title: Pharmacokinetic-pharmacodynamic (PK-PD) modeling for a new antihypertensive agent (neutral metalloendopeptidase inhibitor SCH 42354) in patients with mild to moderate hypertension.
abstract: SCH 42354, a neutral metalloendopeptidase (NEP) inhibitor, is the pharmacologically active form of the prodrug SCH 42495. It exerts antihypertensive effects by potentiating atrial natriuretic peptide (ANP) activity through inhibition of its hydrolysis by NEP. The objective of this study was to characterize the pharmacokinetics (PK) and pharmacodynamics (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-blind, placebo controlled multiple-dose parallel group design. Plasma SCH 42354 concentration and diastolic blood pressure (DBP) data were used to develop a PK-PD model using two approaches. In the first (non-integrated) approach, the ¿link¿ model was used to predict effect-site concentrations, and was applied to data obtained at the 300 and 400 mg BID doses only; data at the other (lower) doses were not amenable to modeling because of high variability. Effect-site concentration and DBP data were then fit to a sigmoid Emax PD model. For the 300 mg BID dose, PD parameters were: maximum effect (Emax), 8.1 mmHg; no-drug effect (Eo), 3.6 mmHg; concentration corresponding to 50% of maximum response (EC50), 0.87 microgram x ml(-1); and gamma, 3.9. In the second (time-integrated) approach, plasma SCH 42354 concentration and effect data obtained over the entire dose range were integrated with respect to time. Average plasma concentration and DBP data were then fit to a simple Emax PD model. PD parameters obtained over the dose range were: Emax, 10.3 mmHg; Eo, 2.0 mmHg; and EC50 0.7 microgram x ml(-1). These were similar to the estimates obtained from the first approach, demonstrating that the integrated (average) data allow PK-PD modeling over the (entire) dose range. The analysis showed that, at steady-state, a 400 mg BID dose of SCH 42495 produced an approximate 10 mmHg decrease in DBP in hypertensive males; the average plasma SCH 42354 concentration attained at this dose was approximately 1.8 microgram x ml(-1).
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033-0530, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Fettner
authors.forename: S
authors.initials: S
authors.lastname: Pai
authors.forename: G R
authors.initials: GR
authors.lastname: Zhu
authors.forename: T
authors.initials: T
authors.lastname: Kosoglou
authors.forename: C R
authors.initials: CR
authors.lastname: Banfield
authors.forename: V
authors.initials: V
authors.lastname: Batra
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D010919:Placebos; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D010919:Placebos; D011355:Prodrugs; D011480:Protease Inhibitors; C069018:SCH 42495; C086374:CGS 26129; D008715:Methionine