Interpatient variability in elimination of anticancer drugs

The traditional method for individualizing an anti-cancer drug dose is based on body-surface area (BSA), calculated according to the Dubois formula using height and weight. In children, morphological criteria (BSA or weight) are a major component of inter-individual pharmacokinetic variability. In adults, clearance of anti-cancer drugs is poorly correlated with BSA, leading to wide variation in drug exposure within patients dosed by this method.

Hepatic and renal functions are the major determinants of drug elimination and have to be explored before administration of anticancer drugs. Renal dysfunction is easily assessed by determining serum creatinine, measuring or calculating creatinine clearance, or most accurately, by determining the clearance of radio-labelled EDTA. The impact of hepatic dysfunction on the drug elimination or metabolism is more difficult to estimate. Because of complex pathophysio-logical mechanisms of liver insufficiency, hepatic enzymes and serum bilirubin levels are often poor indicators of metabolic activity. Alternative hepatic function tests have limited value in predicting pharmacokinetics of chemotherapeutic drugs:

♦ Indocyanine green (a marker of hepatic blood flow)

♦ Antipyrine (a substrate marker for cytochrome P450 activity)

♦ Lorazepam (a substrate marker of hepatic glucuronidation) Practical considerations make these dynamic liver functions inappropriate for routine clinical practice. When metabolism of a drug is largely dependent on a unique catalytic enzyme, subpopulations of poor metabolizers may result from polymorphism in gene coding for the drug-metabolizing enzyme.

Advancing age also represents a cause of pharmacokinetic variability of many drugs. Ageing is characterized by a combination of various physiological disorders, including reduction of hepatic or renal blood flow, possible declines in microsomal activity, and frequent co-medication.

For some drugs, such as carboplatin, anthracyclines, and docetaxel, close relationships between patient characteristics and drug clearance have been established. Then, a priori adaptive dosing based on these characteristics is possible. For other drugs, such as methotrexate, 6-mercaptopurine, and 5-fluorouracil, dose optimization requires determination of plasma concentrations in each patient in order to adjust subsequent doses or to modulate current dose in case of continuous therapy. This approach—'adaptive dosing with feedback control'—requires certain logistics which limit its use for all drugs.

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