Adjusted versus actual body weight dosing of 4-factor prothrombin complex concentrate in obese patients with warfarin-associated major bleeding

Rates of obesity have substantially increased in recent years. Pharmacokinetics of drugs including chemotherapy is different in obese patients due to alteration in the clearance and volume of distribution. Thus, appropriate chemotherapy dosing for obese patients with malignant diseases is a significant issue. Limiting chemotherapy doses in overweight and obese patients may negatively influence the outcomes in these patients. ASCO has recently published clinical practice guidelines for conventional chemotherapy dosing for obese patients with cancer indicating that up to 40% of obese patients received reduced chemotherapy doses that are not based on actual body weight (ABW) [Grigg A, JCO 2012]. Concerns about toxicity or overdosing in obese patients, based on the use of ABW, are unfounded. Moreover, there is a paucity of information addressing the pharmacokinetics of high dose chemotherapy in obese patients undergoing hematopoietic stem cell transplantation (HSCT). A rather small international survey of drug dosing schemes among transplant centers revealed that there is no consensus regarding appropriate dose adjustment for obese patients [Grigg A, Leuk Lymphoma 1997]. Also, there is limited data on outcomes in obese versus non-obese patients in various small retrospective studies. For this reason, the ALWP of the EBMT constructed an electronic survey for assessing current practice of dose adjustment of chemotherapy in patients undergoing HSCT, in transplant centers and for planning retrospective analysis and prospective studies in the future. Fifty six EBMT centers from 27 countries filled the online survey. Among the 56 centers, the percentage of obese patients was less than 10% in 22 centers (40%), between 10 to 19% in 23 centers (42%) and more than 20% in 10 centers (17%). Forty five centers declared they adjust chemotherapy dose for obese patients (80.5%) and only 11 (19.5%) declared they do not adjust dose. Among centers which adjust dose, most uses BMI as the parameter for defining obesity (28 centers, 62%), others use percentage over the actual body weight (ABW) as the basis for defining obesity (11 centers, 24.5%), both BMI and ABW (3 centers, 6.7%) or other parameter (3 centers, 6.7%). Most of the centers that use BMI for adjusting dose define BMI > 30 kg/m2 as the cut-off value (formal definition for obesity), only one center uses morbid obesity (BMI > 40 kg/m2), and the remainder uses other cut-off values. Among 11 centers who use ABW, 9 use ABW more than 120% of ideal body weight for adjustment. Eighty four percents of the centers use one level of obesity for adjustment while the rest uses 2 levels. The method for determining the weight for chemotherapy calculation was actual body weight (ABW) in 16 centers, ideal body weight (IBW) in 10 centers, IBW + 25% of difference between IBW and ABW (IBW+0.25*(ABW-IBW)) in 16 centers and other methods in the rest. Among centers that use dose adjustment, 44% also cap the dose at 2 m2 for chemotherapy dose based on BSA while 56% do not cap. On the contrary, most of the centers (9/11) that do not adjust dose for weight also do not cap the BSA at 2 m2. Seventy nine percents of responding centers use the same approach to dose adjustments for myeloablative, reduced intensity (RIC) or non myeloablative (NMA) conditioning, while 21% reduce the dose less for RIC or NMA conditioning. For Busulfan dose only 7 centers monitor pharmacokinetics (pk). Eleven centers use ideal body weight for calculation, 17 centers use actual weight and 18 centers correct weight according to percentage over actual body weight. Conclusion This EBMT survey reveal large diversity among transplant centers regarding dose adjustment practice for high dose conditioning chemotherapy. Most of the EBMT centers use dose adjustment for obese patients and about half of them also cap BSA at 2 m2, while capping is uncommon in the centers that do not adjust dose. Thus, the range of the final dose is very wide. Even for Busulfan where dose is calculated normally according to ideal body weight, the diversity of dose given for obese patients is wide. Our next step is to analyze outcomes of transplantation according to dose adjustment practice and subsequently to formulate a methodology for future prospective studies. Disclosures: No relevant conflicts of interest to declare.

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The safety of dosing dalteparin based on actual body weight for the treatment of acute venous thromboembolism in obese patients: a rebuttal

Journal of Thrombosis and Haemostasis ◽

10.1111/j.1538-7836.2005.01475.x ◽

2005 ◽

Vol 3 (7) ◽

pp. 1550-1550 ◽

Cited By ~ 2

Author(s):

J. HARENBERG

Keyword(s):

Body Weight ◽

Venous Thromboembolism ◽

Actual Body ◽

Obese Patients ◽

Actual Body Weight ◽

Acute Venous Thromboembolism

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Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from cancer and leukemia group B study 8541.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.11.3000 ◽

1996 ◽

Vol 14 (11) ◽

pp. 3000-3008 ◽

Cited By ~ 129

Author(s):

G L Rosner ◽

J B Hargis ◽

D R Hollis ◽

D R Budman ◽

R B Weiss ◽

...

Keyword(s):

Breast Cancer ◽

Body Weight ◽

Confidence Interval ◽

Actual Body ◽

Obese Patients ◽

Actual Body Weight ◽

Obese Women ◽

Actual Weight ◽

Group B ◽

Leukemia Group

PURPOSE We examined data from a large clinical trial to determine if chemotherapy dosing according to actual body weight places obese patients at greater risk of toxicity. PATIENTS AND METHODS Cancer and Leukemia Group B (CALGB) study 8541, a randomized study of schedule and dose of adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) for stage II breast cancer patients with positive regional lymph nodes, provided data on 1,435 women for analysis. Using body-mass index (BMI), we classified a woman as obese if her BMI was > or = 27.3 kg/m2; doses were considered weight-based if within 5% of values calculated using actual weight. Our primary analysis concerned toxicity risks during cycle 1. RESULTS Among women who received weight-based doses of the most dose-intensive CAF regimen, 47% of obese and 51% of nonobese women experienced severe hematologic toxicity (grade > or = 3) during cycle 1 (P = .51, two-tailed). The overall risk ratio (obese v nonobese) of treatment failure among women who received weight-based doses during cycle 1 was 1.02 (95% confidence interval, 0.83 to 1.26), stratified by treatment and adjusted for number of positive nodes, menopausal status, hormone receptor status, and tumor size. The overall adjusted failure risk ratio (weight-based v reduced initial doses) was 0.73 (95% confidence interval, 0.53 to 1.00) among obese women. CONCLUSION Obese patients initially dosed (within 5%) by actual weight did not experience excess cycle 1 toxicity or worse outcome compared with nonobese women dosed similarly. The data suggest that obese women who received reduced doses in cycle 1 experienced worse failure-free survival. We recommend that initial doses of CAF be computed according to actual body weight.

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An Evaluation of Systemic Vancomycin Dosing in Obese Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofv176 ◽

2015 ◽

Vol 2 (4) ◽

Cited By ~ 3

Author(s):

David W. Kubiak ◽

Mohammed Alquwaizani ◽

David Sansonetti ◽

Megan E. Barra ◽

Michael S. Calderwood

Keyword(s):

Body Mass Index ◽

Morbid Obesity ◽

Body Weight ◽

Actual Body ◽

Initial Dose ◽

Ideal Body Weight ◽

Obese Patients ◽

Actual Body Weight ◽

Trough Concentrations ◽

Ideal Body

Abstract We retrospectively identified 67 patients with severe or morbid obesity (body mass index ≥35 kg/m2) who had received intravenous vancomycin at our institution. We observed that an initial dose of 45 to 65 mg/kg vancomycin per day based upon ideal body weight rather than actual body weight was more predictive of initial trough concentrations between 15 and 20 mcg/mL.

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Daptomycin dosing in obese patients: analysis of the use of adjusted body weight versus actual body weight

Therapeutic Advances in Infectious Disease ◽

10.1177/2049936118820230 ◽

2019 ◽

Vol 6 ◽

pp. 204993611882023 ◽

Cited By ~ 2

Author(s):

Ashley N. Fox ◽

Winter J. Smith ◽

Katherine E. Kupiec ◽

Stephanie J. Harding ◽

Beth H. Resman-Targoff ◽

...

Keyword(s):

Body Weight ◽

Actual Body ◽

Creatine Phosphokinase ◽

Obese Patients ◽

Actual Body Weight ◽

Clinical Failure ◽

Limited Information ◽

Single Center ◽

Historical Cohort ◽

Patient Reported

Background: Food and Drug Administration–approved daptomycin dosing uses actual body weight, despite limited dosing information for obese patients. Studies report alterations in daptomycin pharmacokinetics and creatine phosphokinase elevations associated with higher weight-based doses required for obese patients. Limited information regarding clinical outcomes with alternative daptomycin dosing strategies in obesity exists. Objective: This study evaluates equivalency of clinical and safety outcomes in obese patients with daptomycin dosed on adjusted body weight versus a historical cohort using actual body weight. Methods: This retrospective, single center study compared equivalency of outcomes with two one-sided tests in patients with body mass index ⩾30 kg/m2 who received daptomycin dosed on actual body weight versus adjusted body weight. The primary outcome was clinical failure. Secondary outcomes included 90-day readmission and 90-day mortality. A combined safety endpoint included creatine phosphokinase elevation, patient-reported myopathy, and rhabdomyolysis. Results: A total of 667 patients were screened for inclusion; 101 patients were analyzed with 50 in the actual body weight cohort and 51 in the adjusted body weight cohort. The two regimens were statistically equivalent for clinical failure (2% actual body weight versus 4% adjusted body weight; p < 0.001 for equivalency). The two regimens were also statistically equivalent for 90-day mortality (6% actual body weight versus 4% adjusted body weight; p = 0.0014 for equivalency). Limitations include single center, retrospective design, and sample size. Daptomycin dosing intensified throughout the study period. Conclusion: The two daptomycin dosing cohorts were statistically equivalent for both clinical failure and 90-day mortality. More data are needed to assess outcomes with higher (⩾8 mg/kg/day) daptomycin doses in this patient population.

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Less is More: Low-dose Prothrombin Complex Concentrate Effective in Acute Care Surgery Patients

The American Surgeon ◽

10.1177/000313481508100632 ◽

2015 ◽

Vol 81 (6) ◽

pp. 646-650 ◽

Cited By ~ 8

Author(s):

Jacob A. Quick ◽

Jennifer M. Meyer ◽

Jeffrey P. Coughenour ◽

Stephen L. Barnes

Keyword(s):

Body Weight ◽

Actual Body ◽

Acute Care ◽

Prothrombin Complex Concentrate ◽

Low Dose ◽

Acute Care Surgery ◽

Trauma Patients ◽

Actual Body Weight ◽

Plasma Transfusion ◽

Care Surgery

Optimal dosing of prothrombin complex concentrate (PCC) has yet to be defined and varies widely due to concerns of efficacy and thrombosis. We hypothesized a dose of 15 IU/kg actual body weight of a three-factor PCC would effectively correct coagulopathy in acute care surgery patients. Retrospective review of 41 acute care surgery patients who received 15 IU/kg (610%) actual body weight PCC for correction of coagulopathy. Demographics, laboratory results, PCC dose, blood and plasma transfusions, and thrombotic complications were analyzed. We performed subset analyses of trauma patients and those taking warfarin. Mean age was 69 years (18–94 years). Thirty (73%) trauma patients, 8 (20%) emergency surgery patients, 2 (5%) burns, and 1 (2%) non-trauma neurosurgical patient were included. Mean PCC dose was 1305.4 IU (14.2 IU/kg actual body weight). Mean change in INR was 2.52 to 1.42 (p 0.00004). Successful correction (INR <1.5) was seen in 78 per cent. Treatment failures had a higher initial INR (4.3 vs 2.03, p 0.01). Mean plasma transfusion was 1.46 units. Mean blood transfusion was 1.61 units. Patients taking pre-hospital warfarin (n = 29, 71%) had higher initial INR (2.78 vs 1.92, p 0.05) and received more units of plasma (1.93 vs 0.33, p 0.01) than those not taking warfarin. No statistical differences were seen between trauma and nontrauma patients. One thrombotic event occurred. Administration of low-dose PCC, 15 IU/kg actual body weight, effectively corrects coagulopathy in acute care surgery patients regardless of warfarin use, diagnosis or plasma transfusion.

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Evaluation of Alternate Size Descriptors for Dose Calculation of Anticancer Drugs in the Obese

Journal of Clinical Oncology ◽

10.1200/jco.2007.11.2938 ◽

2007 ◽

Vol 25 (30) ◽

pp. 4707-4713 ◽

Cited By ~ 104

Author(s):

Alex Sparreboom ◽

Antonio C. Wolff ◽

Ron H.J. Mathijssen ◽

Etienne Chatelut ◽

Eric K. Rowinsky ◽

...

Keyword(s):

Body Mass Index ◽

Body Weight ◽

Actual Body ◽

Lean Body Mass ◽

Anticancer Drugs ◽

Body Mass ◽

Dose Calculation ◽

Pharmacokinetic Parameters ◽

Obese Patients ◽

Actual Body Weight

Purpose Despite the rising prevalence of obesity, there is paucity of information describing how doses of anticancer drugs should be adjusted in clinical practice. Here, we assessed the pharmacokinetics of eight anticancer drugs in adults and evaluated the potential utility of alternative weight descriptors in dose calculation for the obese. Patients and Methods A total of 1,206 adult cancer patients were studied, of whom 162 (13.4%) were obese (body mass index ≥ 30). Pharmacokinetic parameters were calculated using noncompartmental analysis, and compared between lean (body mass index ≤ 25) and obese patients. Results The absolute clearance of cisplatin, paclitaxel, and troxacitabine was significantly increased in the obese (P < .023), but this was not observed for carboplatin, docetaxel, irinotecan, or topotecan (P < .17). For doxorubicin, the systemic clearance was statistically significantly reduced in obese women (P = .013), but not in obese men (P = .52). Evaluation of alternate weight descriptors for dose calculation in the obese, including predicted normal weight, lean body mass, (adjusted) ideal body weight, and the mean of ideal and actual body weight, indicated that, for most of the evaluated drugs, weight scalars used to calculate body-surface area should consider actual body weight regardless of size. Conclusion The results suggest that a number of widely used empiric strategies for dose adjustments in obese patients, including a priori dose reduction or dose capping, should be discouraged.

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