Transl Clin Pharmacol.  2017 Mar;25(1):43-51. 10.12793/tcp.2017.25.1.43.

Decreased potency of fimasartan in liver cirrhosis was quantified using mixed-effects analysis

• Kim CO
• Jeon S
• Han S
• Hong T
• Park MS
• Yoon YR
• Yim DS

• KMID: 2411418
• DOI: http://doi.org/10.12793/tcp.2017.25.1.43

Abstract

Fimasartan is a nonpeptide angiotensin II receptor blocker. In a previous study that compared the pharmacokinetics (PK) of fimasartan between patients with hepatic impairment (cirrhosis) and healthy subjects, the exposure to fimasartan was found to be higher in patients, but the decrease of blood pressure (BP) was not clinically significant in those with moderate hepatic impairment. The aims of this study were to develop a population PK-pharmacodynamic (PD) model of fimasartan and to evaluate the effect of hepatic function on BP reduction by fimasartan using previously published data. A 2-compartment linear model with mixed zero-order absorption followed by first-order absorption with a lag time adequately described fimasartan PK, and the effect of fimasartan on BP changes was well explained by the inhibitory sigmoid function in the turnover PK-PD model overlaid with a model of circadian rhythm (NONMEM version 7.2). According to our PD model, the lower BP responses in hepatic impairment were the result of the increased fimasartan ECâ‚…â‚€ in patients, rather than from a saturation of effect. This is congruent with the reported pathophysiological change of increased plasma ACE and renin activity in hepatic cirrhosis.

Keyword

Population PK-PD modeling; NONMEM; hepatic impairment; fimasartan; blood pressure

MeSH Terms

Absorption
Blood Pressure
Circadian Rhythm
Colon, Sigmoid
Healthy Volunteers
Humans
Linear Models
Liver Cirrhosis*
Liver*
Pharmacokinetics
Plasma
Receptors, Angiotensin
Renin
Receptors, Angiotensin
Renin

Figure

• 

  Figure 1 The structure of the pharmacokinetic and pharmacodynamics models for fimasartan. Notes: (1) 0 < time < D2, zero-order input; (2) first-order input after ALAG, Abbreviations: Ka, rate of constant for first-order absorption; Q/F, intercompartmental clearance; CL/F, clearance; kin, input rate for production of response; kout, first-order rate constant for loss of response; BP, blood pressure; D2, duration of absorption for the zero-order absorption process; ALAG, lag time before first-order absorption.

• 

  Figure 2 Goodness-of-fit plots for the final population pharmacokinetic and pharmacodynamic models of fimasartan. Notes: (A) Plasma concentration of fimasartan; (B) systolic blood pressure; (C) diastolic blood pressure. Black line indicates identity, and gray line indicates locally-weighted regression smooth line. Abbreviation: IWRES, individual weighted residuals.

• 

  Figure 3 Visual predictive check plots for the final pharmacokinetic model. Notes: (A) Healthy subjects, (B) subjects with mild hepatic impairment, (C) subjects with moderate hepatic impairment, (D) total study population. Solid lines indicate median predicted concentration, and dotted dashed lines indicate 5th and 95th percentile predicted concentration.

• 

  Figure 4 Visual predictive check plots for the final pharmacodynamic model. Notes: (A) SBP: Predicted median and 90% confidence interval for each group. (B) DBP: Predicted median and 90% confidence interval for each group. Abbreviations: A, group with mild hepatic impairment; B, group with moderate hepatic impairment; H, group of healthy subjects; SBP, systolic blood pressure; DBP, diastolic blood pressure.

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