PHARMACOKINETIC PHARMACOKINETIC (PK-PD) MODELING FOR A NEW ANTIHYPERTENSIVE AGENT (NEUTRAL METALLOENDOPEPTIDASE INHIBITOR SCH-42354) IN PATIENTS WITH MILD-TO-MODERATE HYPERTENSION

SCH 42354, a neutral metalloendopeptidase (NEP) inhibitor, is the phar macologically active form of the prodrug SCH 42495. It exerts antihype rtensive effects by potentiating atrial natriuretic peptide (ANP) acti vity through inhibition of its hydrolysis by NEP. The objective of thi s study was to characterize the pharmacokinetics (PK) and pharmacodyna mics (PD) of SCH 42354 in hypertensive males. SCH 42495 12.5 to 400 mg was administered orally to hypertensive men twice daily in a double-b lind, placebo controlled multiple-dose parallel group design. Plasma S CH 42354 concentration and diastolic blood pressure (DBP) data were us ed to develop a PK-PD model using two approaches. In the first (non-in tegrated) approach, the ''link'' model was used to predict effect-site concentrations, and was applied to data obtained at the 300 and 400 m g BID doses only; data at the other (lower) doses were not amenable to modeling because of high variability Effect-site concentration and DB P data were then fit to a sigmoid E(max) PD model. For the 300 mg BID dose, PD parameters were: maximum effect (E(max)), 8.1 mmHg; no-drug e ffect (Eo), 3.6 mmHg; concentration corresponding to 50% of maximum re sponse (EC(50)), 0.87 mu g . ml(-1); and gamma, 3.9. In the second (ti me-integrated) approach, plasma SCH 42354 concentration and effect dat a obtained over the entire dose range were integrated with respect to time. Average plasma concentration and DBP data were then fit to a sim ple E(max) PD model. PD parameters obtained over the dose range were: E(max), 10.3 mmHg; Eo, 2.0 mmHg; and EC(50), 0.7 mu g . ml(-1). These were similar to the estimates obtained from the first approach, demons trating that the integrated (average) data allow PK-PD modeling over t he (entire) dose range. The analysis showed that, at steady-state, a 4 00 mg BID dose of SCH 42495 produced an approximate 10 mmHg decrease i n DBP in hypertensive males; the average plasma SCH 42354 concentratio n attained at this dose was approximately 1.8 mu g . ml(-1).