Thu-Lan T. Luonga; Chelsea N. Powers, PhDa; Brian J. Reinhardt, MSa; Michael J. McAnulty, PhDa; Peter J. Weina, MDb; Karen J. Shou, DOa; Caban B. Ambar, MSa
Correspondence: Thu-Lan T. Luong (thu-lan.t.luong.civ@health.mil)
aWalter Reed National Military Medical Center, Bethesda, Maryland
bFort Belvoir Community Hospital, Virginia
Author disclosures
The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the Department of Defense, the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Ethics and consent
The study protocol was approved by the Walter Reed National Military Medical Center Institutional Review Board and complied with the Health Insurance Portability and Accountability Act as an exempt protocol.
Physicians’ notes on AEs were not detailed in most cases. Notes for gastrointestinal effects, life-altering pruritis, intolerance, peripheral vascular disease, pneumonitis, and progressive disease described the change in status or appearance of a new medical condition but did not indicate whether erlotinib or gefitinib caused the changes or worsened a pre-existing condition.
The causes of AEs were not described in the available notes or the databases. This retrospective data analysis only focused on identifying drugs involved with erlotinib and gefitinib treatment; further mapping of DDIs among patients experiencing AEs needs to be performed, then in vitrodata testing before researchers can reach a conclusion.
DDIs With Antidepressants
We used the PDTS database to evaluate patients who experienced AEs, excluding patients who switched treatment. Thirteen patients filled a prescription for erlotinib and reported taking 220 cancer and noncancer prescription drugs. One patient (pruritis) was taking gefitinib along with 16 noncancer prescription drugs.
Table 4 details CYP information for cancer drugs, antidepressants, and noncancer drugs (top 11 drugs) among patients who recorded AEs with erlotinib.3-4,23-47
Selective serotonin reuptake inhibitors and other antidepressants have been implicated in CYP 2D6 inhibition and DDIs.48,49 Losartan is a widely used antihypertensive drug with a favorable DDI profile.50 Erlotinib and gefitinib are primarily metabolized via CYP 2D6 and 3A4 pathways. DDIs from in vitro human hepatocytes assays revealed that gefitinib had significant metabolic changes in a 1:1 (P < .05) combination with paroxetine or sertraline, and a 1:1:1 combination with losartan and fluoxetine, fluvoxamine, paroxetine, or sertraline. Citalopram and venlafaxine seemed to be unaffected by any combination (P ≥ .05).51 Erlotinib with fluoxetine or losartan 1:1 yielded insignificant differences in metabolism for all drugs (P ≥ .05). Three drug combinations of 1:1:1 involving fluoxetine and losartan with erlotinib yielded significant degrees of inhibition of fluoxetine and losartan metabolism (P < .05) but not erlotinib.52
Our data showed that 16 antidepressants (amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, imipramine, fluoxetine, fluvoxamine, mirtazapine, nortriptyline, paroxetine, phenelzine, sertraline, trazodone, and venlafaxine) were recorded with concomitant erlotinib or gefitinib from initiation to completion of therapy or a buffer of 6 months from the first diagnosis date. Based on the date dispensed and days’ supply, only escitalopram could be used in combination with gefitinib treatment. The one patient who filled a prescription for gefitinib and escitalopram completed treatment without recorded AEs. PDTS database confirmed that patients experienced AEs with 5 antidepressants (amitriptyline, mirtazapine, paroxetine, trazodone, and venlafaxine) with concomitant erlotinib use.
Based on the date dispensed and days’ supply, only trazodone could be used in combination with erlotinib. PDTS database showed that cancer drugs (erlotinib and megestrol) and 39 noncancer drugs (including acetaminophen, azithromycin, dexamethasone, hydrocortisone, and polyethylene glycol) were filled by 1 patient whose physician noted skin rash. Another limitation of using databases to reflect clinical practice is that although megestrol is listed as a cancer drug by code in the PDTS database, it is not used for nonendometrial or gynecologic cancers. However, because of the PDTS database classification, megestrol is classified as a cancer drug in this retrospective review.
This retrospective review found no significant DDIs for erlotinib or gefitinib, with 1 antidepressant taken by 1 patient for each respective treatment. The degree of inhibition and induction for escitalopram and trazodone are categorized as weak, minimal, or none; therefore, while 1:1 DDIs might be little or no effect, 1:1:1 combination DDIs could have a different outcome. This retrospective data collection cannot be linked to the in vitro hepatocyte DDIs from erlotinib and gefitinib in previous studies.51,52
