Evaluation of Age-Related Changes in Teneligliptin Pharmacokinetics in Japanese and European Descent Subjects Using a Physiologically Based Pharmacokinetic Model.

IF 3.8 3区医学 Q2 Medicine

Diabetes Therapy Pub Date : 2024-04-01 Epub Date: 2023-12-20 DOI:10.1007/s13300-023-01514-1

Hiroaki Iijima, Hidetoshi Shimizu, Kazumi Mori-Anai, Atsuhiro Kawaguchi, Yoji Mochida, Toshimasa Yamauchi, Takashi Kadowaki

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引用次数: 0

Abstract

Introduction: Drugs often show differing pharmacokinetic (PK) profiles, such as higher plasma concentrations, in older people than in younger people owing to age-related decreases in physiological functions. However, it is difficult to evaluate the PK in older populations. Therefore, we simulated the plasma age-related changes in the PK of teneligliptin, a dipeptidyl peptidase-4 inhibitor, using physiologically based PK (PBPK) models.

Methods: The previously developed PBPK model was revalidated by comparison between simulated data and clinical study data that included older subjects (up to 75 years old). We then simulated the plasma concentration-time profiles for teneligliptin at a dose of 20 mg (single and multiple doses) in virtual Japanese (20-70 years old) and European descent (20-98 years old) subjects. PK parameters were calculated by race and age group.

Results: We confirmed the validity of the previous PBPK model by comparison between simulated data and clinical study data. In the evaluation of age-related changes in PK after single and multiple doses using the PBPK model, the area under the plasma concentration-time curve (AUC) of teneligliptin tended to increase slightly with age in both populations up to 70 years old. However, no clear age-related change in the maximum plasma concentration (C_max) of teneligliptin was observed. In the European descent subjects aged ≥ 70 years, the AUC tended to increase but the ratio of the change in C_max was smaller than that in AUC. In both populations, there were positive correlations between AUC and age, but not between C_max and age.

Conclusion: The simulation using a PBPK model showed a tendency for the AUC of teneligliptin to increase with age, whereas C_max was less affected by age than AUC.

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使用基于生理学的药代动力学模型评估日本和欧洲血统受试者替尼列汀药代动力学中与年龄相关的变化

导言：由于与年龄有关的生理机能减退，药物在老年人体内的药代动力学（PK）曲线通常与年轻人不同，如血浆浓度较高。然而，很难对老年人群的药代动力学进行评估。因此，我们使用基于生理学的PK（PBPK）模型模拟了二肽基肽酶-4抑制剂替格列汀与血浆年龄相关的PK变化：通过比较模拟数据和包括老年受试者（75 岁以下）的临床研究数据，重新验证了之前开发的 PBPK 模型。然后，我们模拟了剂量为 20 毫克（单剂量和多剂量）的替尼列汀在虚拟日本人（20-70 岁）和欧洲人后裔（20-98 岁）受试者体内的血浆浓度-时间曲线。按种族和年龄组计算了 PK 参数：结果：通过比较模拟数据和临床研究数据，我们证实了先前 PBPK 模型的有效性。在使用 PBPK 模型评估单次和多次给药后与年龄相关的 PK 变化时，在 70 岁以下的两种人群中，替格列汀的血浆浓度-时间曲线下面积（AUC）随着年龄的增长而略有增加。不过，在替格列汀的最大血浆浓度（Cmax）方面没有观察到明显的年龄相关变化。在年龄≥ 70 岁的欧洲血统受试者中，AUC 有增加的趋势，但 Cmax 的变化比值小于 AUC 的变化比值。在这两个人群中，AUC 与年龄呈正相关，但 Cmax 与年龄不呈正相关：结论：使用 PBPK 模型模拟显示，随着年龄的增长，替格列汀的 AUC 有增加的趋势，而 Cmax 受年龄的影响小于 AUC。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Diabetes Therapy Medicine-Endocrinology, Diabetes and Metabolism

CiteScore

6.90

自引率

7.90%

发文量

130

审稿时长

6 weeks

期刊介绍： Diabetes Therapy is an international, peer reviewed, rapid-publication (peer review in 2 weeks, published 3–4 weeks from acceptance) journal dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of therapeutics and interventions (including devices) across all areas of diabetes. Studies relating to diagnostics and diagnosis, pharmacoeconomics, public health, epidemiology, quality of life, and patient care, management, and education are also encouraged. The journal is of interest to a broad audience of healthcare professionals and publishes original research, reviews, communications and letters. The journal is read by a global audience and receives submissions from all over the world. Diabetes Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an international and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of all scientifically and ethically sound research.