Date: October 20, 2003
by Chaya Venkat
As every cancer patient knows, chemotherapy is a double-edged sword. It holds the promise of survival, the possibility of a cure, and a way of defeating the cancer. It also has a darker side, the fear of debilitating side effects, systemic toxicity that can compromise liver and kidney function, potential for secondary malignancies, and a host of other serious health issues. One particular fear that is often not voiced is the risk of "chemo brain", a term that encompasses partial loss of memory and cognitive functions. Undergoing chemotherapy is a very stressful experience to many cancer patients, and for older patients the frequent trips to the hospital or the oncologist's office to receive intravenous infusions of chemotherapy may present practical problems.
Modern chemotherapy drugs are becoming more effective and varied, with better toxicity profiles. Nevertheless, oncologists still talk in terms of "maximum tolerable dosages" and "non-overlapping toxicities" in defining chemotherapy regimens, to maximize cancer cell kill. It is well known that the systemic toxicity and the not-so-pleasant side effects of many drugs are dose dependent.
The following is a link to information provided by the Center for Drug Evaluation and Research (CDER) on dose dependent toxicity for a standard CLL drug, fludarabine: Fludarabine dosage dependent toxicity.
Here is where the method of drug delivery becomes important, and how the drug is administered becomes as important as the identity of the drug. We have seen lots of evidence, for example, that slow infusion of Rituxan over several hours is better than doing it quickly. The slower approach is likely to bore you silly but the fast approach may give you "infusion related side-effects", that means in plain English: chills, rigors, nausea, low blood pressure, etc.
Most chemotherapy drugs are given via intravenous administration, subcutaneous injection, or as orally delivered pills and capsules. These three methods are described below, as well as the advantages and some potential problems associated with them. But before we do that, it might help to understand a bit more about the lymphatic system. Blood circulation is the sexy subject, but for some reason not too many people think about the equally important lymphatic system. I guess all that changes when you hear the fateful words "chronic lymphocytic leukemia".
Most of us are familiar with blood circulation, how the heart pumps the blood to the lungs where it picks up life-giving oxygen which is then transported to all the other parts of the body. Blood vessels and narrower capillaries run through every part of our body. In addition, blood is also the transport mechanism for nutrients absorbed from your stomach and gut.
Blood capillaries are like very fine but leaky tubes, which leak nutrients, fats, lipids, pathogens and a host of other stuff into the interstitial space between the living cells that surround the capillaries. Cells absorb what they need from this nourishing liquid surrounding them. They also put back into this 'soup' all their waste products. This milky colored liquid surrounding each cell of our body is called lymph.
The lymphatic system closely parallels the blood system. Where ever blood vessels and capillaries are found, lymphatic vessels and lymph capillaries are also present. The major function of the lymphatic system is to act as a drainage system throughout the body returning excess fluid, protein and waste products from the tissue space into the blood circulatory system. In addition, it also maintains the body's water balance. Certain large molecules including long chain fatty acids, triglycerides, cholesterol, fat soluble vitamins, drugs, and poisons, are transported via the lymphatic system. Eventually, all of the lymph draining from all over the body reaches the region of your neck, and the lymph is poured back into the blood stream at the junction of the jugular and subclavian veins, the only location where it does so. Unlike blood circulation, lymphatic flow happens without any pumping action, under gravity flow and due to large muscle activity. For this reason, lymph flow occurs at low pressure, unlike blood circulation, and it is very slow compared to blood circulation. The rate at which lymph is returned back to the large jugular and subclavian veins is only about 3 liters per day. In contrast, blood in your body literally rushes around, finishing a full circuit in a few minutes.
All along the lymphatic system there are attached little sacs about the size of a large pea, that act as reservoirs. These are the lymph nodes. It is through the actions of lymphatic system which includes the spleen, the thymus, lymph nodes and lymph ducts that the body is able to fight infection and to ward off invasion from foreign invaders. Lymph plays an important role in the immune system, and the term "lymphocytes" is used to describe B-cells and T-cells, because these two important cell lines of the immune system are mainly located in the lymphatic system. When you get your periodic blood test, the lymphocyte counts reported in the CBC is only an accounting of the lymphocytes that happen to be traveling through the blood stream at that particular time. As we have discussed before, less than 10% of the lymphocytes are normally present in the blood, the rest of them are in the many nooks and crannies of the lymphatic system. For this reason, WBC results obtained from blood tests can sometimes be misleading. The real action is not taking place in the blood, it is happening in the lymphatic system of your body.
This is probably the most common method of administrations for many of the well known chemotherapy drugs. Typically, the amount of the drug calculated for the patient's body size (based on BSA or body surface area) is dissolved in sterile saline solution and then put into a plastic bag, hung from a tall pole, and fed through a catheter into a vein into your arm, by gravity driven flow. Intravenous administration is almost always done in the hospital or by oncologists on an outpatient basis. As a practical matter, frequent IV administration of drugs becomes a logistics problem for patients and takes up resources such as the time of oncology nursing staff, hospital bed capacity, etc.
A detailed backgrounder on Intravenous (IV) Therapy is available at Wikipedia. It describes the different intravenous access methods — so if you want to know more or simply need to consider ports or PICC lines or some other variation on the theme, please do look up this useful reference.
With intravenous administration, the drug is available in the blood as soon as it is administered. If you have high level of cancer cells in your peripheral blood, and the chemotherapy drug is administered quickly, the rapid reaction between the drug and cancer cells may cause serious infusion-related side effects. An extreme form of this is seen in Tumor Lysis Syndrome where the cancer cells are killed in large numbers over a short period of time, overwhelming your body's capacity to get rid of the debris from the cell kill. Tumor Lysis Syndrome can be quite dangerous and toxic to the kidneys, liver and other organs of your body, and can even prove fatal in some situations. Pre-medications such as allopurinol, cimetidine, benadryl are used to control such run-away scenarios. (Here is a useful link to the Wikipedia entry on Tumor Lysis Syndrome.)
As we said, blood zips around quite rapidly within your body, completing a full circuit in a matter of minutes. The high pressure pumping action of the heart exposes all organs of your body to the drug infused. In particular, the drug introduced into the blood stream quickly reaches your liver. The liver is a critical organ of the body that is involved in detoxification and elimination of dangerous materials in the blood. Since most chemotherapy drugs are toxic by definition, your liver may convert a significant portion of the drug into inactive or less active forms (metabolites) prior to elimination from your body. This is a well known mechanism whereby the actual amount of the drug available to do you any good, the bioavailability of the drug, is less than the amount administered via intravenous infusion.
It is only after the drug is fully distributed through the entire blood circulatory system and body tissue, that the drug gradually seeps from the blood capillaries into the space between cells, into the lymph pool surrounding each cell. If the lymphatic system is the main area where the tumor or disease resides, it is ironic that using IV administration in such cases means the drug reaches the lymphatic system last in line, after much of the drug has been taken up by other tissues and organs, and partially eliminated via liver detoxification.
Many drugs used routinely in chemotherapy are anti-platelet and anti-red blood cells. In other words, targeting the drug delivery to the blood circulatory system means potential destruction of these valuable cell lines in the blood, ahead of the drug becoming available in the lymphatic system where it is needed and can do some good.
There is another reason why you may not want rapid "spiking" of the drug concentration in your blood plasma. Some of you may have heard of the "blood-brain barrier", which keeps out most of the toxic compounds that may be circulating in the blood. As the most critical organ of your body, this barrier is an extra precaution to protect the precious brain tissue. Well, no precaution is 100% perfect. At high peak concentration, chemotherapy drugs may overwhelm the blood-brain-barrier and allow traces of the drug into brain tissue. This is the scenario proposed to explain so-called "chemo brain" effect. Not all doctors agree about this, but many patients swear that chemo-brain is a real phenomenon, and that it causes some loss in the level of memory and cognition functions.
Because of the very efficient systems of the body, toxins are often cleared quickly from the body. Normally, this is something to be desired, it keeps you from getting poisoned. However, our perspective is a little different when it comes to chemotherapy drugs, since they are there for a very serious purpose of killing cancer cells. Some of the drugs have short residence time in your body when they are introduced by intravenous administration, measured in hours or even less. Without frequent administration, IV drug concentration in the blood plasma is often not uniform over time. Instead the high concentration peaks over a short period immediately after the infusion, and is followed by periods where insufficient amount of the drug is available for therapeutic purposes. Such large fluctuations in plasma concentration of drugs is not considered desirable.
Drugs delivered orally as a pill or capsule are usually the most familiar method of drug administration. The bottle specifies how many pills you should take, how often, with or without food, etc. All of these are very important details as they impact the efficiency of drug delivery, and the process depends very much on your following the instructions specified. Oral administration has some very specific problems associated with it.
Drug formulations have to take into account the very highly acid environment of your stomach, and the general digestive processes in the stomach, intestines etc. Only a percentage of the drug actually makes it unchanged into the blood circulation, the rest is excreted by normal processes. Drug formulations have also to take into account the effect of partially digested metabolites of the original drug getting into the blood stream, such metabolites may be less effective, or even toxic to the body. Both the percent of the drug that is transported into the blood stream, as well as the concentration and nature of the metabolites depend on when the drug is taken, with or without food, as well as factors such as stomach pH, intestinal flora and fauna etc., which are highly variable between patients. A definition of the "correct dosage" is therefore hard to come by, and this explains why the same dosage may be more or less effective in different individuals.
If the drug causes stomach upset, nausea, etc., after oral ingestion, this may be sufficient to influence patient acceptance of the medication and reduce compliance with guidelines regarding dosage and frequency. Patient compliance is one of the biggest problems associated with oral drug delivery.
Once the drug (and its metabolites) enters into your blood stream after its journey through your stomach and gut, it is immediately transported via the portal vein to the liver. Since majority of drugs administered are by definition "toxic substances", the liver works very hard to convert them, detoxify them and remove them from blood circulation. This has the effect of both reducing the amount of drug available for therapeutic purposes, as well as increasing the work load on the liver. Liver toxicity is a crucial issue to consider in defining safe dosage limits, especially in the case of cancer patients who are likely to have impaired liver function to begin with. The loss of a significant portion of the drug to excretion from the digestive system and the conversion, detoxification and elimination of a significant portion of the drug in the liver constitute what is termed "first pass metabolism losses" associated with oral administration of drugs. Because of first pass metabolism losses, the actual amount of the drug available to do its job in the blood plasma after oral administration is rarely equal to that of intravenous administration. In order to compensate for this loss, oral dosages are usually higher than IV dosages.
A clear example of this is seen in the case of fludarabine. The standard dose of this very important chemotherapy drug by IV administration is 25 mg/M2. Fludarabine has recently been approved for oral delivery in Europe. The standard dosage in the case of oral delivery is between 40 to 45 mg/M2, reflecting oral bioavailablity in the range of 54%. (See the first abstract below.)
Once the drug enters your body, all of it has to be eventually excreted and eliminated by your body. Oral administration compared to IV administration requires, in this example, that the body deal with 60% - 80% more fludarabine, in order to achieve the same therapeutic benefit. The "real cost" of higher doses of chemotherapy drugs such as fludarabine necessary for oral administration is not in the cost of materials or cost of manufacturing of the drug. The real cost is paid by the patients, in terms of systemic and liver toxicity absorbed by the body in the process of dealing with the higher amount of this toxic drug.
Are there any advantages to offset this very real cost? Yes. From the patient's perspective, self administration of a pill is less of a hassle than going to the doctor's office for an IV infusion. For people juggling the many conflicting priorities of family and work, this is a real plus. It is also of value to older patients who may have trouble with making the frequent trips. These are undeniable logistics advantages, for the patient. But the major benefits, in my opinion, are in reduced costs to the healthcare system. With oral administration, the oncologist gives you a prescription to get filled at the pharmacy and you go away to do your thing. With IV administration, there is a lot more cost associated with nursing staff, office staff, supervisors, etc. Don't get me wrong, reduced costs to the healthcare system are not to be sneezed at. After all, we are all smart enough to figure out that there is only one pocket, one wallet, from which the money comes to pay for everything. Yours, as consumer and taxpayer.
I suspect a great deal of the comfort associated with good old chlorambucil therapy is that it is an orally available drug. No muss, no fuss. When CLL was defined as "an old man's disease", and there was no hope of long term remissions let alone cures, it made sense to minimize hassles all around. Watch & Wait, followed by a prescription for chlorambucil when the B-symptoms got really bad, that was just about right. I will let you decide if it is still just right for you, today, in view of currently available options (and what we pay for our healthcare).
One last point, as described in the discussion of IV administration, in the case of oral administration too the drug reaches the lymphatic system after it is well dispersed through out the blood circulation and body organs and tissues, and been worked over by your liver. This is clearly not desirable if the targeted cancer or disease resides mainly in the lymphatic system, as in our situation.
A description of the advantages and disadvantages of oral administration may be found at A First Course in Pharmacokinetics and Biopharmaceutics by David A. Bourne, PhD., at Oklahoma University College of Pharmacy. You can, of course, go on to examine other pages at this site covering topics like Buccal/Sublingual and Rectal administration. For a discussion of buccal/sublingual administration of EGCG, please read Harvey's Chocolates.
In this method of drug delivery, all of the drug is administered as an injection at one shot ("bolus") just under the skin. The injected drug gradually diffuses from the location of the injection into the blood and lymphatic systems, over a several hours. This form of drug delivery may have fewer complications from infusion related toxicity, since not all of the drug enters the blood circulation over a short period of time. There is a limit as to how much drug can be injected at one time as a bolus, and administration of large doses often leads to pain, rash or other dermal problems at the site of the injection.
A detailed pamphlet on subcutaneous injections in PDF form is available from the National Institutes of Health. It provides background, detailed instructions and some useful tips. It will be particularly useful to patients who elect to self-administer any part of their therapy in this form and generally helpful to anyone who wants to understand this important delivery mechanism.
The effect of the size of the drug molecule makes a difference. Remember, we said blood capillaries are like fine tubes with very small pores through which stuff passes from the blood system into the lymph pools around cells. Drugs that are composed of small, water soluble molecules are readily taken up by the blood circulation. Larger molecules, or those that are more fat soluble, do not find it easy to get in through the fine holes in the blood capillaries. These types of drug molecules stay in the lymphatic system, gradually working their way through the many lymph nodes and the like, until they are finally returned back into the blood circulation when the lymph drains back at the junction of your jugular and subclavian veins.
Sounds interesting, right? If even a small percent of the drug travels through the lymphatic system, as opposed to the general blood circulation, you might expect to get more bang for the buck, right? Right. The second abstract below shows that subcutaneous injection is more efficient than intravenous administration, for fludarabine administration in Lupus. The efficiency of oral, IV and subcutaneous administration are, respectively, 54: 100: 105.
Methods of Drug Delivery
Copyright © CLL Topics, Inc., 2003
I don't know about you folks, but my interest level goes up when I see something like this. Hmmm, if we can do better than IV infusion of fludarabine by means of subcutaneous injection, possibly because a small percentage of this drug is now transported by the lymphatic system, is there any way of making that effect even more pronounced? Is there some way we can make most of the fludarabine travel only in the lymphatic system, not get into the blood stream at all, or only to a very small degree? Would that mean the drug is more efficiently delivered where it can do most good, and not get gobbled up by the liver, or cause systemic toxicity to other tissues in your body? Would this mean we can reduce the drug dose and still get the same therapeutic benefit, if we could persuade the fludarabine to spend more time in the lymphatic system instead of gallivanting around in the blood circulation? Would this approach, if we can pull it off, do a better job of clearing out bulky lymph nodes and spleen, give better remissions to advanced stage patients with heavy tumor burden, since lymph nodes and spleen are part of the lymphatic system? Would this approach reduce the sharp concentration spikes of the drug in your blood, and therefore reduce the worry of the drug crossing the sacred blood-brain barrier, and take away your excuse of "chemo-brain" for not doing the stuff on your honey-do list?
Stay tuned. The story gets interesting right about here. Who ever said all we can do is sit on our backsides, watching and worrying, helpless cancer victims waiting for the axe to fall?
Plosker G, Figgitt D.
Adis International Limited, Auckland, New Zealand.
Fludarabine is an antimetabolite antineoplastic agent used in the treatment of various haematological malignancies, particularly B-cell chronic lymphocytic leukaemia (CLL). An oral formulation of fludarabine has recently become available in the majority of European countries for the treatment of patients with relapsed or refractory B-cell CLL after initial treatment with an alkylating agent-based regimen. It is the first oral formulation of a purine analogue available for clinical use in B-cell CLL. Pharmacokinetic studies evaluating the bioavailability of oral fludarabine indicate that an oral dose of 40 mg/m(2)/day would provide similar systemic drug exposure to the standard intravenous dose of 25 mg/m(2)/day. A phase II study evaluated the clinical efficacy of six to eight cycles of oral fludarabine 40 mg/m(2)/day for 5 days of each 28-day cycle in 78 patients with previously treated B-cell CLL. Depending on the criteria used, the overall response rate was 46.2% (20.5% complete response [CR], 25.6% partial response [PR]) or 51.3% (17.9% CR, 33.3% PR). These results were similar to the 48% overall response rate reported in a similar historical control group treated with intravenous fludarabine. Myelosuppression (WHO grade 3 or 4) was the most frequently reported adverse effect with oral fludarabine therapy. Other common adverse effects included infection and gastrointestinal disturbances, although these were usually of mild to moderate severity (WHO grade 1 or 2). Overall, the tolerability profile of oral fludarabine is similar to that of the intravenous formulation.
Pharmacotherapy. 2001 May;21(5):528-33.
Fludarabine pharmacokinetics after subcutaneous and intravenous administration in patients with lupus nephritis.
Kuo GM, Boumpas DT, Illei GG, Yarboro C, Pucino F, Burstein AH.
Department of Pharmacy, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD.
STUDY OBJECTIVE: To compare the pharmacokinetics of subcutaneous and intravenous fludarabine in patients with lupus nephritis.
DESIGN: Open-label, randomized, crossover trial conducted with a phase I-II trial.
SETTING: Government research hospital.
PATIENTS: Five patients with lupus nephritis.
INTERVENTION: Fludarabine 30 mg/m2/day was administered either subcutaneously or as a 0.5-hour intravenous infusion for 3 consecutive days. All patients received oral cyclophosphamide 0.5 g/m2 on the first day of each cycle.
MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected before and 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the first dose. Urine was collected at 6-hour intervals for 24 hours. Plasma and urine were analyzed for fluoro-arabinofuranosyladenine (F-ara-A), fludarabine's main metabolite, using high-performance liquid chromatography. Compartmental techniques were used to determine the pharmacokinetics of F-ara-A; a linear two-compartment model best described them. Comparison of the pharmacokinetics between subcutaneous and intravenous administration was done by using a Wilcoxon signed rank test. No significant differences were found between subcutaneous and intravenous administration in median (interquartile range) maximum concentrations of 0.51 (0.38-0.56) and 0.75 (0.52-0.91) mg/L, respectively, or in fitted area under the concentration-time curves from 0-24 hours of 4.65 (4.17-4.98) and 4.55 (3.5-4.94) mg x hour/L, respectively. Bioavailability of F-ara-A after subcutaneous dosing was approximately 105% of the bioavailability after intravenous administration. Differences in renal clearance and percentage of dose excreted in urine for subcutaneous and intravenous administration were nonsignificant. No injection site reactions were seen with subcutaneous dosing.
CONCLUSION: Subcutaneous and intravenous administration of fludarabine appear to have similar pharmacokinetics in patients with lupus nephritis. Subcutaneous injection may offer a convenient alternative to intravenous administration.
Cancer Invest. 2002;20(7-8):904-13.
The pharmacokinetics and pharmacodynamics of fludarabine phosphate in patients with renal impairment: a prospective dose adjustment study.
Lichtman SM, Etcubanas E, Budman DR, Eisenberg P, Zervos G, D'Amico P, O'Mara V, Musgrave K, Cascella P, Melikian A, Hinderling PH, Ferrer JM, Williams GJ.
Don Monti Division of Medical Oncology, North Shore University Hospital-NYU School of Medicine, 300 Community Drive, Manhasset, NY.
A significant number of chronic lymphocytic leukemia, follicular non-Hodgkin's lymphoma and Waldenstrom's macroglobulinemia patients, treated with fludarabine phosphate (fludarabine), are elderly with diminished renal function. Since the kidney eliminates approximately 60% of fludarabine's primary metabolite (F-ara-A), dose modification is necessary for all patients with impaired renal function including elderly patients. In this study, 22 patients with varying levels of renal function received a single intravenous dose of fludarabine (25 mg/m3), followed one week later by five (one per day) doses that were adjusted according to three predefined creatinine clearance (CLcr) levels. Relationships between renal function and F-ara-A clearance, F-ara-A exposure and F-ara-A--related toxicities were examined. The results demonstrate that total F-ara-A clearance correlated with CLcr and that F-ara-A exposure levels and patient toxicity profiles were similar across treatment groups.
IN CONCLUSION: The CLcr-based fludarabine dose adjustments used in this study provided reasonably equivalent F-ara-A exposure with acceptable safety in patients with varying degrees of renal function.
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