Dosing in Obesity: A Simple Solution to a Big Problem

Han, Phey Yen; Duffull, Stephen B.; Kirkpatrick, Carl M.; Green, Bruce

doi:10.1038/sj.clpt.6100381

Cited by 223 publications

(191 citation statements)

References 10 publications

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“…6 Total body weight (TBW) is the body size variable that is often used to estimate dose, although it is already well known that this will not result in comparable drug exposure (ie, the same drug concentration) across the spectrum of body compositions. 7 Further, because clinicians are worried about toxicity, particularly in an elderly population, the dose may be "capped"-resulting in subtherapeutic exposure and the risk of treatment failure. 8 The American Society of Clinical Oncology (ASCO) 2012 Clinical Practice Guideline for Appropriate Chemotherapy Dosing for Obese Adult Patients With Cancer indicates that up to 40% of obese patients receive limited chemotherapy doses that are not based on actual body weight.…”

Section: Obesitymentioning

confidence: 99%

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

Lucas

Martin

2017

The Journal of Clinical Pharma

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Generally, licensed drug-dosing recommendations for chemotherapy are based on results from clinical trials in which subjects are usually of relatively normal body size, middle-aged, and are relatively racially homogeneous, with minimal comorbidity and specific tumor characteristics. Very few nontrial patients meet these characteristics, resulting in clinical practice having to extrapolate dosing recommendations to the specific patient. There is insufficient research on the impact of obesity-associated physiological changes prevalent in patients with common cancers on standard pharmacokinetic and pharmacodynamic parameters. Yet quantifying the influence of obesity on the pharmacology of chemotherapy is vital, as dosing inappropriate for body composition (ie, flat dosing or mg/kg based on total body weight) may increase the risk of adverse events and reduce clinical effectiveness. Unfortunately, there are few cancer guidelines to aid clinicians in selecting the optimal dose in the obese-even recent guidelines are based predominantly on clinical opinion/current practice in treating obese patients, rather than evidence. Data in many other vulnerable groups, for example, those with significant comorbidity and older patients, are also scarce. Because of the known limitations of body surface area-guided dosing, therapeutic drug monitoring or pharmacokinetic-guided dosing, which predicts an individual's exposure, has increasingly been shown to be a powerful tool in cancer therapy. Used appropriately, it can adjust for differences in pharmacokinetic parameters not considered when body size-based dosing or "one dose fits all" is used. This review will focus predominantly on the rationale for pharmacokinetic-guided dosing of the newer oral molecularly targeted antineoplastics in people whose drug exposure is not predicted by their physiology or body composition.

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Section: Obesitymentioning

confidence: 99%

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

Lucas

Martin

2017

The Journal of Clinical Pharma

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“…It would be possible of course to have a separate weight descriptor for each gender. For example it has been argued that CL should relate best to lean body weight, as both are dependent on protein synthesis [8]. Since lean body weight as a fraction of total weight is lower in females, then there would be a separate adjustment factor for males and females if lean body weight was used.…”

Section: − ( )mentioning

confidence: 99%

A unified pharmacokinetic approach to individualized drug dosing

Begg

Chin

2012

Brit J Clinical Pharma

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The ideal in drug therapy is to achieve the right dose, of the right drug, for the right time, in the right patient. Choice of drug dosage regimen in order to achieve optimal drug concentrations in an individual patient is based on the likely pharmacokinetics in that individual. In the case of loading doses it is the volume of distribution (Vd) that is the major determinant, while for maintenance dosing the most important determinant is clearance (CL). The half-life is important for choice of dose interval, time to steadystate and time for drug removal from the body. While the broad approach is well defined, adoption of the principles in clinical practice is far from universal. This is exacerbated by the fact that the details of how Vd and CL are affected by different covariates are often not well defined. A logical approach would assist clinical practice and help direct further research.The initial doses chosen for an individual are based on an estimate of that individual's likely pharmacokinetic characteristics, usually by utilizing all known information about others in the population who resemble this individual. The population pharmacokinetic values are then adjusted for covariates such as age, weight, gender and any other characteristics that might make the individual different from the mean member of the population.Underlying this process are simple equations for loading dose (LD), which is based on Vd, and maintenance dose-rate, which is based on CL for drugs with first order elimination.The aim of the LD is to achieve an initial target concentration (Cinitial), whereas for the dose-rate it is to achieve a target steady state concentration (Css).Dose-rate CL ss = ×CBoth Vd and CL are usually estimated after intravenous administration. If calculated after oral administration then the oral availability needs to be considered. For simplicity in this paper we will ignore oral availability.These equations can be adjusted to accommodate any factor known to explain some of the variance in Vd or CL.The main covariates of CL are shown in Table 1 and are similar for Vd. Some of these covariates may be interdependent and should not be accounted for twice. It would be useful if the effect of covariates could be incorporated into universal equations for dose-individualization.As loading dose is often a single dose only, Vd matters less clinically than CL. The discussion is therefore focussed on CL and maintenance dosing.

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“…For calculating dosage adjustments, the individual GFR (assuming GFR ϭ creatinine Cl) according to Cockcroft and Gault (in ml/min) can be used to predict the drug Cl from S-crea (in mg/dl), weight (in kg), and age (in years) better than the normalized MDRD GFR (30). For females, 15% should be subtracted from Cockcroft and Gault GFR, and for overweight individuals, the lean body weight should be considered (31).…”

Section: Age-related Changes In Organ Functionmentioning

confidence: 99%

Review on Pharmacokinetics and Pharmacodynamics and the Aging Kidney

Aymanns¹,

Keller²,

Maus³

et al. 2010

Clinical Journal of the American Society of Nephrology

132

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In people who are aged >65 years, pharmacokinetics are influenced more by the loss of kidney function than by the aging process of any other organ. A GFR of 30 to 60 ml/min, suggestive of stage 3 kidney disease, is observed in 15 to 30% of elderly people. Drug dosing must be adjusted to both changing pharmacokinetics and pharmacodynamics; the pharmacodynamics might be influenced by the aging of other organs, too. Using our NEPharm database, we extracted abstracts with pharmacokinetic parameters since 1999 from a weekly PubMed search. The recorded data were analyzed and compared with published recommendations on drug dosage and use in the elderly. Purely age-related changes in pharmacokinetic parameters were recorded from publications on 127 drugs. The analysis of our NEPharm records revealed an average (mean ؎ SD) age-related prolongation of half-life of 1.39-fold (corresponding to ؉39 ؎ 61%). Contrasting to common opinion, mean changes in clearance (؊1 ؎ 54%) and volume of distribution (؉24 ؎ 56%) were even less. The modest changes in pharmacokinetics do not suggest general dosage modifications in the elderly for most drugs. Changes in pharmacodynamics justify the common medication rule in the elderly-"start low ؉ go slow"-especially for drugs that act on the central nervous system; however, in the case of anti-infective and anticancer therapy, the rule should be "hit hard ‫؍‬ start high ؉ go fast" to produce the target effect also in the elderly.

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Dosing in Obesity: A Simple Solution to a Big Problem

Cited by 223 publications

References 10 publications

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

A unified pharmacokinetic approach to individualized drug dosing

Review on Pharmacokinetics and Pharmacodynamics and the Aging Kidney

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