy delivery time affects treatment outcomes of female patients with diffuse large B-cell lymphoma [In Press Preview] Dae Wook Kim, … , Jae Kyoung Kim, Youngil Koh Published December 13, 2022 Citation Information: JCI Insight. 2022. Article Chemotherapy delivery time affects treatment outcomes of fem...
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