Systemic exposure of most drugs varies from 4 to 10 fold between individuals including oral cancer agents. The cause for the variation are genetic and (therefore fixed throughout a person’s life) and environmental due to drug interactions, variation in absorption, issues with drug elimination due to disease (which can vary over time).
Many oncology drugs have a narrow therapeutic index meaning the drug level that causes harm is similar to that which gives the anticancer effect. Body surface area is used to try and dose individualise parentally administered chemotherapy but this only reduces variation by about 20%. Oral cancer therapies are usually given as a fixed dose, with no attempt to individualise. Subsequently, the systemic exposure in a significant proportion of patients may be too high, leading to toxicity or too low, leading in ineffective anticancer effect. Guidelines exist for dose reduction in the presence of toxicity but few exist for dose increase in the absence of toxicity. Unlike other areas of medicine (antiepileptics, digoxin, transplant immunosupressives), therapeutic drug monitoring is not utilised for anticancer drugs.
Issues regarding dose will be explained by using two examples – tamoxifen and sunitinib. Our studies have shown that for tamoxifen, low blood levels occur in up to 25% of patients, cannot be accurately predicted by CYP2D6 genotype or the presence of hot flushes, but can be monitored by measuring endoxifen blood levels allowing therapeutic levels to be achieved in over 95%. Sunitinib is used to treat renal cell cancer and a substantial proportion of patients have excessive toxicity leading to dose reduction below the recommended dose. We have shown that toxicity-adjusted dosing (using target toxicity to imply and adequate drug level) is a realistic option and gives a three-fold range of dose and is associated with therapeutic levels in the majority of patients.