PHARMACODYNAMIC MONITORING OF IMMUNOSUPPRESSIVE DRUGS

Pharmacodynamic (PD) monitoring measures the biological response to a drug, which alone-or coupled with pharmacokinetics-provides a novel me thod for optimization of drug dosing. PD monitoring has been investiga ted by us and other investigators primarily for four immunosuppressive drugs: cyclosporine (CsA), azathioprine (AZA), mycophenolate mofetil (MMF), and rapamycin (RAPA). PD monitoring of CsA and MMF involves mea suring the activity of the enzymes calcineurin and inosine monophospha te dehydrogenase, respectively. The PD of AZA is assessed by measuring the activity of thiopurine methyltransferase, which is induced by a m etabolite of AZA, 6-mercaptopurine. The PD for RAPA involves measuring the activity of a P70 S6 kinase in lymphocytes. To date, the most det ailed studies have been performed with PD monitoring of CsA and MMF. S imilarities exist in the PD responses to CsA and MMF in renal-transpla nt patients. At trough concentrations in blood, both drugs reduce the activity of their target enzymes by only 50%; however, considerable in terpatient variability is evident. Throughout the dosing interval, the enzyme activities parallel the respective drug concentrations. AZA tr eatment of renal-transplant patients who exhibited an increase in thio purine methyltransferase activity from time of transplantation resulte d in fewer episodes of active rejection. Additional clinical trials ar e currently underway to relate various pharmacokinetics and PD paramet ers to clinical response, to ascertain which provides the best guide f or dosing. PD monitoring may provide an alternative approach to additi onal measurements of drug concentrations.