Pharmacodynamic-pharmacokinetic relationships and therapeutic drug monitoring

Pharmacokinetic-pharmacodynamic studies are becoming increasingly important in the development of new anti-cancer drugs. The Hill maximal effect model describes a sigmoidal dose-response relationship and has been applied to analyses of both haematological and non-haematological toxicity. This review discusses several approaches to population pharmacodynamics, including the two stage, NONMEM, and non-parametric approaches. Pharmacodynamic models for the haematological toxicity of amonafide, carboplatin, doxorubicin, etoposide, HMBA and menogaril are discussed, as are models for non-haematological toxicity. Adaptive control methods and therapeutic drug monitoring are useful in dosing drugs with narrow therapeutic windows, but the indications for using such strategies should be carefully selected. Models for 5FU, HMBA, methotrexate, 6-mercaptopurine, carboplatin and etoposide are discussed. Limited sampling strategies can facilitate the completion of pharmacokinetic studies and should be developed during phase I testing of new compounds. A new area of future importance is the investigation of drugs with active metabolites, such as the anthracyclines and amonafide.