Prediction of Clearance and Volume of Distribution in the Obese from Normal Weight Subjects

Mahmood, Iftekhar

doi:10.1007/bf03261929

Cited by 27 publications

(12 citation statements)

References 46 publications

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“…Nevertheless, nonlinear functions of total body weight (TBW) show good performance as predictors of clearance in several pharmacokinetic studies covering wide ranges in body weight (74,75,78). Similarly, in a large study on the variation in clearance and volume of distribution of 12 different drugs, total body weight appeared to be a consistent and reliable size descriptor for the prediction of these parameters in the obese (79).…”

Section: Measures To Quantify Body Size and Overweightmentioning

confidence: 94%

“…In obese subjects, changes in volume of distribution may be expected to result from increased blood volume, increased cardiac output and blood flow, increased LBW, increased adipose tissue and reduced tissue perfusion (19-22, 91, 92), with only a limited influence of changes in blood proteins (i.e., albumin, alpha acid glycoprotein) (23,94). From the available evidence, the values of the volume of distribution appear highly variable in obese individuals and more difficult to predict than the values of clearance (79,90). While intuitively more influence of obesity on lipophilic drugs than on hydrophilic drugs may be expected (93), Jain et al (90) concluded, on the basis of an overview of the ratios of volume of distribution of various drugs in obese versus nonobese individuals, that changes in volume of distribution cannot be predicted on the basis of lipophilicity alone.…”

Section: The Influence Of Obesity On Drug Distributionmentioning

confidence: 97%

“…Volume of distribution is an important parameter that is often substantially altered in obese patients (79,(90)(91)(92). It is particularly important to characterize changes in volume of distribution when a rapid onset of the effect is needed as the peak concentration after single-dose administration is largely determined by the volume of distribution.…”

Section: The Influence Of Obesity On Drug Distributionmentioning

confidence: 99%

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Drug Disposition in Obesity: Toward Evidence-Based Dosing

Knibbe

Brill

Rongen

et al. 2015

Annu. Rev. Pharmacol. Toxicol.

108

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Obesity and morbid obesity are associated with many physiological changes affecting pharmacokinetics, such as increased blood volume, cardiac output, splanchnic blood flow, and hepatic blood flow. In obesity, drug absorption appears unaltered, although recent evidence suggests that this conclusion may be premature. Volume of distribution may vary largely, but the magnitude and direction of changes seem difficult to predict, with extrapolation on the basis of total body weight being the best approach to date. Changes in clearance may be smaller than in distribution, whereas there is growing evidence that the influence of obesity on clearance can be predicted on the basis of reported changes in the metabolic or elimination pathways involved. For obese children, we propose two methods to distinguish between developmental and obesity-related changes. Future research should focus on the characterization of physiological concepts to predict the optimal dose for each drug in the obese population.

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Section: Measures To Quantify Body Size and Overweightmentioning

confidence: 94%

Section: The Influence Of Obesity On Drug Distributionmentioning

confidence: 97%

Section: The Influence Of Obesity On Drug Distributionmentioning

confidence: 99%

See 1 more Smart Citation

Drug Disposition in Obesity: Toward Evidence-Based Dosing

Knibbe

Brill

Rongen

et al. 2015

Annu. Rev. Pharmacol. Toxicol.

108

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show abstract

“…In general, the human clearance of SMs is more predictable combining in vitro and in vivo animal data by means of well-stirred model and commonly used allometric scaling etc [95][96][97][98][99]. The examples applying allometric scaling have been reviewed for predictions of clearance and volume distribution of therapeutic proteins recently [37].…”

Section: Analysis and Interpretation Of Preclinical Animal Pk Of Adcsmentioning

confidence: 99%

An Overall Comparison of Small Molecules and Large Biologics in ADME Testing

Wan

2016

ADMET DMPK

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Biologics mainly monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) as new therapeutics are becoming increasingly important biotherapeutics. This review is intended to provide an overall comparison between small molecules (SMs) and biologics or large molecules (LMs) concerning drug metabolism and pharmacokinetic (DMPK) or associated with absorption, distribution, metabolism and elimination (ADME) testing from pharmaceutical industry drug discovery and development points of view, which will help design and conduct relevant ADME testing for biologics such as mAbs and ADCs. Recent advancements in the ADME for testing biologics and related bioanalytical methods are discussed with an emphasis on ADC drug development as an example to understand its complexity and challenges from extensive in vitro characterization to in vivo animal PK studies. General non-clinical safety evaluations of biologics in particular for ADC drugs are outlined including drug-drug interaction (DDI)and metabolite/catabolite assessments. Regulatory guidance on the ADME testing and safety evaluations including immunogenicity as well as bioanalytical considerations are addressed for LMs. In addition, the preclinical and human PK data of two marked ADC drugs (ADCETRIS, as examples are briefly discussed with regard to PK considerations and PK/PD perspectives.

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“…Investigators who focus only on obese subjects rather than a broad weight range that included normal-weight subjects, may not find a realistic allometric relationship [58]. Strange reports of negative exponents that imply clearance decreases with weight have been published [61].…”

Section: Propofolmentioning

confidence: 99%

Unraveling Pharmacokinetics and Pharmacodynamics in Infants and Children

Sumpter¹,

Anderson

2012

Curr Anesthesiol Rep

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Our knowledge of the pharmacology of the drugs used in pediatric anesthesia has advanced with a greater understanding of their pharmacokinetics (PK) and pharmacodynamics. This has resulted in a refinement of their uses, broader indications, and alternative methods of delivery. For example, methadone is becoming increasingly popular for spinal surgery, the dosing of etomidate has been clarified and the PK of intravenous acetaminophen from neonates to adults has been revealed. Morphine PK have also been clarified, although pharmacodynamic ethnic differences remain unexplained. The optimal size descriptor to predict correct drug doses in the obese remains controversial. Efforts to reduce adverse effects of individual drugs have spawned investigations into beneficial drug interactions, although combinations such as propofol and ketamine await PK and safety review. The nasal route may be a reasonable alternative to intravenous administration for many drugs. Oral ketamine may serve as a valuable premedication for children suffering burns. Expanded indications can have unfavorable consequences; propofol may cause profound hypotension in neonates.

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Prediction of Clearance and Volume of Distribution in the Obese from Normal Weight Subjects

Abstract: The study indicated that allometric scaling can be applied to predict CL in the obese from normal weight subjects with high accuracy. The predicted CL can then be used to select a dose to initiate a clinical trial (pharmacokinetics, safety and efficacy).

Cited by 27 publications

References 46 publications

Drug Disposition in Obesity: Toward Evidence-Based Dosing

Drug Disposition in Obesity: Toward Evidence-Based Dosing

An Overall Comparison of Small Molecules and Large Biologics in ADME Testing

Unraveling Pharmacokinetics and Pharmacodynamics in Infants and Children

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