Physiologically Based Pharmacokinetic Modeling of Fimasartan, Amlodipine, and Hydrochlorothiazide for the Investigation of Drug–Drug Interaction Potentials

Rhee, Seunghyun; Lee, Hyun A.; Lee, So‐Young; Kim, Eunwoo; Jeon, Inseung; Song, Im Sook; Yu, Kyung‐Sang

doi:10.1007/s11095-018-2511-5

Cited by 6 publications

(6 citation statements)

References 42 publications

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“…A fixed-dose triple combination of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg exhibited pharmacokinetic profiles similar to those of the corresponding doses of the three drugs [ 6 ]. In addition, a physiologically based pharmacokinetic (PBPK) model for fimasartan, amlodipine, and hydrochlorothiazide was developed by Rhee et al, and they predicted no remarkable DDIs using this PBPK model when fimasartan (120–240 mg) was co-administered with amlodipine (10 mg) and hydrochlorothiazide (25 mg), which is consistent with the observed clinical data [ 1 ]. In addition to combination therapy, the use of herbal supplements is continuously increasing.…”

Section: Introductionsupporting

confidence: 53%

“…For the management of hypertension, approximately 70% of patients with hypertension take two or more antihypertensive drugs for effective blood pressure control. Among these combination drugs, calcium channel blockers, angiotensin II receptor antagonists, and thiazide diuretics are the most commonly used [ 1 ]. Fimasartan is an angiotensin II receptor antagonist that has been approved in Korea and several Latin American countries for the treatment of mild-to-moderate hypertension.…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous Analysis of a Combination of Anti-Hypertensive Drugs, Fimasartan, Amlodipine, and Hydrochlorothiazide, in Rats Using LC-MS/MS and Subsequent Application to Pharmacokinetic Drug Interaction with Red Ginseng Extract

Jeon

Park

et al. 2022

Toxics

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Fimasartan, amlodipine, and hydrochlorothiazide are commonly used in combination therapies as antihypertensive drugs. This study aimed to develop and validate an analytical method for fimasartan, its active and major metabolite fimasartan-amide, amlodipine, and hydrochlorothiazide in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The standard calibration curves for fimasartan (1–500 ng/mL), its active and major metabolite fimasartan-amide (0.3–100 ng/mL), amlodipine (0.5–200 ng/mL), and hydrochlorothiazide (5–5000 ng/mL) were linear with R2 > 0.9964, and the inter- and intra-day accuracy and precision and stability were within the acceptable criteria. Using this validated analytical method, the pharmacokinetic interaction of these triple combination drugs between single administration and concomitant administration of the triple combination was investigated; the results did not reveal a significant difference in any of the pharmacokinetic parameters. Based on these results, we investigated the effects of red ginseng extract (RGE) on the pharmacokinetics of fimasartan, fimasartan-amide, amlodipine, and hydrochlorothiazide after oral administration of the combination in rats. No significant difference was observed in the pharmacokinetic parameters of fimasartan, fimasartan-amide, amlodipine, and hydrochlorothiazide, except for the Tmax values of amlodipine. The delayed Tmax value of amlodipine was attributed to its decreased intestinal permeability after repeated RGE treatments. In conclusion, using a combination of antihypertensive drugs and simultaneous analytical methods, we established efficient drug interaction and toxicokinetic studies using a small number of animals.

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Section: Introductionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Simultaneous Analysis of a Combination of Anti-Hypertensive Drugs, Fimasartan, Amlodipine, and Hydrochlorothiazide, in Rats Using LC-MS/MS and Subsequent Application to Pharmacokinetic Drug Interaction with Red Ginseng Extract

Jeon

Park

et al. 2022

Toxics

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“…The amlodipine compound file that was developed based on compilations of information and parameter optimisation from several publications was verified in four populations, including non-obese adults, obese adults, non-obese paediatrics, and obese paediatrics [ 63 , 64 , 65 ]. The simulated plasma concentrations and pharmacokinetic parameters for non-obese adults and obese adults met the acceptance criteria for the VPC and 2-fold comparison with observed data except for 3 out of 54 comparisons.…”

Section: Discussionmentioning

confidence: 99%

“…Physiochemical and pharmacokinetic parameters describing the amlodipine model utilised in this study were obtained and adapted from several publications [ 63 , 64 , 65 ] ( Table 4 ). For the distribution model, we utilised a full-body PBPK model with the V ss, which was estimated using the Rodgers and Rowland approach based on the tissue partition coefficients (Kp) [ 49 , 50 ].…”

Section: Methodsmentioning

confidence: 99%

The Impact of Paediatric Obesity on Drug Pharmacokinetics: A Virtual Clinical Trials Case Study with Amlodipine

Burhanuddin,

Mohammed,

Badhan

2024

Pharmaceutics

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The incidence of paediatric obesity continues to rise worldwide and contributes to a range of diseases including cardiovascular disease. Obesity in children has been shown to impact upon the plasma concentrations of various compounds, including amlodipine. Nonetheless, information on the influence of obesity on amlodipine pharmacokinetics and the need for dose adjustment has not been studied previously. This study applied the physiologically based pharmacokinetic modelling and established a paediatric obesity population to assess the impact of obesity on amlodipine pharmacokinetics in children and explore the possible dose adjustments required to reach the same plasma concentration as non-obese paediatrics. The difference in predicted maximum concentration (Cmax) and area under the curve (AUC) were significant between children with and without obesity across the age group 2 to 18 years old when a fixed-dose regimen was used. On the contrary, a weight-based dose regimen showed no difference in Cmax between obese and non-obese from 2 to 9 years old. Thus, when a fixed-dose regimen is to be administered, a 1.25- to 1.5-fold increase in dose is required in obese children to achieve the same Cmax concentration as non-obese children, specifically for children aged 5 years and above.

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“…The performance of these models was demonstrated by the evaluation method. Physiology-based bile acid (PBBA) and the PBPK model of AMLO were developed [ 30 , 31 , 32 ] to investigate bile recirculation and AMLO DDI prediction with other drugs. Therefore, we first developed a model of CA administration to reduce submental fat and test DDI of CA with AMLO, SIM, and PIO.…”

Section: Discussionmentioning

confidence: 99%

Evaluation for Potential Drug–Drug Interaction of MT921 Using In Vitro Studies and Physiologically–Based Pharmacokinetic Models

Ryu

Moon

Lee³

et al. 2021

Pharmaceuticals

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MT921 is a new injectable drug developed by Medytox Inc. to reduce submental fat. Cholic acid is the active pharmaceutical ingredient, a primary bile acid biosynthesized from cholesterol, endogenously produced by liver in humans and other mammals. Although individuals treated with MT921 could be administered with multiple medications, such as those for hypertension, diabetes, and hyperlipidemia, the pharmacokinetic drug–drug interaction (DDI) has not been investigated yet. Therefore, we studied in vitro against drug-metabolizing enzymes and transporters. Moreover, we predicted the potential DDI between MT921 and drugs for chronic diseases using physiologically-based pharmacokinetic (PBPK) modeling and simulation. The magnitude of DDI was found to be negligible in in vitro inhibition and induction of cytochrome P450s and UDP-glucuronosyltransferases. Organic anion transporting polypeptide (OATP)1B3, organic anion transporter (OAT)3, Na+-taurocholate cotransporting polypeptide (NTCP), and apical sodium-dependent bile acid transporter (ASBT) are mainly involved in MT921 transport. Based on the result of in vitro experiments, the PBPK model of MT921 was developed and evaluated by clinical data. Furthermore, the PBPK model of amlodipine was developed and evaluated. PBPK DDI simulation results indicated that the pharmacokinetics of MT921 was not affected by the perpetrator drugs. In conclusion, MT921 could be administered without a DDI risk based on in vitro study and related in silico simulation. Further clinical studies are needed to validate this finding.

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Physiologically Based Pharmacokinetic Modeling of Fimasartan, Amlodipine, and Hydrochlorothiazide for the Investigation of Drug–Drug Interaction Potentials

Cited by 6 publications

References 42 publications

Simultaneous Analysis of a Combination of Anti-Hypertensive Drugs, Fimasartan, Amlodipine, and Hydrochlorothiazide, in Rats Using LC-MS/MS and Subsequent Application to Pharmacokinetic Drug Interaction with Red Ginseng Extract

Simultaneous Analysis of a Combination of Anti-Hypertensive Drugs, Fimasartan, Amlodipine, and Hydrochlorothiazide, in Rats Using LC-MS/MS and Subsequent Application to Pharmacokinetic Drug Interaction with Red Ginseng Extract

The Impact of Paediatric Obesity on Drug Pharmacokinetics: A Virtual Clinical Trials Case Study with Amlodipine

Evaluation for Potential Drug–Drug Interaction of MT921 Using In Vitro Studies and Physiologically–Based Pharmacokinetic Models

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