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.