ABSTRACT
Physiologically based pharmacokinetic (PB-PK) model simulates the circulation of blood flow in systemic organs by using mathematical model to quantitatively describe the behavior characteristics of drugs in the body. The application of PB-PK model to special population to predict the pharmacokinetic behavior of drugs in special populations can provide support for clinical rational drug use. In recent years, chronic liver disease has gradually become an important health problem. Due to the impairment of patients' liver function, the disposal process of drug in vivo will change to some extent. Therefore, it is necessary to evaluate the impact of liver dysfunction on the drug absorption, distribution, metabolism, elimination (ADME) in order to ensure the safety and effectiveness of drug use. PB-PK model can accurately determine the ADME process of drugs in patients according to the level of liver function, and play an important role in guiding clinical rational drug use. This review will start from the impact of liver function on the process of drug ADME, summarize and discuss how PB-PK model can build a model according to the physiological and pathological changes of patients with liver dysfunction for more accurate extrapolation prediction.
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 EC₅₀ 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.
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Humans , Absorption , Blood Pressure , Circadian Rhythm , Colon, Sigmoid , Healthy Volunteers , Linear Models , Liver Cirrhosis , Liver , Pharmacokinetics , Plasma , Receptors, Angiotensin , ReninABSTRACT
Objective To obserue that bortezomib lead to hepatic impairment and even hepatic insufficiency. Methods Four multiple myeloma patients with hepatic impairment in velcade therapy were analyzed. All of 4 patients ranged from 46 to 60-year-old were relapsed and refractory, including 3 cases of male and 1 of female; 2 of K light chain type, 1 of non secretion type and 1 of IgGλλ biclonal type; 3 in stage ⅢB and 1 in stage ⅢA. Results Four patients had normal hepatic function before bortezomib therapy, but all appeared hepatic impairment during therapy. ALT and aspartate aminotransferase were increased by 2-80 and 1.5-70 times compared with before the chemotherapy, respectively, and bilirubin and alkaline phosphatase in 2 patients and glutamyltranspeptidase in 1 patient were increased. Hepatic function restored normally after patients were given liver securing drug and discontinued bortezomib therapy. Conclusion It isn't rare that bortezomib causing hepatic impairment in the patients with multiple myeloma.
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0.05). Conclusion The elimination half-life of magnesium isoglycyrrhizinate in patients with chronic hepatic impairment is 27 h,and the regiment of 100 mg once a day is recommended.