Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients

Jung, Eui Hyun; Cho, Chang‐Keun; Kang, Pureum; Park, Hye-Jung; Lee, Yun Jeong; Bae, Jung‐Woo; Choi, Chang‐Ik; Jang, Choon‐Gon; Lee, Seok‐Yong

doi:10.1007/s12272-021-01363-1

Cited by 15 publications

(5 citation statements)

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“…In recent published articles [9,[11][12][13]15,18], the PBPK model related to the genetic polymorphism of CYP2C9 established and described the pharmacokinetics of piroxicam in different CYP2C9 genotypes. The PBPK model can be used as an alternative to predict PK in different clinical conditions [10,11,14,16,17,19].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, some researchers have described a new mechanistic approach to predict drug PK [9][10][11], called Physiologically Based Pharmacokinetics (PBPK). Studies using this model have shown that PBPK is useful for guiding dose adjustment in various clinical settings, such as the effects of genetic polymorphisms [11][12][13][14][15]. Some PBPK models for NSAIDs have been established in different CYP2C9 genotypes [10,16,17].…”

Section: Introductionmentioning

confidence: 99%

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CYP2C9 Polymorphism Influence in PK/PD Model of Naproxen and 6-O-Desmethylnaproxen in Oral Fluid

et al. 2022

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Polymorphisms in CYP2C9 can significantly interfere with the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen. The present research aimed to study the PK/PD parameters of naproxen and its metabolite, 6-O-desmethylnaproxen, associated with allelic variations of CYP2C9. In our study, a rapid, selective, and sensitive Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) method was developed and validated for the determination of naproxen and its main metabolite, 6-O-desmethylnaproxen, in oral fluid. Naproxen and its main metabolite were separated using a Shim-Pack XR-ODS 75L × 2.0 column and C18 pre-column at 40 °C using a mixture of methanol and 10 mM ammonium acetate (70:30, v/v), with an injection flow of 0.3 mL/min. The total analytical run time was 3 min. The volunteers, previously genotyped for CYP2C9 (16 ancestral—CYP2C9 *1 and 12 with the presence of polymorphism—CYP2C9 *2 or *3), had their oral fluids collected sequentially before and after taking a naproxen tablet (500 mg) at the following times: 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6 8, 11, 24, 48, 72 and 96 h. Significant differences in the PK parameters (* p < 0.05) of naproxen in the oral fluid were: Vd/F (L): 98.86 (55.58–322.07) and 380.22 (261.84–1097.99); Kel (1/h): 0.84 (0.69–1.34) and 1.86 (1.09–4.06), in ancestral and mutated CYP2C9 *2 and/or *3, respectively. For 6-O-desmethylnaproxen, no PK parameters were significantly different between groups. The analysis of prostaglandin E2 (PGE2) proved to be effective and sensitive for PD parameters analysis and showed higher levels in the mutated group (p < 0.05). Both naproxen and its main metabolite, 6-O-desmethylnaproxen, and PGE2 in oral fluid can be effectively quantified using LC-MS/MS after a 500 mg oral dose of naproxen. Our method proved to be effective and sensitive to determine the lower limit of quantification of naproxen and its metabolite, 6-O-desmethylnaproxen, in oral fluid (2.4 ng/mL). All validation data, such as accuracy, precision, and repeatability intra- and inter-assay, were less than 15%. Allelic variations of CYP2C9 may be considered relevant in the PK of naproxen and its main metabolite, 6-O-desmethylnaproxen.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CYP2C9 Polymorphism Influence in PK/PD Model of Naproxen and 6-O-Desmethylnaproxen in Oral Fluid

et al. 2022

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“… 40 We have experience with PBPK modeling and have developed accurate PBPK models for a variety of innovative and generic medications. 41 , 42 Based on the study reported by Jung et al ., 31 we developed PBPK models for candesartan in healthy European and Asian subjects in this investigation. Then, the PBPK model specific for candesartan in the population with hepatic and renal impairment was developed and validated by relevant clinical investigations, taking into account the physiological differences between disease stages and healthy populations.…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…26 The input compound parameters of candesartan and candesartan cilexetil, including physicochemical properties, specific intestinal permeability, enzymatic kinetic, and glomerular filtration fraction (f GFR ) parameters, were obtained from DrugBank, the guidelines of the US Food and Drug Administration or the European Medicines Agency, and the literature. [27][28][29][30][31] Using Monte Carlo simulations, system-specific parameters obtained from the PK-Sim built-in database (i.e. physiological and anatomical parameters of the virtual population) were fixed to suit 4 mg oral tablet clinical data in European healthy subjects.…”

Section: Adult Pbpk Model Developmentmentioning

confidence: 99%

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Physiologically based pharmacokinetic modeling of candesartan to predict the exposure in hepatic and renal impairment and elderly populations

Guo,

Zhu,

Zhang

et al. 2023

Therapeutic Advances in Drug Safety

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Background: Candesartan cilexetil is a widely used angiotensin II receptor blocker with minimal adverse effects and high tolerability for the treatment of hypertension. Candesartan is administered orally as the prodrug candesartan cilexetil, which is wholly and swiftly converted to the active metabolite candesartan by carboxylesterase during absorption in the intestinal tract. In populations with renal or hepatic impairment, candesartan’s pharmacokinetic (PK) behavior may be altered, necessitating dosage adjustments. Objectives: This study was conducted to examine how the physiologically based PK (PBPK) model characterizes the PKs of candesartan in adult and geriatric populations and to predict the PKs of candesartan in elderly populations with renal and hepatic impairment. Design: After developing PBPK models using the reported physicochemical properties of candesartan and clinical data, these models were validated using data from clinical investigations involving various dose ranges. Methods: Comparing predicted and observed blood concentration data and PK parameters was used to assess the fit performance of the models. Results: Doses should be reduced to approximately 94% of Chinese healthy adults for the Chinese healthy elderly population; approximately 92%, 68%, and 64% of that of the Chinese healthy adult dose in elderly populations with mild, moderate, and severe renal impairment, respectively; and approximately 72%, 71%, and 52% of that of the Chinese healthy adult dose in elderly populations with Child–Pugh-A, Child–Pugh-B, and Child–Pugh-C hepatic impairment, respectively. Conclusion: The results suggest that the PBPK model of candesartan can be utilized to optimize dosage regimens for special populations.

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Effects of CYP2C93 and 13 alleles on the pharmacokinetics and pharmacodynamics of glipizide in healthy Korean subjects

et al. 2021

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Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients

Cited by 15 publications

References 54 publications

CYP2C9 Polymorphism Influence in PK/PD Model of Naproxen and 6-O-Desmethylnaproxen in Oral Fluid

CYP2C9 Polymorphism Influence in PK/PD Model of Naproxen and 6-O-Desmethylnaproxen in Oral Fluid

Physiologically based pharmacokinetic modeling of candesartan to predict the exposure in hepatic and renal impairment and elderly populations

Effects of CYP2C93 and 13 alleles on the pharmacokinetics and pharmacodynamics of glipizide in healthy Korean subjects

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Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients

Cited by 15 publications

References 54 publications

CYP2C9 Polymorphism Influence in PK/PD Model of Naproxen and 6-O-Desmethylnaproxen in Oral Fluid

CYP2C9 Polymorphism Influence in PK/PD Model of Naproxen and 6-O-Desmethylnaproxen in Oral Fluid

Physiologically based pharmacokinetic modeling of candesartan to predict the exposure in hepatic and renal impairment and elderly populations

Effects of CYP2C9*3 and *13 alleles on the pharmacokinetics and pharmacodynamics of glipizide in healthy Korean subjects

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Effects of CYP2C93 and 13 alleles on the pharmacokinetics and pharmacodynamics of glipizide in healthy Korean subjects