关于阿法替尼（Bibw 2992）耐药的一些理论和解决方案

Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor
http://europepmc.org/articles/PMC2859699/
http://www.nature.com/onc/journal/v29/n16/full/onc2009526a.html
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib are effective therapies against mutant non-small cell lung cancers (NSCLCs). Treatment is limited by the development of resistance in part explained by the gain of a secondary EGFR mutation, T790M, at the gatekeeper residue. Irreversible EGFR inhibitors, including PF00299804, are effective in vitro and in vivo against EGFR mutant tumors that contain EGFR T790M and are currently under clinical development. In this study, we generate models of resistance to PF00299804, using cell lines with EGFR T790M and show that the PF00299804-resistant models develop focal amplification of EGFR that preferentially involves the T790M-containing allele. These PF00299804-resistant cell lines remain dependent on EGFR for growth as downregulation of EGFR by shRNA compromises their viability. We show that resistance to PF00299804 arises, at least in part, through selection of a pre-existing EGFR T790M-amplified clone both in vitro and using a xenograft model in vivo. Our findings show that EGFR T790M is a common resistance mechanism to both reversible, and when amplified, the irreversible EGFR kinase inhibitors further emphasizing the need to develop more potent therapies against EGFR T790M. These findings can be used to guide studies of patient tumor specimens from ongoing clinical trials of irreversible EGFR kinase inhibitors.

Pre-existence and clonal selection of MET amplification in EGFR mutant NSCLC
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2980857/
A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours
http://www.nature.com/bjc/journal/v98/n1/full/6604108a.html
  阿法替尼的半衰期是33.9小时，口服4小时后到达最高血药浓度，经过8天达到稳定血药浓度。
The addition of low dose 17-DMAG to BIBW-2992 effectively inhibits lung cancer cells with acquired resistance by T790M mutation
http://cancerres.aacrjournals.or ... etingAbstracts/2753
The majority of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is caused by secondary T790M mutation. We established gefitinib or erlotinib-resistant cells which acquired different proportions of T790M from PC-9 cells with activating EGFR mutation. Anti-cancer effects of EGFR modulation and strategies overcoming resistance were investigated. The amount of T790M and EGFR gene copy number were proportional to increase of resistance. BIBW-2992, an irreversible EGFR-TKI, could suppress the growth and survival of cells harboring lower level of T790M while it failed in cells with higher level of T790M although p-EGFR was completely down-regulated in both, suggesting blocking of phosphorylation of EGFR is not sufficient to inhibit these cells. However, EGFR siRNA treatment could inhibit cell growth regardless of T790M level and resistance showing that EGFR dependency would be persistent. 17-DMAG, a HSP90 inhibitor, also effectively controlled both resistant cells. Considering a report showing that a HSP90 inhibitor was not clinically effective possibly because of inadequate dose, the efficacy of low dose 17-DMAG was examined. Interestingly, we found that combined treatment of BIBW-2992 with low dose 17-DMAG was very effective even in cells with higher level of T790M although either of both showed no activity in single treatment suggesting it would be one of promising strategies with immediate clinical implications overcoming T790M-mediated resistance. Further investigations on exact mechanism should be pursued even though capability of HSP90 inhibitor to modulate NF-kB signaling can be one of possible explanations.

The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor
http://www.ncbi.nlm.nih.gov/pubmed/18413800
http://mct.aacrjournals.org/content/7/4/874.full
Patients with non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) kinase domain tend to respond well to the tyrosine kinase inhibitors, gefitinib and erlotinib. However, following clinical response, these patients typically relapse within a year of treatment. In many cases, resistance is caused by an acquired secondary EGFR kinase domain mutation, T790M. In vitro studies have shown that a new class of EGFR-irreversible inhibitors could overcome the resistance conferred by T790M. Clinical trials are under way to examine the efficacy of one of these inhibitors, HKI-272, in patients with NSCLC who initially responded to gefitinib/erlotinib and subsequently relapsed. To anticipate the possibility that patients who respond to irreversible inhibitors will develop secondary resistance to such inhibitors, as has been seen in other similar settings, we modeled acquired resistance to the dual EGFR/HER2-irreversible tyrosine kinase inhibitor HKI-272 in a NSCLC cell culture model. We found that HKI-272-resistant clones fall into two biochemical groups based on the retention of EGFR phosphorylation in the presence of the drug. Cells that retain phosphorylated EGFR have acquired the secondary mutation T790M. Moreover, HKI-272 can overcome T790M resistance only at suprapharmacologic concentrations. We further model mutations at EGFR C797 as a mechanism of resistance to irreversible EGFR inhibitors and show that although these mutants are resistant to the irreversible inhibitor, they retain erlotinib sensitivity. Our findings suggest that HKI-272 treatment at maximally tolerated dosing may lead to the emergence of T790M-mediated resistance, whereas treatment with a more potent irreversible inhibitor could yield a resistance mutation at EGFR C797.
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The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor.

Molecular target therapies using first-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib or erlotinib, have been shown to be effective for patients with non-small cell lung cancer (NSCLC) who harbor activating mutations in EGFR. However, these patients eventually develop resistance to the reversible TKIs, and this has led to the development of second-generation, irreversible EGFR inhibitors. Currently, the mechanism of acquired resistance to irreversible EGFR inhibitors is not clear. Using an in vitro cell culture system, we modeled the acquired resistance to first-line treatment with second-generation EGFR-TKIs using an EGFR-mutant NSCLC cell line. Here, we report a mechanism of resistance involving T790M secondary mutation as well as a corresponding clinical case. The results of these findings suggest that inhibition of EGFR by currently available second-generation EGFR-TKIs may not be sufficient to physiologically prevent the emergence of cells that are still dependent on EGFR signaling. This finding bears important implications on the limitations of currently available second-generation EGFR-TKIs.

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Novel EGFR mutations that cause drug resistance to irreversible pyrimidine but not quinazoline based EGFR inhibitors
http://cancerres.aacrjournals.or ... etingAbstracts/4832
Background: Oncogenic EGFR T790M causes drug resistance to quinazoline based EGFR kinase inhibitors by increasing ATP affinity (Yun PNAS 2008). Mutant selective irreversible pyrimidine EGFR kinase inhibitor, WZ4002, is effective in non-small cell lung cancer (NSCLC) models harboring EGFR T790M (Zhou Nature 2009). We aimed to determine potential mechanisms of resistance to WZ4002 and explore alternative strategies to overcome acquired resistance to pyrimidine based EGFR inhibitors. Methods and Results: We performed an ENU mutagenesis screen in Ba/F3 cells expressing EGFR L858R, L858R/T790M, Del E746_A750 and Del E746_A750/T790M followed by culture in the presence of WZ4002 (100 nM or 1 μM). Using RT-PCR, we sequenced resistant clones for secondary EGFR mutations. No EGFR T790M mutations were identified. We detected novel secondary EGFR L718Q (9/27; 33%) or L844V (1/27; 3%) mutations in the drug resistant cells. We also recovered the EGFR C797S (1/27; 3%) mutation previously known to prevent covalent binding and decrease potency of WZ4002. Unlike EGFR T790M, EGFR L718Q and EGFR L844V did not lead to constitutive EGFR phosphorylation, were not transforming in Ba/F3 cells and required EGF for proliferation and survival. The EGFR L858R/L844V Ba/F3 cells were resistant to WZ4002 (IC50 0.7 μM) but sensitive to irreversible quinazoline EGFR inhibitors CL-387,785, HKI-272 (neratinib) and BIBW2992 (afatinib) (IC50 values all < 10 nM). Similar findings were observed with the EGFR L858R/L718Q cells although the IC50 values were slightly higher (100 nM or less) and with the Del E746_A750/L718Q and Del E746_A750/L844V cells. All triple mutants harboring EGFR T790M (e.g. L858R/T790M/L844V) were resistant to WZ4002 and irreversible quinazoline EGFR inhibitors. EGFR L858R/L844V and L858R/L718Q Ba/F3 cells were growth inhibited by clinical concentrations (1 μM) of gefitinib and the combination of 1 μM gefitinib and 100 nM WZ4002 completely prevented the emergence of resistant clones in our ENU assay. Using structural modeling, both the L718Q and L844V mutations likely lead to steric hindrance and could impact WZ4002 binding. To verify this hypothesis, we developed a biotinylated-WZ4002 compound and used it to assay binding to different EGFR mutant proteins. This agent effectively bound to EGFR L858R and DelE746_A750 (with or without T790M). However, in the presence of a concurrent L718Q or L844V mutation, protein binding was significantly reduced, consistent with the reduced in vitro efficacy in the Ba/F3 cells. Conclusions: We identify novel EGFR mutations that confer drug resistance to irreversible pyrimidine but not quinazoline EGFR kinase inhibitors. Our findings have implications for understanding drug resistance mechanisms and for the development of combinations of EGFR kinase inhibitors as therapies for cancer patients.

Clin Cancer Res. 2012 Mar 15;18(6):1663-71. doi: 10.1158/1078-0432.CCR-11-1171. Epub 2012 Feb 8.
Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer.
Wang W, Li Q, Takeuchi S, Yamada T, Koizumi H, Nakamura T, Matsumoto K, Mukaida N, Nishioka Y, Sone S, Nakagawa T, Uenaka T, Yano S.
Source
Kanazawa University, Kanazawa, Ishikawa, Japan.

Abstract
PURPOSE:
Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI-resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs.
EXPERIMENTAL DESIGN:
The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into severe combined immunodeficient mice, and the therapeutic effects of E7050 plus gefitinib were assayed.
RESULTS:
E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells.
CONCLUSIONS:
A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.
http://www.ncbi.nlm.nih.gov/pubmed/22317763

golvatinib (also known as E7050) is an orally bioavailable dual kinase inhibitor of c-Met (hepatocyte growth factor receptor) and VEGFR-2 (vascular endothelial growth factor receptor-2) tyrosine kinases with potential antineoplastic activity. c-Met/VEGFR kinase inhibitor E7050 binds to and inhibits the activities of both c-Met and VEGFR-2, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases. c-Met and VEGFR-2 are upregulated in a variety of various tumor cell types and play important roles in tumor cell growth, migration and angiogenesis.
Name: Golvatinib
CAS#: 928037-13-2
Chemical Formula: C33H37F2N7O4
Exact Mass: 633.28751
Molecular Weight: 633.69 Elemental Analysis: C, 62.55; H, 5.89; F, 6.00; N, 15.47; O, 10.10

E7050 is the first kinase inhibitor with dual action against both c-Met and VEGFR-2. The dual inhibitory activity of E7050 against tumor growth and angiogenesis results in drastic tumor regression and disappearance and also prolongation of lifespan without adverse effects.  E7050 is currently under evaluation in a phase I clinical trial.    (Cancer Sci. 2010 Jan;101(1):210-5. Epub 2009 Sep 2.).

   

E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells.
CONCLUSIONS: A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs. (source: Clin Cancer Res. 2012 Mar 15;18(6):1663-71. Epub 2012 Feb 8.)

Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor targeted multi-kinase inhibitor, administered orally QD to patients with advanced solid tumors.  Print this page  


Sub-category:
Other Novel Agents


Category:
Developmental Therapeutics - Experimental Therapeutics


Meeting:
2012 ASCO Annual Meeting


Session Type and Session Title:
Poster Discussion Session, Developmental Therapeutics - Experimental Therapeutics


Abstract No:
3030


Citation:
J Clin Oncol 30, 2012 (suppl; abstr 3030)


Author(s):
Gennaro Daniele, Malcolm Ranson, Montserrat Blanco-Codesido, Emma Jane Dean, Krunal Jitendrakumar Shah, Matthew Krebs, Andre Brunetto, Alastair Greystoke, Claire Johnston, Galina Kuznetsov, Mark Matijevic, Bipin Mistry, Begona de las Heras, L Rhoda Molife; Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom; Christie NHS Foundation Trust, Manchester, United Kingdom; Eisai, Hertfordshire, United Kingdom; Eisai, Andover, MA; Eisai, Woodcliff Lake, NJ



Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^) here and in the printed Proceedings.

Abstract Disclosures

Abstract:

Background: Golvatinib is a highly potent, small molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family as well as c-Kit and Ron, based on isolated kinase assays. Golvatinib showed preclinical evidence of anti-tumor activity. This phase 1 study was performed to determine the MTD, safety, PK, PD and preliminary activity of golvatinib. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0-1, ≥ 18 years (yrs) and adequate organ function were eligible. Golvatinib was administered orally, once daily (QD), continuously. Blood samples for PK and PD analysis were collected at multiple time-points. Mandatory tumor biopsies for PD analysis were taken pre and post Cycle 1 in an expanded MTD cohort. Results: 34 pts (M/F: 21/13; median age 63.5yrs [range 32-78]) were treated at 6 dose levels: 100, 200, 270, 360, 450 and 400 mg. Tumor types were colorectal (n=15), lung (n=4), renal (n=4), esophageal (n=2), melanoma (n=2) and others (n=7). Three DLTs were observed: Gr3 GGT and alkaline phosphatase (n=1; 200mg) and repeated Gr2 (n=1) and Gr3 (n=1) fatigue, both at 450mg. The MTD was determined to be 400 mg QD. Frequently occurring adverse events ([AEs]; all grades) were fatigue: 68% (Gr3: 15%), diarrhea: 65%, nausea: 62%, vomiting: 53%, decreased appetite: 47% (Gr3: 9%), ALT increase: 38% and AST increase: 23%. No Gr4 AEs were observed. Best response was stable disease in 6 pts lasting >84 days. PK showed high variability and plasma concentration increased with dose. The Cmax was reached within a median time of 4 hours. Plasma PD analysis showed an increase in soluble c-Met and Ang 2 levels after golvatinib treatment. Tumor PD analysis in 5 pts at 400 mg demonstrated a baseline elevated MET gene copy number, with c-Met overexpression and post treatment decline in phospho(p)-c-Met expression in 1 pt; post-treatment decline in p-c-Met in a 2nd pt, and post-treatment decline in p-ERK in a 3rd pt. Conclusions: Golvatinib at an MTD of 400 mg QD has manageable toxicity. Preliminary PD analysis demonstrated evidence of c-Met target modulation. Further evaluation will continue in phase 2 combination studies.
http://www.asco.org/ASCOv2/Meeti ... mp;abstractID=97955

一步错步步错 发表于 2013-3-2 23:38

                               
登录/注册后可看大图

再请问下如果全脑放疗，放疗期间是继续用易好还是换药

谢谢老马。

E7050，一种新，口服活性，小分子抑制c-MetR和VEGFR2化合物。体外研究表明E7050强烈阻止两个靶TK受体的磷酸化。还有，药物分别可抑制c-MetR用特异性生长因子，HGF和VEGF刺激放大的肿瘤细胞和内皮细胞。体内，E7050显示肿瘤中抑制c-MetR和VEGFR2磷酸化的作用和在移植瘤模型中肿瘤生长和血管生成的抑制作用，提示对癌治疗潜能。
出现数据还显示E7050在EGFR-突变体肺癌逆转HGF-引发TK抑制剂耐药性的三种不同机制。这个化合物避免对可逆性，不可逆性耐药性和被外源性和/或内源性HGF在EGFR-突变体肺癌细胞株诱导的突变体-选择性EGFR TKIs (EGFR-突变体PC-9和HCC827有一种外显子19缺失；H1975有一种T790M继发突变)，通过阻断Met/Gab1/PI-3K/Akt通路。此外，E7050阻止吉非替尼-耐药HCC827细胞株被HGF连续暴露诱导的出现。

1119 Weekend Drug Holiday of Dasatinib in CML Patients Not Tolerating Standard
Dosing Regimens. Reducing Toxicity with Maintained Disease Control
Oral and Poster Abstracts
Poster Session: Chronic Myeloid Leukemia - Therapy Poster I

Saturday, December 5, 2009, 5:30 PM-7:30 PM
Hall E (Ernest N. Morial Convention Center)
Poster Board I-141
Paul La Rosee, MD1*, Armin Leitner, MD2*, Philippe Martiat, MD3, Thomas Klag,
MD1*, Samina Shazi, MD2*, Anne Treschl, MD2*, Martin C M黮ler, MD2*, Thomas
Schenk, MD1*, Benjamin Hanfstein2* and Andreas Hochhaus, MD1

1Hematology/Oncology, Universit鋞sklinikum Jena, Jena, Germany
2III. Medizinische Klinik, Universit鋞smedizin Mannheim, Universit鋞 Heidelberg,
Mannheim, Germany
3Dept. of Experimental Hem., Institut Jules Bordet, Brussels, Belgium

Dasatinib (DA) is a multitargeted tyrosine kinase inhibitor (TKI) approved for
2nd line treatment of chronic myelogenous leukemia (CML) patients after imatinib
failure. DA-related toxicity mandates dose reduction in selected patients beyond
the labelled reduced continuous dosing. In chronic phase (CP) patients,
intermittent targeting of BCR-ABL by a once daily regimen reduces side effects
with equal efficacy compared to the initially explored twice daily regimen.
Thus, considering the short half-life of DA (3-5 hours) additional treatment
interruptions to reduce the total weekly dose may not negatively affect
treatment outcome while allowing continued treatment with an effective drug. In
a retrospective analysis 33 CML patients (pts; 20 m, 13 f, median age 66 years,
range 39-81) with intolerance (n=11) or resistance (n=22) to imatinib were
investigated. Pts were selected based on the toxicity-guided administration of a
dose reduced dasatinib regimen and were treated with an on/off regimen (3 to 5
days on, 4 to 2 days off) expecting a reduction of DA dependent off-target
toxicity. Pts were followed by routine hematologic and cytogenetic assessment,
and molecular monitoring (quantitative reverse transcriptase polymerase chain
reaction, PCR) to safeguard clinical response to the altered drug schedule.
Further, resistant pts were regularly screened for BCR-ABL mutations. Median
time since CML diagnosis until start of DA treatment was 38 mo (range, 6-189).
The median number of preceding treatment modalities was 3 (range, 1-5). The
median follow up of interval treatment was 23 mo (range, 3-41). 30 patients were
in CP, 2 in accelerated phase, and one in blast phase CML. 13/33 patients
carried mutant BCR-ABL prior to onset of DA-treatment. Non-exclusive reasons for
dose reduction were hematologic toxicity (17/33; 51%), and fluid retention
(18/33, 55%), including 17 patients with pleural effusions. 27 patients (82%)
suffered from grade III/IV (CTC) side effects. The median weekly dose of the DA
weekend holiday schedule was 500mg (range, 320-500). During interval treatment,
mean CTC grade for hematologic toxicity improved from grade 3.2 to 1.5
(p<0.001), and for fluid retention from grade 2.9 to 1.6 (p<0.001). All but 2
pts (89%) affected by fluid retention, and all but one patient suffering from
hematologic toxicity (94%) achieved a lower CTC toxicity level by allowing drug
holiday. In 6/33 pts, resistance mutations (T315I x 2, F317L x 3, L248V) were
recovered. For response analysis, 2 pts were excluded due to early stem cell
transplantation or loss of follow up. 13/31 (42%) did either show transient
improved molecular response or remained on stable BCR-ABL load over time. 3/31
progressed to advanced phase CML. 18/31 (58%) pts showed the desired disease
control according to established criteria despite reduced total weekly DA doses
either demonstrated by achieving an improved response level (12/31), or keeping
the response level achieved by continuous dosing (6/31). Fourteen of the 18 pts
achieved or maintained major molecular response (MMR) with 5 pts repeatedly
tested negative by PCR. The remainder four pts demonstrated response by
achieving complete cytogenetic remission (CCyR, 2x) or reduced BCR-ABL load <1%
according to the international scale. Of note, 10/12 pts with improved response
have been treated for a minimum of 6 mo with continuous dosing DA regimens
without having achieved the response level observed after allowing drug holiday.
We conclude that weekend treatment interruption allows continuation of DA
treatment for pts suffering from side effects. This retrospective analysis in
pts resistant or intolerant to imatinib with up to 5 preceding treatment
modalities suggests good and in many cases even improved efficacy of interval
treatment compared to continuous dosing. These data mandate the initiation of
clinical trials to investigate alternative intermittent targeting regimens.

What is a Drug Holiday?
By Lynne Eldridge MD, About.com Guide
Updated October 11, 2012
Question: What is a Drug Holiday?
A reader wrote in saying that her oncologist recommended a "drug holiday" from a medication she was taking for lung cancer. She asked what this meant, what she should be concerned about, and what questions she should ask her doctor.
Answer:
A drug holiday doesn’t sound like something a physician would prescribe, but sometimes it can be exactly what the doctor orders. Also known as a medication vacation, drug holidays have been prescribed for virtually every medication and medical condition. What are some of the reasons your doctor may suggest a drug holiday, and what are the risks and benefits?

Definition of a Drug Holiday
A drug holiday is defined as the conscious decision to stop using a regularly-prescribed medication for a period of time. Forgetting to use a medication, running out of pills, or stopping a medication without discussing the change with your doctor does not classify as a drug holiday. The decision is a joint one by both you and your physician to discontinue a medication for a period of hours, days or months for a particular reason. In medical lingo, a medication vacation is referred to as a “structured treatment interruption.”
&#8226;Don’t Stop Medication Without a Doctor’s Input
&#8226;Remembering to Take Your Medications
&#8226rescription Assistance Programs
Reasons Your Doctor Might Prescribe a Drug Holiday
There are many reasons your doctor may recommend, or that you may suggest, an interrupted use of a prescribed medication. Some of these include:
&#8226;To diminish the side effects of a medication - Most medications come with at least a few side effects. Temporarily stopping a medication may give you a break from these side effects, and in some cases, they don’t return when a medication is resumed. Some of the side effects that may have you wishing for a medication vacation include fatigue, loss of sexual drive or potency, nausea, sleep disruption, or loss of appetite on your medication.


&#8226;To allow the use of another medication - It’s well known that one medication can interact with another, and the more medications you're taking, the more likely this is to occur. An example of this would be if your physician recommends temporarily stopping a medication you're using regularly while you're prescribed another medication, such as an antibiotic for an infection.


&#8226;To see if you still need the medication - If you and your doctor aren’t certain whether you still need a medication, a drug holiday may be recommended as a form of trial.


&#8226;To decrease tolerance to the drug - Medication tolerance can develop to several medications, requiring higher doses to achieve the same desired effect. Through stopping a medication for a period of time, your body may again become sensitive to its effects (it may become effective again), or you may require a lower dosage. Sometimes, a drug holiday is recommended before tolerance develops to maintain sensitivity to the drug.


&#8226;To allow the medication to become effective again - In some cases, if a drug no longer works for a condition, discontinuing it for a period of time may allow it to once again become effective. One type of medication used for lung cancer, for example, loses effectiveness over time as the tumor becomes resistant. In one small study, it was found that the tumor was again sensitive to the medication after it was stopped for a period of time.


&#8226;Weekends and summer vacations - Some medications, such as ADHD medications that are used to help students concentrate, may not be needed when school is out of session. Discontinuing the medication during summer vacations and on weekends is referred to as an ADHD Drug Holiday.


&#8226;For special events - Your high school reunion is coming up, and you really want to have a glass of wine at the celebration, but your medication requires that you avoid alcohol. There are many alcohol-medication interactions. In some cases, your doctor will advise a drug holiday so that you can enjoy a special time before returning to your regular schedule of treatment.


&#8226;For surgery - If you are taking a blood thinner, your surgeon may recommend stopping medication for a period of time before and after surgery. Blood Thinners and Their Side Effects.
Possible Benefits
The benefits of a drug holiday will depend on the reason for the holiday, but may include:
&#8226;Renewed effectiveness of the medication.


&#8226;Decreased tolerance for the medication.


&#8226;Reduced side effects of the medication.


&#8226;A “vacation” from the side effects of a drug.


&#8226;Ability to discontinue a medication if it's found to be unnecessary.


&#8226;Renewed motivation if a medication vacation deems that a medication truly is needed.
Possible Risks
Just as there may be benefits, there are always risks to consider if you temporarily stop a medication. Some of these include:
&#8226;Loss of the effectiveness of the medication. In some cases, when a medication is stopped and started again, the effectiveness is lost.


&#8226;A worsening of the symptoms of the condition the drug is treating. This can be serious, for example, if the medication is treating depression or a serious heart condition.


&#8226;Risk of Relapse. Stopping a medication that is controlling a condition may cause the condition to recur or flare, and the relapse may be irreversible.


&#8226;Rebound of symptoms. In some cases, after stopping a medication, you may need higher doses of medication to again get symptoms under control.


&#8226;Excessive drug effects when the drug is resumed.


&#8226;Increased risk of poor medication compliance. Starting and then stopping a medication may make it more difficult to stick with a routine.
Questions to Ask
&#8226;Is this the right time to try a drug holiday?
&#8226;What are the risks and benefits?
&#8226;What side effects might I experience?
&#8226;Is there a chance the medication will no longer work if I stop it for a period of time?
&#8226;Whom should I call if I experience side effects on a night or weekend?
&#8226;Under what circumstances should I restart the medication?
&#8226;How long will I be stopping the medication?
&#8226;When should I schedule a follow-up visit?