Clinical Predictors Of Toxic Effects

When we administer a drug to a patient, we assume that the patient will achieve maximal benefit from the drug with minimal toxicity. As drugs used for the treatment of cancer have the narrowest therapeutic index in all of medicine, delivering

Variables:

Patient genes Tumor genes

Non-responders

Toxic responders

Responders

Drug

Variables:

Age Diet Illness

Drug

Non-responders

Patient genes Tumor genes

Toxic responders

Toxic non-responders

FIGURE 1 Variability of response.

Current clinical ability to predict response FIGURE 2 Value of pharmacogenetic test is high in cancer. Source: Adapted from Ref. 37.

the right dose is crucial if morbidity is to be avoided. Thus, understanding the mechanisms behind the variability in response and toxicity profile seen with these medications is even more important when dealing with a cancer patient. At the clinical level, variability of the drug can be understood by considering both its pharmacokinetic and pharmacodynamic profiles (Fig. 3). Pharmacokinetics, simply described, is "what the body does to the drug." It describes the relationship between time and plasma concentration of the drug metabolites being affected by variables such as absorption, distribution, metabolism, and excretion of the drug. Pharmacodynamics tells us "what the drug does to the body" in terms of effect (drug response and toxicity) allowing us to monitor events clinically that take place at the molecular level.

Pharmacokinetics and pharmacodynamics can be considered as a spectrum of continuous events starting with the ingestion of the drug and ending with a clinical effect seen in the patient. Thus, variability in the processes of absorption, distribution, metabolism, and excretion may be associated with either an increase or a decrease in a pharmacodynamic effect. Figure 4 illustrates the relationship between the two parameters. As the plasma concentration of the drug increases, so does its effect, illustrating how most of the toxicity that a patient experiences is not idiosyncratic but predictable on a concentration-response curve.

Pharmacokinetics Pharmacodynamics

Diagnosis

Drug administration

Pharmacokinetics Pharmacodynamics

Drug administration

Absorption

Distribution

Drug Effect

Metabolism

Drug Toxicity

Excretion

FIGURE 3 Drug processing.

FIGURE 4 Mathematical representation of pharmacokinetic and pharmacodynamic relationship.

0.1 1 10 100 Relative Concentration (LOG scale)

FIGURE 4 Mathematical representation of pharmacokinetic and pharmacodynamic relationship.

Concentrations of drugs will predictably be altered in a number of special population groups (Table 1). Patients with organ dysfunction will be unable to metabolize or excrete (depending on the drug administered) drugs properly resulting in either an increase or a decrease in effect (response and toxicity). One such example is the use of carboplatin in patients with renal dysfunction. Carboplatin is excreted primarily by the kidney. Early pharmacological studies of carboplatin demonstrated a close relationship between its thrombocytopenic effect and the area under the curve (AUC) in the individual, a parameter that is closely related to the renal function. On the basis of these observations, a number of formulas (6,7) have been derived using creatinine clearance either to predict the percentage change in platelet count or to determine the target AUC, thereby avoiding unacceptable throm-bocytopenia while maximizing dose intensity in the individual being treated.

Taxanes are primarily metabolized and excreted in the liver with their main hematological toxicity being neutropenia. Patients with hepatic dysfunction are particularly sensitive to the taxanes, experiencing severe neutropenia if given regular doses (Fig. 5). Liver function tests, however, are not very reliable for individualized dosing, but this could be improved upon by testing the function of specific enzymes, which would be more accurate. However, such tests are not readily available. There are two tests that can be used to evaluate the activity of the hepatic isoenzyme CYP3A that is involved in the metabolism of docetaxel. They include the midazolam clearance test and the C14 erythromycin breath test; however, both are not routinely used in clinical practice. Currently in the clinic, we rely upon

TABLE 1 Populations with Altered PK/PD

Groups

Examples

Renal dysfunction

Carboplatin, cisplatin

Hepatic dysfunction

Paclitaxel, docetaxel

Hypoalbuminemia

Coumadin, paclitaxel, docetaxel

Elderly patients

Fewer reserves

Obese patients

Increased volume of distribution, fatty liver

Female patients

Less clearance of gemcitabine, doxorubicin

FIGURE 5 Relationship of paclitaxel and neutropenia.

FIGURE 5 Relationship of paclitaxel and neutropenia.

basic liver function tests; although inconsistent, they have been useful in preventing excessive toxicity with taxanes. In addition, due to the significant amount of plasma protein binding of taxanes, patients with low protein levels are also more sensitive to taxanes.

Elderly patients also represent a special population group where individual dosing is important due to reduced physiological reserves, especially in terms of both hepatic and renal function. In addition, interindividual variability plays a role in this group of patients as illustrated by the paclitaxel pharmacokinetic trial conducted by CALGB (8). This prospective study looked at the pharmacokinetic parameters and toxicity profile of paclitaxel administered to patients greater than 55 years of age. The study showed that with increasing age there was a decrease in total body clearance of paclitaxel, an increase in AUC, and an increase in grades 3 and 4 neutropenia. However, the altered pharmacokinetic and pharmaco-dynamic parameters did not translate into a statistically significant increase in the rate of febrile neutropenia or hospitalization. More studies are thus needed before we can make definitive recommendations about individual dosing strategies for elderly patients.

Consideration of patient weight in individual dosing of drugs can also present a problem. Dosing drugs in patients who are obese using actual body weight or ideal body weight may lead to either overdosing or underdosing, respectively, both of which will alter the pharmacodynamic effect of the administered drug. Patient gender is also important, although it is not routinely considered in the clinic when administering chemotherapeutic agents. It is well known that the clearance of certain agents such as gemcitabine and doxorubicin is 20% less in female patients and could certainly account for their increased sensitivity.

Thus, the first step to individualizing therapy is to consider dose modification based on simple clinical variables that influence the various parameters of the

TABLE 2 Genes Affecting Therapeutic Outcome

Gene

Malignancy

Estrogen receptor Progesterone receptor HER2/neu overexpression p53

BCR/ABL

ALL1

AML1

PML-RARA

MDR1

Thymidylate synthase

Colon cancer

Breast Breast Breast Breast

Leukemia Leukemia Leukemia Leukemia Leukemia Leukemia pharmacokinetic profile of a drug. Usually, sophisticated tests are not required for this, underlying the importance of a good clinical assessment of a patient.

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