Examples of dosing strategies for individual therapy

Carboplatin

Carboplatin is mainly eliminated by the kidney. Egorin first established two relationships:

♦ First: between carboplatin clearance and measured creatinine clearance.

♦ Second: between the AUC and the percentage decrease in platelets following carboplatin administration as a single agent.

By combining these, a formula was derived for individual dose calculation according to measured creatinine clearance and desired platelet count at nadir. The concept of optimum AUC for carboplatin was demonstrated for treatment of ovarian and testicular cancers.

Calvert developed a formula to allow a dose of carboplatin to be calculated in order to achieve a target AUC:

Dose (mg) = AUC x (GFR + 25 ml/min) with GFR determined by isotopic measurement of 51Cr-EDTA clearance. The value of 25 ml/min corresponds to the mean non-renal clearance of carboplatin.

The carboplatin target AUC must be chosen with reference to any other cytotoxics given in combination. Drugs (e.g. cyclophos-phamide) potentiate the haematological toxicity of carboplatin, but with others such as paclitaxel it is safe to administer an AUC similar to that of carboplatin administered alone. Moreover, patients without prior exposure to chemotherapy may support a larger AUC than those who are heavily pre-treated.

Anthracyclines and taxanes

In the case of impaired hepatic function, guidelines have been proposed for doxorubicin dosage reduction as a function of serum biliru-bin level: dose reductions by 50%, 75%, or 100% are recommended when bilirubin exceeds 12, 30, or 50 mg/l. For docetaxel, five co-variables (age > 70 years, hypoalbuminaemia, elevation of a1-glyco-

protein, and raised ALT and AST) are predictive of reduced clearance. Since correlation was found between docetaxel clearance and risk of severe neutropenia, these parameters may allow prediction of patients with high risk of toxicity and application of rational dose reduction.

Methotrexate

Monitoring of plasma drug concentration in patients receiving highdose methotrexate is routinely performed. High levels 48 hours after the intravenous infusion and thereafter are associated with a risk of serious toxicity. For these patients with decreased methotrexate clearance and/or a large volume of distribution of the drug (generally due to the presence of a 'third space'—pleural effusion or ascites), folinic acid rescue is administered at a dosage adjusted according to methotrexate plasma levels.

Mercaptopurine

The effect of mercaptopurine is dependent on formation of the active 6-thioguanine nucleotide (6-TGN) metabolites. This anabolic pathway competes with the catabolic pathway mediated by thiopurine methyltransferase. The latter enzyme expression is subject to genetic polymorphism with about 10% of patients having intermediate activity and about 1 in 300 inheriting a deficiency who are exposed to prohibitive toxicity if standard mercaptopurine dosage is administered. The concentration of 6-TGN inside red blood cells has been shown to be an independent and important predictor of treatment outcome of patients taking daily oral mercaptopurine.

Although no definite recommendation on how to individualize treatment can be given, monitoring of erythrocyte 6-TGN should identify patients with a high-risk pharmacokinetic profile (low levels of 6-TGN), allowing assessment of patient compliance.

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