Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat

Abstract

Background: The angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form. This paper describes the first human physiologically based pharmacokinetic (PBPK) model of this drug class.

Methods: The model was applied to the experimental data of van Griensven et. al for the pharmacokinetics of ramiprilat and its prodrug ramipril. It describes the time course of the inhibition of the N and C ACE sites in plasma and the different tissues. The model includes: 1) two independent ACE binding sites; 2) non-equilibrium time dependent binding; 3) liver and kidney ramipril intracellular uptake, conversion to ramiprilat and extrusion from the cell; 4) intestinal ramipril absorption. The experimental in vitro ramiprilat/ACE binding kinetics at 4 degrees C and 300 mM NaCl were assumed for most of the PBPK calculations. The model was incorporated into the freely distributed PBPK program PKQuest.

Results: The PBPK model provides an accurate description of the individual variation of the plasma ramipril and ramiprilat and the ramiprilat renal clearance following IV ramiprilat and IV and oral ramipril. Summary of model features: Less than 2% of total body ACE is in plasma; 35% of the oral dose is absorbed; 75% of the ramipril metabolism is hepatic and 25% of this is converted to systemic ramiprilat; 100% of renal ramipril metabolism is converted to systemic ramiprilat. The inhibition was long lasting, with 80% of the C site and 33% of the N site inhibited 24 hours following a 2.5 mg oral ramipril dose. The plasma ACE inhibition determined by the standard assay is significantly less than the true in vivo inhibition because of assay dilution.

Conclusion: If the in vitro plasma binding kinetics of the ACE inhibitor for the two binding sites are known, a unique PBPK model description of the Griensven et. al. experimental data can be obtained.

Figure 1

PBPK model of the pharmacokinetics of prodrug ramipril (R) and active drug ramiprilat (D). The figure schematically illustrates the events in three different tissues (typical "tissue", the liver and the kidney), the intestinal absorption, the renal clearance and enterohepatic recirculation.

Figure 2

Schematic diagram of the arrangement of the different tissues in the PBPK model. The organ "portal" refers to all the organs drained by the portal vein. The connective tissue is divided between two organs: "tendon" with a relatively low blood flow and "other" with a higher blood flow.

Figure 3

Semi-log plot of model plasma ramiprilat (nanomoles/liter) following IV ramiprilat in subject 4 (black line) and the corresponding fraction of the C and N site of plasma ACE that is occupied by ramiprilat (red lines). The open squares are the experimental plasma ramiprilat values.

Figure 4

Plasma ramiprilat concentration following IV ramiprilat for subjects 1 to 7.

Figure 5

Plasma ramiprilat concentration following IV ramiprilat for subjects 8 to 12.

Figure 6

Plasma ramipril (top panels) and ramiprilat (bottom panels) following IV ramipril for subject 4. Left column: early time data on absolute scale. Right column: long time data on semi-log scale. The open squares are the experimental plasma values. The dashed red line indicates ramipril detectable limit and the red square indicates that the plasma value was below this limit.

Figure 7

Plasma ramipril (top panels) and ramiprilat (bottom panels) following oral ramipril for subject 4. Left column: early time data. Right column: all data. The open squares are the experimental plasma values. The dashed red line indicates the analytical detection limit for ramipril.

Figure 8

PBPK model (solid line) plasma ramipril (left column) and ramiprilat (right column) following IV ramipril for subjects 1 to 5. The open squares are the experimental data.

Figure 9

PBPK model (solid line) plasma ramipril (left column) and ramiprilat (right column) following IV ramipril for subjects 6 to 9. The open squares are the experimental data.

Figure 10

PBPK model (solid line) plasma ramipril (left column) and ramiprilat (right column) following IV ramipril for subjects 10 to 12. The open squares are the experimental data.

Figure 11

PBPK model (solid line) plasma ramipril (left column) and ramiprilat (right column) following oral ramipril for subjects 1 to 5. The open squares are the experimental data.

Figure 12

PBPK model (solid line) plasma ramipril (left column) and ramiprilat (right column) following oral ramipril for subjects 6 to 9. The open squares are the experimental data.

Figure 13

PBPK model (solid line) plasma ramipril (left column) and ramiprilat (right column) following oral ramipril for subjects 10 to 12. The open squares are the experimental data.

Figure 14

PBPK model (solid line) rate of intestinal ramipril absorption (sum of fast and slow components) for all subjects.

Figure 15

Variation of the ACE activity (= fraction of N and C ACE sites not occupied by ramiprilat) during the 60 minute incubation with the test substrate during the standard ACE assay. The activity at time 0 represents the true in vivo fractional ACE activity.

Figure 16

Comparison of true in vivo fraction of C and N site of ACE that is inhibited by ramiprilat (black) versus the activity determined from the standard ACE assay (red) as a function of the plasma ramiprilat concentration.

Figure 17

PBPK model prediction of the true in vivo fraction of C (red) and N (black) site of plasma ACE that is inhibited by ramiprilat (black) following IV ramiprilat (top), IV ramipril (middle) and oral ramipril (bottom) for subject 4. The open squares are the experimental plasma ACE activity determined by the standard assay for subject 4.

Figure 18

Top: model plasma (black), heart (red) and skeletal muscle (green) ramiprilat concentration following oral ramipril in a subject with average PBPK parameters. Bottom: fraction of C site (left) and N site (right) ACE in plasma (black), heart (red) and skeletal muscle (green) that is inhibited by ramiprilat following oral ramipril in same average subject.

Figure 19

Top: model plasma ramiprilat for entire experimental period (left) and at long times (right) following 2.5 mg (red), 5 mg(black), 10 mg (green) or 20 mg (blue) oral ramiprilat in "average" subject. Bottom: Fraction of C site (left) or N site (right) inhibited in same subject for same set of oral ramipril doses.

Figure 20

Top: five day plasma ramiprilat for either once per day 2.5 mg oral ramipril (black) or twice per day 1.25 mg oral ramipril (red). Bottom: Fraction of C site (left) or N site (right) inhibited in same subject for same multiple dose regimen.

Figure 21

Influence of reductions in renal function on plasma ramiprilat following 4 days of 2.5 mg oral ramipril once per day in the "average" subject.