PK PD MODELING OF HIGH-DOSE DILTIAZEM - ABSORPTION-RATE DEPENDENCY OFTHE HYSTERESIS LOOP/

To investigate bioequivalence of 2 different sustained-release diltiaz em formulations the preparations each containing 180 mg diltiazem-HCl were given to 20 healthy male volunteers in an open, randomized. 2-way crossover design. Blood samples were taken before drug administration and at 14 times until 30 hours post application. 12-lead ECGs were re corded at the same time points, and atrioventricular conduction time w as monitored as a safety parameter, Plasma samples of 8 subjects were assayed by HPLC. Peak values of plasma concentrations and prolongation of the PQ interval were taken from the plasma concentration or ECG da ta directly, AUCs of pharmacokinetic and pharmacodynamic effects were calculated bf the linear trapezoidal rule, MRTs were calculated as the first moment over AUC. Bioequivalence was tested according to Schuirm an (ratios of parameters and shortest 90% confidence intervals) using pharmacokinetic and pharmacodynamic data sets. Relative bioavailabilit y of the test preparation with respect to AUC(0-30) was 110% with the 90% confidence interval ranging from 100 to 130%. Bioavailability with respect to C-max was significantly higher (190%) with a 90% confidenc e interval not even including 100%, Consequently, MRT was significantl y lower with the test preparation (80%), again with a confidence inter val not including unity. Relative bioavailability of the test product in terms of pharmacodynamic parameters was 160% in the extent of the e ffect (AUEC(0-10)), 190% even with the rate of the effect (E-max) and 80% with the mean residence time (MRTE). All parameters differ signifi cantly between the products, Bioinequivalence was therefore concluded from these results. The functional relationship between pharmacokineti c and pharmacodynamic parameters could be described by hysteresis leap s, however, with a clockwise rotation. This cannot be explained in the classical way by the time-lag between central and effect compartments , Two alternative conceivable explanations, namely formation of antago nistic metabolites or downregulation, were tested for plausibility. A comparison of the present results to literature data favors the model of downregulation/tolerance development. This model is additionally su pported by the finding that the shape of the hysteresis is dependent o n the absorption rate of diltiazem, calculated as mean input time acco rding to MIT = MRT - 1/lambda(z). It is concluded that acute tolerance develops at least with the electrophysiological action of diltiazem a fter oral application and that the extent of tolerance development inc reases when decreasing its absorption rate. Bioequivalence assessment of diltiazem is possible using pharmacodynamic parameters, however, si nce PK/PD relationships are influenced by the absorption rate, extent parameters may be misinterpreted when rate parameters of the test form ulations are different.