Population pharmacokinetic and pharmacodynamic modelling of the effects of nicorandil in the treatment of acute heart failure

Abstract

Aims: The aims of the study were 1) to evaluate the pharmacokinetics of nicorandil in healthy subjects and acute heart failure (AHF) patients and 2) to evaluate the exposure-response relationship with pulmonary arterial wedge pressure (PAWP) in AHF patients and to predict an appropriate dosing regimen for nicorandil.

Methods: Based on the data from two healthy volunteer and three AHF patient studies, models were developed to characterize the pharmacokinetics and pharmacodynamics of nicorandil. PAWP was used as the pharmacodynamic variable. An asymptotic exponential disease progression model was used to account for time dependent changes in PAWP that were not explained by nicorandil exposure. The modelling was performed using NONMEM version V.

Results: The pharmacokinetics of nicorandil were characterized by a two-compartment model with linear elimination. CL, V1 and V2 in AHF patients were 1.96, 1.39 and 4.06 times greater than in healthy subjects. Predicted plasma concentrations were assumed to have an immediate concentration effect relationship on PAWP. An inhibitory E(max) model with E(max) of -11.7 mmHg and EC(50) of 423 microg l(-1) was considered the best relationship between nicorandil concentrations and PAWP. PAWP decreased independently of nicorandil exposure. This drug independent decline was described by an asymptotic decrease of 6.1 mmHg with a half-life of 5.3 h.

Conclusions: AHF patients have higher clearance and initial distribution volume of nicorandil compared with healthy subjects. The median target nicorandil concentration to decrease PAWP by 30% is predicted to be 748 microg l(-1), indicating that a loading dose of 200 microg kg(-1) and a maintenance dose of 400 microg kg(-1) h(-1) would be appropriate for the initial treatment of AHF.

Figure 6

Concentration–effect (PAWP) plots of nicorandil. These data were obtained from a bolus injection study of patients with AHF. PAWP was measured using a Swan-Ganz catheter. Concentrations of nicorandil were measured by HPLC. Each plot shows individual data. Panels A, B, C, and D show a 4, 8, 12 and 18 mg kg⁻¹ bolus dose of nicorandil

Figure 1

Individual plasma concentrations of nicorandil in healthy volunteers

Figure 2

Individual plasma concentration profiles of nicorandil following administration to acute heart failure patients. Left upper panel: bolus injection of nicorandil at a dose of 4, 8, 12 and 18 mg kg⁻¹. Right upper panel: 6 h or 24 h infusion of nicorandil at a dose of 50, 100, 150, 200 and 250 µg kg⁻¹ h⁻¹ following a bolus injection of nicorandil at a dose of 200 µg kg⁻¹. Left lower panel: 48 h infusion of nicorandil at a dose of 200 µg kg⁻¹ h⁻¹ following a bolus injection of nicorandil at a dose of 200 µg kg⁻¹

Figure 3

Goodness of fit plots under the final pharmacokinetic model for nicorandil. Lines in upper right and left panel show unity

Figure 4

Visual predictive check of PKPD model 10 for nicorandil concentration in acute heart failure patients (symbols are observation, median is thick line, 90% prediction intervals are thin lines). Low (), median (), high (), observed ()

Figure 5

Visual predictive check of PKPD model 10 for nicorandil concentration in acute heart failure patients (lines with symbols are observations and without symbols are predictions; median is thick line, 90% prediction intervals are thin lines). Low (), median (), high (), OBS low (), OBS median (), OBS high ()

Figure 7

Individual PAWP profiles of nicorandil following administration to acute heart failure patients. Left upper panel: bolus injection of nicorandil at a dose of 4, 8, 12 and 18 mg kg⁻¹. Right upper panel: 6 h or 24 h infusion of nicorandil at a dose of 50, 100, 150, 200 and 250 µg kg⁻¹ h⁻¹ following a bolus injection of nicorandil at a dose of 200 µg kg⁻¹ h⁻¹. Left lower panel: 48 h infusion of nicorandil at a dose of 200 µg kg⁻¹ h⁻¹ following a bolus injection of nicorandil at a dose of 200 µg kg⁻¹

Figure 8

Goodness of fit plots for the final pharmacokinetic-pharmacodynamic model (model 10)

Figure 9

Visual predictive check of PKPD model 10 for PAWP in patients with acute heart failure (symbols are observations, median is thick line, 90% prediction intervals are thin lines). Low (), median (), high (), observed ()

Figure 10

Visual predictive check of PKPD model 10 in patients with acute heart failure for PAWP (lines with symbols are observations and without symbols are predictions; median is thick line, 90% prediction intervals are thin lines). Low (), median (), high (), OBS low (), OBS median (), OBS high ()