Table 2.

Simulation summary.

Schedule (mg/kg)	Ang(1–7) (%)	5%ile	95%ile	AngI(1–10) (%)	5%ile	95%ile	AngII(1–8) (%)	5%ile	95%ile	AngIII (%)	5%ile	95%ile	AngIV (%)	5%ile	95%ile
q24h 0.25 (8 a.m.)	94.8	6.8	284	155	34.4	417	− 55.6	− 78.9	− 8.2	− 56.4	− 85	12.8	− 56.2	− 85.2	10.7
q24h 0.25 (8 p.m.)	94.1	5.7	282	155	31.7	411	− 54.7	− 79.2	− 6.1	− 56.2	− 85.3	14.9	− 56.1	− 85	11.4
q12h 0.25	120	21.6	324	196	50.6	504	− 69.7	− 86.6	− 32.7	− 70.8	− 90.7	− 17.3	− 70.7	− 90.6	− 18.5
q12h 0.5	135	31	342	222	60.7	559	− 79.6	− 91.8	− 45.7	− 80.1	-94.3	− 36.9	− 80.8	− 94.3	− 39.7

Four administration schedules are compared in this simulation scenario: (1) 0.25 mg/kg every 24 h at 8 a.m.; (2) 0.25 mg/kg every 24 h at 8 p.m.; (3) 0.25 mg/kg twice a day at 8 a.m. and 8 p.m.; (4) 0.5 mg/kg twice a day at 8 a.m. and 8 p.m. 500 individuals were simulated for each scenario (for a total of 2500 individuals, with placebo). Comparisons between schedules are made by calculating the percent difference between the median AUC and placebo (of each schedule). Median time-courses are plotted in Fig. 8. There was little difference between morning and night dosing at steady state. For 0.25 mg/kg q24h, independent of the time of dosing, we saw an approximate 55% decrease compared to placebo for AngII and a 95% increase in Ang(1–7). With a schedule of 0.5 mg/kg q12h, we saw an approximate 80% decrease versus placebo for AngII and 135% increase in Ang(1–7). Of the schedules compared, the most robust downregulation of classical RAAS biomarkers and upregulation of alternative RAAS biomarkers was observed with the 0.5 mg/kg PO q12h dose of benazepril. However, this should be put in context because the improvement of 0.5 mg/kg q12h over 0.25 mg/kg q12h is 12.5%, 13.3%, 14.2%, 13.1% and 14.3% for Ang(1–7), AngI(1–10), AngII(2–8), AngIII, and AngIV, respectively. 5%ile: 5th percentile; 95%ile: 95th percentile.