A Digital Twin of the Angiotensin II Receptor Blocker Losartan: Physiologically Based Modeling of Blood Pressure Regulation

Figures

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  Figure 1. PRISMA flow diagram of the literature search and study selection process. Initially, through the search in PKPDAI, PubMed, and manual search, 787 studies were identified. After removing non-eligible articles, 25 studies were left and curated. PK—pharmacokinetics, PD—pharmacodynamics.

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  Figure 2. Overview of the physiologically based model of losartan. (A) Whole body model showing circulation via the arterial and venous blood, with organs (liver, GI tract, kidney) influencing the pharmacokinetics of losartan (LOS). (B) Intestine model illustrating the dissolution and absorption of LOS by enterocytes and the P-glycoprotein-mediated efflux back into the intestine. Approximately 49–58% of the dose is excreted as losartan or metabolites (E3174 and L158). (C) Hepatic model depicting the uptake of losartan by hepatocytes and its conversion by cytochrome p450 2C9 and 3A4 (CYP2C9, CYP3A4) to losartan carboxylic acid E3174 (14% of losartan dose) and the following conversion by UDP-glucuronosyltransferase (UGT) to L158. Losartan and its metabolites can also re-enter the intestinal model via enterohepatic circulation (biliary export). (D) Renal model showing excretion of losartan, E3174 and L158 via urine, approximately 5–12%, 6–7% and 24–25%, respectively. (E) Pharmacodynamic model of E3174 acting on the RAAS. Renin catalyzes the conversion of angiotensinogen to angiotensin I and subsequently to angiotensin II, which stimulates aldosterone secretion. All hormones undergo…

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  Figure 3. Dose-dependent pharmacokinetics and pharmacodynamics of losartan. (A) Illustration of the losartan dose range (10–100 mg) evaluated in the simulations. (B) Simulated plasma concentration profiles of losartan, E3174 and L158, urinary excretion profile of losartan and E3174, a fecal excretion profile of losartan, as well as simulated RAAS biomarkers (renin, angiotensin I and aldosterone) and blood pressure responses across doses (10–100 mg). Dose intensity is indicated by line color. (C) Dose–response curves for AUC, maximum concentration Cmax and half-life. (D) Dose dependent maximum or minimum values of systolic blood pressure (SBP) and diastolic blood pressure (DBP). (E) Simulated (solid lines) versus observed (symbols) losartan pharmacokinetics. Data from [17,77,83]. (F) Simulated (solid lines) versus observed (symbols) losartan pharmacodynamics. Data from [17,75,77,83].

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  Figure 4. Effect of hepatic impairment on losartan pharmacokinetic and pharmacodynamic profiles. (A) Illustration of the level of cirrhosis evaluated in the simulations. (B) Simulated plasma concentration profiles of losartan, E3174 and L158, urinary excretion profile of losartan and E3174, a fecal excretion profile of losartan, as well as simulated RAAS biomarkers (renin, angiotensin I and aldosterone) and blood pressure responses across cirrhosis degrees. Cirrhosis degree is indicated by line color. (C) Cirrhosis degree-dependent curves for AUC, Cmax and half-life. (D) Cirrhosis degree-dependent maximum or minimum values of systolic blood pressure SBP and diastolic blood pressure DBP. (E) Simulated (solid lines) versus observed (symbols) pharmacodynamic timecourses for different degrees of cirrhosis in FDA1995S67 [19].

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  Figure 5. Effect of renal impairment on losartan pharmacokinetics and pharmacodynamic profiles. (A) Illustration of the level of renal impairment evaluated in the simulations. (B) Simulated plasma concentration profiles of losartan, E3174 and L158, urinary excretion profile of losartan and E3174, a fecal excretion profile of losartan, as well as simulated RAAS biomarkers (renin, angiotensin I and aldosterone) and blood pressure responses across degrees of renal function. Renal function degree is indicated by line color. (C) Renal function-dependent curves for AUC, Cmax and half-life. (D) Renal function-dependent maximum or minimum values of SBP and DBP. (E) Simulated (solid lines) versus observed (symbols) pharmacokinetic timecourses for different degrees of renal impairment in Sica1995 [20].

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  Figure 6. Pharmacokinetics and pharmacodynamics of losartan and metabolites across varying ABCB1 activity levels (A) Illustration of the level of CYP2C9 activity evaluated in the simulations. (B) Simulated plasma concentrations and excretion profiles of losartan, E3174 and L158, urinary excretion profile of losartan and E3174, a fecal excretion profile of losartan, as well as simulated RAAS biomarkers (renin, angiotensin I and aldosterone) and blood pressure responses across varying ABCB1 activity. Allele function degree is indicated by color. (C) ABCB1 activity-dependent curves for AUC, Cmax and half-life. (D) ABCB1 allele activity-dependent maximum or minimum values of SBP and DBP. (E) Simulated (solid lines) versus observed (symbols) pharmacodynamic timecourses for different degrees of ABCB1 activity in Shin2020 [33].

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  Figure 7. Pharmacokinetics and pharmacodynamics of losartan and metabolites across varying CYP2C9 activity levels. (A) Illustration of the level of CYP2C9 activity evaluated in the simulations. (B) Simulated plasma concentrations and excretion profiles of losartan, E3174 and L158, urinary excretion profile of losartan and E3174, a fecal excretion profile of losartan, as well as simulated RAAS biomarkers (renin, angiotensin I and aldosterone) and blood pressure responses across varying CYP2C9 activity. Activity degree is indicated by color. (C) CYP2C9 activity-dependent curves for AUC, Cmax, and half-life. (D) CYP2C9 allele activity-dependent maximum or minimum values of SBP and DBP. (E) Simulated (solid lines) versus observed (symbols) losartan pharmacokinetics. Data from [37,73,79,82]. (F) Simulated (solid lines) versus observed (symbols) losartan pharmacokinetics. Data from [36,41,78]. (G) Simulated (solid lines) versus observed (symbols) SBP and DBP for different CYP2C9 genotypes [37].