Impact of Obesity on Hepatic Drug Clearance: What are the Influential Variables?

IF 5 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Tan Zhang, Elisa A M Calvier, Elke H J Krekels, Catherijne A J Knibbe
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Abstract

Drug clearance in obese subjects varies widely among different drugs and across subjects with different severity of obesity. This study investigates correlations between plasma clearance (CLp) and drug- and patient-related characteristics in obese subjects, and evaluates the systematic accuracy of common weight-based dosing methods. A physiologically-based pharmacokinetic (PBPK) modeling approach that uses recent information on obesity-related changes in physiology was used to simulate CLp for a normal-weight subject (body mass index [BMI] = 20) and subjects with various severities of obesity (BMI 25-60) for hypothetical hepatically cleared drugs with a wide range of properties. Influential variables for CLp change were investigated. For each drug and obese subject, the exponent that yields perfect allometric scaling of CLp from normal-weight subjects was assessed. Among all variables, BMI and relative changes in enzyme activity resulting from obesity proved highly correlated with obesity-related CLp changes. Drugs bound to α1-acid glycoprotein (AAG) had lower CLp changes compared to drugs bound to human serum albumin (HSA). Lower extraction ratios (ER) corresponded to higher CLp changes compared to higher ER. The allometric exponent for perfect scaling ranged from -3.84 to 3.34 illustrating that none of the scaling methods performed well in all situations. While all three dosing methods are generally systematically accurate for drugs with unchanged or up to 50% increased enzyme activity in subjects with a BMI below 30 kg/m2, in any of the other cases, information on the different drug properties and severity of obesity is required to select an appropriate dosing method for individuals with obesity.

Abstract Image

肥胖对肝脏药物清除率的影响:影响因素有哪些?
不同药物和不同肥胖程度的受试者在肥胖受试者体内的药物清除率差异很大。本研究调查了肥胖受试者血浆清除率(CLp)与药物和患者相关特征之间的相关性,并评估了基于体重的常用剂量方法的系统准确性。我们采用基于生理学的药代动力学(PBPK)建模方法,利用与肥胖相关的最新生理学变化信息,模拟了正常体重受试者(体重指数 [BMI] = 20)和不同肥胖程度受试者(体重指数 25-60)的假定肝脏清除率(CLp)。对影响 CLp 变化的变量进行了研究。针对每种药物和肥胖受试者,评估了与正常体重受试者的 CLp 完全成比例的指数。在所有变量中,体重指数和肥胖导致的酶活性相对变化与肥胖相关的 CLp 变化高度相关。与人血清白蛋白(HSA)结合的药物相比,与α1-酸糖蛋白(AAG)结合的药物的CLp变化较低。与较高的萃取率(ER)相比,较低的萃取率(ER)对应较高的CLp变化。完美缩放的等比数列指数从-3.84到3.34不等,说明没有一种缩放方法在所有情况下都表现良好。在体重指数低于 30 kg/m2 的受试者中,对于酶活性不变或最多增加 50%的药物,这三种给药方法一般都比较准确,但在任何其他情况下,都需要了解不同药物的特性和肥胖的严重程度,以便为肥胖者选择合适的给药方法。
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来源期刊
AAPS Journal
AAPS Journal 医学-药学
CiteScore
7.80
自引率
4.40%
发文量
109
审稿时长
1 months
期刊介绍: The AAPS Journal, an official journal of the American Association of Pharmaceutical Scientists (AAPS), publishes novel and significant findings in the various areas of pharmaceutical sciences impacting human and veterinary therapeutics, including: · Drug Design and Discovery · Pharmaceutical Biotechnology · Biopharmaceutics, Formulation, and Drug Delivery · Metabolism and Transport · Pharmacokinetics, Pharmacodynamics, and Pharmacometrics · Translational Research · Clinical Evaluations and Therapeutic Outcomes · Regulatory Science We invite submissions under the following article types: · Original Research Articles · Reviews and Mini-reviews · White Papers, Commentaries, and Editorials · Meeting Reports · Brief/Technical Reports and Rapid Communications · Regulatory Notes · Tutorials · Protocols in the Pharmaceutical Sciences In addition, The AAPS Journal publishes themes, organized by guest editors, which are focused on particular areas of current interest to our field.
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