Drugs 1: Adriamycin (doxorubicin)

To date, I haven't really looked much at all at any of my medications.  I didn't really want to.  I realize this may be odd for a pharmacist, but I've always been like that for my own treatment.  Now, as the routine goes on and side effects accumulate, I have decided I probably will do some amount of reading.  I've decided to do my own little monographs here of what I think is interesting about these drugs.  Today, I've decided to explore the A (for Adriamycin) in my ABVD regimen.   Adriamycin is the brand name for the generic drug doxorubicin.  I'll use both terms interchangeably.

Drugs 1: Adriamycin (doxorubicin)

This one is the so called "Red-Devil." It literally looks like red Kool-aid in a syringe. Two very large syringes in my case. It needs to be pushed slowly, or the nausea is supposedly worse. Another reason to push it slowly is because it is a vesicant. This one is interesting to watch flow through the lines and into your veins. The correct rate per one oncology nurse appeared to be a thin ribbon of red through the normal saline drip which runs concurrently.

My dose is 56mg IV push each time. Assuming I get 6 cycles, that puts my total dose at 672mg. I don't know my "official" BSA, but per my math, at 6'5" and 205lbs, I am 2.26m2. That means I'll get about 297mg/m2, total.

According to the package insert:

"The probability of developing impaired myocardial function based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at 450 mg/m2 and 6 to 20% at 500 mg/m2.  The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m2."

In other words, my chance for heart failure is about 1-2%.  

It is difficult to tease out the precise percentages to side effects of doxorubicin by itself.  Chemo is usually given in combination.  The same package insert lists side effects of AC (Adriamycin and Cyclophosphamide) in breast cancer as a neat table, but I'm not getting cyclophosphamide.  It is safe to say, however, that doxorubicin can commonly cause complete hair loss, rash, photosensitivity, nausea, vomiting, mucositis, fever, chills, infertility, peripheral neurotoxicity, leukopenia/neutropenia, and malaise.  It has also been implicated in secondary leukemias.

How does it work?   Per the same package insert:

"The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin.  Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases.  The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin cytocidal activity.   

Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death.  Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both."

In other words,  the drug inserts itself into the genetic material of the cell and precludes cell division.  
This picture stolen from wikipedia shows how that might look.

Doxorubicin distributes very rapidly, and has a huge volume of distribution.  What this means in practical terms is that it very quickly finds itself in the tissues and not the bloodstream.  Comparing the package insert to other drug databases, it seems doxorubicin has extremely variable elimination (possibly multicompartmental), with a terminal half-life of anywhere from 20-54 hours.  This means it isn't even 97% "gone" until more than 11 days, potentially.   It is a substrate of 2D6 and 3A4 and a weak inhibitor of 2B6, 2D6, and 3A4.   It is also likely a substrate and inhibitor of p-glycoprotein.  (These are enzymes in the liver which metabolize drugs, and can be used to predict interactions.  PGP is found a few other places).


What else can doxorubicin be used for?   FDA approvals include: 

"Doxorubicin has been used successfully to produce regression in disseminated neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms’ tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin’s disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types.  

Doxorubicin is also indicated for use as a component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer." 

What else to say about doxorubicin?   Wikipedia has a nice history.  If I haven't cited it enough times, the Pfizer package insert for Adriamycin can be found here.  Chemocare also has a great website.