Evaluation of an Alternate Dosing Strategy for Cisplatin in Patients With Extreme Body Surface Area Values

2006 ◽  
Vol 24 (10) ◽  
pp. 1499-1506 ◽  
Author(s):  
Walter J. Loos ◽  
Felix E. de Jongh ◽  
Alex Sparreboom ◽  
Ronald de Wit ◽  
Desiree M. van Boven-van Zomeren ◽  
...  
Keyword(s):  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Drug Exposure ◽  
Normal Population ◽  
Fixed Dose ◽  
Interpatient Variability ◽  
Average Patient ◽  
Dosing Strategy ◽  
Adjusted Dose

Purpose The majority of cytotoxic drugs for adults are dosed based on body surface area (BSA), aiming to reduce interpatient variability in drug exposure. We prospectively studied the usefulness of BSA-based dosing of cisplatin in patients at extremes of BSA values. Patients and Methods Patients were randomly assigned to receive a fixed dose of cisplatin in course 1, and a BSA-adjusted dose in course 2, or vice versa. The fixed dose was based on the average BSA for males and females, while extremes were set at BSA values exceeding the average ± 1 standard deviation. Subsequently, we retrospectively analyzed data from a normal population. Results In 25 patients assessable for both courses, the use of a fixed dose of cisplatin resulted in reduced exposure to unbound platinum in patients at the upper extremes of BSA (P = .003) and higher exposures in patients at the lower extremes (P = .009), as compared with exposures following the BSA-adjusted dose. Although clearance was related to BSA (R2 = 0.44; P < .001), only a small reduction in interpatient variability in clearance after correction for BSA was achieved (20.8% v 17.1%). In the retrospective analysis, compared with the average patient, the clearance of unbound platinum in patients with a BSA value ≤ 1.65 m2 was 16% slower (P < .001), while an 18% faster clearance (P < .001) was observed in patients with a BSA value ≥ 2.05 m2. Conclusion Unless better predictors for platinum clearance are identified, fixed-dose regimens per BSA cluster (≤ 1.65 m2; 1.66 m2 to 2.04 m2; ≥ 2.05 m2) are recommended.

Predictors of Vinorelbine Pharmacokinetics and Pharmacodynamics in Patients With Cancer

2006 ◽  
Vol 24 (16) ◽  
pp. 2448-2455 ◽  
Author(s):  
Mark Wong ◽  
Rosemary L. Balleine ◽  
Elaine Y.L. Blair ◽  
Andrew J. McLachlan ◽  
Stephen P. Ackland ◽  
...  
Keyword(s):  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Drug Disposition ◽  
Multivariable Analysis ◽  
Drug Clearance ◽  
Interindividual Variation ◽  
Fixed Dose ◽  
Population Pharmacokinetic ◽  
Patients With Cancer

Purpose Marked interindividual variation in drug disposition and toxicity pose an ongoing challenge to chemotherapy dosage individualization. The aim of this study was to evaluate pretreatment clinical features, genotype and functional indicators of drug clearance as predictors of vinorelbine clearance, and myelotoxicity that could inform dosage optimization. Patients and Methods Forty-one patients with cancer received a 60 mg intravenous dose of vinorelbine. Pretreatment routine body size measurements and blood tests were performed. Midazolam clearance and hepatic technetium labeled sestamibi (99mTc-MIBI) clearance were used to investigate CYP3A and ABCB1 (MDR1, P-glycoprotein) phenotype respectively and selected single nucleotide polymorphisms in CYP3A and ABCB1 were documented. A limited blood sampling strategy was employed and vinorelbine concentrations were determined by high-performance liquid chromatography. Posterior Bayesian estimates of vinorelbine clearance were obtained for each patient using population pharmacokinetic modeling. Myelotoxicity was estimated from the fractional survival of neutrophils post-treatment. Results There was 4.3-fold variation in vinorelbine clearance across the cohort. In a multivariable analysis, pretreatment estimated creatinine clearance (P < .01) and hepatic 99mTc-MIBI clearance (P = .01) were independent predictors of vinorelbine clearance. Fractional survival of neutrophils ranged from 1.3% to 100% and was significantly correlated with vinorelbine clearance (P < .01). Body-surface area was the only pretreatment predictor of fractional survival of neutrophils independent of vinorelbine clearance (P = .02). Conclusion Specific indicators of drug clearance provide predictive information about vinorelbine pharmacokinetics, and body-surface area, probably reflecting normal bone marrow reserve, provides an additional pharmacodynamic indicator. Use of a fixed dose of vinorelbine with modifications guided by pretreatment measures is worthy of prospective evaluation.

scholarly journals Population Pharmacokinetic Model for Gatifloxacin in Pediatric Patients

2007 ◽  
Vol 51 (4) ◽  
pp. 1246-1252 ◽  
Author(s):  
Christopher M. Rubino ◽  
Edmund V. Capparelli ◽  
John S. Bradley ◽  
Jeffrey L. Blumer ◽  
Gregory L. Kearns ◽  
...  
Keyword(s):  
Body Weight ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Population Pharmacokinetic ◽  
Forward Selection ◽  
Once Daily

ABSTRACT The broad spectrum of antimicrobial activity, oral bioavailability, extensive tissue distribution, and once-daily intravenous or oral dosing of gatifloxacin, an expanded-spectrum 8-methoxy fluoroquinolone, make it a potentially useful agent for the treatment of pediatric infections. A population pharmacokinetic model was developed to describe the pharmacokinetics of gatifloxacin in children. Data for analysis were obtained from a single-dose safety/pharmacokinetic study utilizing intensive blood sampling in patients aged 6 months to 16 years. Each subject received a single oral dose of gatifloxacin as a suspension, at doses of 5, 10, or 15 mg/kg of body weight. A total of 845 samples were obtained from 82 patients. A one-compartment model with first-order absorption and elimination was the most appropriate to describe the gatifloxacin concentrations. Covariate analysis using forward selection and backward elimination found that apparent clearance was related to body surface area, and apparent volume of distribution was related to body weight. No effect of age on drug clearance could be identified once clearance was corrected for body surface area. Based on pharmacokinetic simulations, the 10-mg/kg (maximum, 400 mg) once-daily dose of gatifloxacin is expected to provide drug exposure similar to that in healthy adults. The population pharmacokinetic model described herein will be used for Bayesian analyses of sparse pharmacokinetic sampling in phase II/III clinical trials and for Monte Carlo simulation experiments. The success of this strategy provides a model for future pediatric drug development programs.

scholarly journals Body surface area-based equivalent dose calculation in tree shrew

2021 ◽  
Vol 104 (2) ◽  
pp. 003685042110169
Author(s):  
Wei Xia ◽  
Zong-Jian Huang ◽  
Yi-Wei Feng ◽  
An-Zhou Tang ◽  
Lei Liu
Keyword(s):  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Tree Shrew ◽  
Dose Calculation ◽  
The Body ◽  
Equivalent Dose ◽  
Tree Shrews ◽  
Km Value ◽  
Dosing Strategy

Tree shrew (Tupaia belangeri) is a promising experimental animal in biomedical research, but the equivalent doses of drugs between tree shrew and human and other animals has not been explored, which hinders its further application in a wider scope. The main objective of this article is to provide a method of equivalent dose conversion between tree shrews and other species based on body surface area (BSA). BSA of tree shrews were measured by Image J software, and then the average Km value of tree shrews was figured out based on the body weights and BSA, then the conversion coefficients of equivalent dose among tree shrew and other species of experimental animals were calculated based known data. The Km value of tree shrews was 0.105 ± 0.001. Through BSA conversion, the equivalent dose for tree shrews (D-ts) relative to rats was obtained by formula: D-ts = 1.36 × D-a (rats weighing 200 g as example), and the error was less than 10% when the BW of the tree shrew was 0.09 kg–0.15 kg. The coefficients of equivalent dose transferring from tree shrews to human and other species were calculated in article. These parameters could be used to determine a suitable dosing strategy for tree shrew studies.

Randomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous Cortisol

2005 ◽  
Vol 23 (6) ◽  
pp. 1061-1069 ◽  
Author(s):  
Noboru Yamamoto ◽  
Tomohide Tamura ◽  
Haruyasu Murakami ◽  
Tatsu Shimoyama ◽  
Hiroshi Nokihara ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Urinary Metabolite ◽  
Interpatient Variability ◽  
Time Curve ◽  
Percentage Decrease ◽  
Cytochrome P450 Activity ◽  
Individualized Dosing

Purpose Docetaxel is metabolized by cytochrome P450 (CYP3A4) enzyme, and the area under the concentration-time curve (AUC) is correlated with neutropenia. We developed a novel method for estimating the interpatient variability of CYP3A4 activity by the urinary metabolite of exogenous cortisol (6-beta-hydroxycortisol [6-β-OHF]). This study was designed to assess whether the application of our method to individualized dosing could decrease pharmacokinetic (PK) and pharmacodynamic (PD) variability compared with body-surface area (BSA) –based dosing. Patients and Methods Fifty-nine patients with advanced non–small-cell lung cancer were randomly assigned to either the BSA-based arm or individualized arm. In the BSA-based arm, 60 mg/m2 of docetaxel was administered. In the individualized arm, individualized doses of docetaxel were calculated from the estimated clearance (estimated clearance = 31.177 + [7.655 × 10−4 × total 6-β-OHF] − [4.02 × alpha-1 acid glycoprotein] − [0.172 × AST] − [0.125 × age]) and the target AUC of 2.66 mg/L · h. Results In the individualized arm, individualized doses of docetaxel ranged from 37.4 to 76.4 mg/m2 (mean, 58.1 mg/m2). The mean AUC and standard deviation (SD) were 2.71 (range, 2.02 to 3.40 mg/L · h) and 0.40 mg/L · h in the BSA-based arm, and 2.64 (range, 2.15 to 3.07 mg/L · h) and 0.22 mg/L · h in the individualized arm, respectively. The SD of the AUC was significantly smaller in the individualized arm than in the BSA-based arm (P < .01). The percentage decrease in absolute neutrophil count (ANC) averaged 87.1% (range, 59.0 to 97.7%; SD, 8.7) in the BSA-based arm, and 87.4% (range, 78.0 to 97.2%; SD, 6.1) in the individualized arm, suggesting that the interpatient variability in percent decrease in ANC was slightly smaller in the individualized arm. Conclusion The individualized dosing method based on the total amount of urinary 6-β-OHF after cortisol administration can decrease PK variability of docetaxel.

scholarly journals Comparison of toxicity and effectiveness between fixed-dose and body surface area-based dose capecitabine

2019 ◽  
Vol 11 ◽  
pp. 175883591983896 ◽  
Author(s):  
Femke M. de Man ◽  
G.D. Marijn Veerman ◽  
Esther Oomen-de Hoop ◽  
Maarten J. Deenen ◽  
Didier Meulendijks ◽  
...  
Keyword(s):  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Progression Free Survival ◽  
Fixed Dose ◽  
Large Set ◽  
Chi Square ◽  
Comparable Group ◽  
Radiotherapy Group ◽  
Toxicity Scores

Background: Capecitabine is generally dosed based on body surface area (BSA). This dosing strategy has several limitations; however, evidence for alternative strategies is lacking. Therefore, we analyzed the toxicity and effectiveness of fixed-dose capecitabine and compared this strategy with a BSA-based dose of capecitabine in a large set of patients. Methods: Patients treated with fixed-dose capecitabine between 2003 and 2015 were studied. A comparable group of patients, dosed based on BSA, was chosen as a control cohort. A total of two combined scores were used: capecitabine-specific toxicity (diarrhea, National Cancer Institute Common Toxicity Criteria grade ⩾3, hand-foot syndrome ⩾2, or neutropenia ⩾2), and clinically relevant events due to toxicity, that is, hospital admission, dose reduction, or discontinuation. Per treatment regimen, patients were divided into three BSA groups based on BSA quartiles corrected for sex. Toxicity scores were compared by a Chi-square test between cohorts, and within cohorts using BSA groups. Progression-free survival (PFS) was estimated by the Kaplan–Meier method. Results: A total of 2319 patients were included (fixed dosed, n = 1126 and BSA-based dose, n = 1193). Overall, four regimens were evaluated: capecitabine-radiotherapy ( n = 1178), capecitabine-oxaliplatin ( n = 519), capecitabine triplet ( n = 181) and capecitabine monotherapy ( n = 441). The incidence of capecitabine-specific toxicity and clinically relevant events was comparable between fixed-dose and BSA-dosed patients, while a small difference (7.1%) in absolute dose was found. Both cohorts showed only a higher incidence of both toxicity scores in the lowest BSA group of the capecitabine-radiotherapy group ( p < 0.05). Subgroups of the fixed-dose cohort analyzed for PFS, showed no differences between BSA groups. Conclusions: Fixed-dose capecitabine is as comparably well tolerated and effective as BSA-based dosing and could be considered as a reasonable alternative for BSA-based dosing.

Body-Surface Area–Based Dosing Does Not Increase Accuracy of Predicting Cisplatin Exposure

2001 ◽  
Vol 19 (17) ◽  
pp. 3733-3739 ◽  
Author(s):  
Felix E. de Jongh ◽  
Jaap Verweij ◽  
Walter J. Loos ◽  
Ronald de Wit ◽  
Maja J.A. de Jonge ◽  
...  
Keyword(s):  
Surface Area ◽  
Body Surface Area ◽  
Anticancer Drugs ◽  
Body Surface ◽  
Interindividual Variability ◽  
Drug Effects ◽  
Pharmacokinetic Interaction ◽  
Absorption Spectrometry ◽  
Interpatient Variability ◽  
Large Patient

PURPOSE: Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population. PATIENTS AND METHODS: Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel. Cisplatin was administered either weekly (n = 93) or once every 3 weeks (n = 175) at dose levels of 50 to 100 mg/m2 (3-hour infusion). Analysis of 485 complete courses was based on measurement of total and non–protein-bound cisplatin in plasma by atomic absorption spectrometry. RESULTS: No pharmacokinetic interaction was found between cisplatin and the anticancer drugs used in combination therapies. A linear correlation was observed between area under the curves of unbound and total cisplatin (r = 0.63). The mean plasma clearance of unbound cisplatin (CLfree) was 57.1 ± 14.7 L/h (range, 31.0 to 116 L/h), with an interpatient variability of 25.6%. BSA varied between 1.43 and 2.40 m2 (mean, 1.86 ± 0.19 m2), with an interpatient variability of 10.4%. When CLfree was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CLfree and BSA (r = 0.42). Intrapatient variability in CLfree, calculated from 90 patients was 12.1% ± 7.8% (range, 0.30% to 32.7%). CONCLUSION: In view of the high interpatient variability in CLfree relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin.

Randomized Cross-Over Evaluation of Body-Surface Area–Based Dosing Versus Flat-Fixed Dosing of Paclitaxel

2003 ◽  
Vol 21 (2) ◽  
pp. 197-202 ◽  
Author(s):  
Carolien H. Smorenburg ◽  
Alex Sparreboom ◽  
Marijke Bontenbal ◽  
Gerrit Stoter ◽  
Kees Nooter ◽  
...  
Keyword(s):  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Interindividual Variability ◽  
Dose Calculation ◽  
Fixed Dose ◽  
Total Blood ◽  
Mean Values ◽  
Wide Interindividual Variability

Purpose: Despite dose calculation using body-surface area (BSA), pharmacokinetics of most anticancer drugs show wide interindividual variability. In this study, we evaluated the role of BSA in paclitaxel disposition. Patients and Methods: Paclitaxel pharmacokinetics were prospectively studied in 12 patients that were treated in a randomized cross-over design with paclitaxel (3-hour infusion at a 3-week interval) at 175 mg/m2 in cycle 1 (A) and a flat-fixed dose of 300 mg in cycle 2 (B), or vice versa. Blood samples were collected up to 24 hours after dosing and analyzed for total and unbound paclitaxel. Results: The area under the curves (AUC) of unbound paclitaxel were similar in both dosing groups, with mean values ± SD (A v B) of 1.34 ± 0.158 versus 1.30 ± 0.329 μM•h, indicating that BSA-based dosing reduced the coefficient of variation by 53.3%. Unbound and total paclitaxel clearance was also significantly related to various body-size measures, including BSA (R ≥ 0.617; P ≤ .033), weight (R ≥ 0.621; P ≤ .031), and lean-body mass (r ≥ 0.630; P ≤ .028). We hypothesize that this is caused by the association of paclitaxel in the circulation with Cremophor EL, the distribution of which is linked to total blood volume, and thus to BSA. Conclusion: This study indicates that paclitaxel disposition is significantly related to BSA. This provides a pharmacokinetic rationale for BSA-based dosing of this drug.

Risk Factors for Bleeding during Treatment of Acute Venous Thromboembolism

1996 ◽  
Vol 76 (05) ◽  
pp. 682-688 ◽  
Author(s):  
Jos P J Wester ◽  
Harold W de Valk ◽  
Karel H Nieuwenhuis ◽  
Catherine B Brouwer ◽  
Yolanda van der Graaf ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Small Body ◽  
Bleeding Risk ◽  
Risk Scores ◽  
Risk Of Bleeding ◽  
Acute Venous Thromboembolism

Summary Objective: Identification of risk factors for bleeding and prospective evaluation of two bleeding risk scores in the treatment of acute venous thromboembolism. Design: Secondary analysis of a prospective, randomized, assessor-blind, multicenter clinical trial. Setting: One university and 2 regional teaching hospitals. Patients: 188 patients treated with heparin or danaparoid for acute venous thromboembolism. Measurements: The presenting clinical features, the doses of the drugs, and the anticoagulant responses were analyzed using univariate and multivariate logistic regression analysis in order to evaluate prognostic factors for bleeding. In addition, the recently developed Utrecht bleeding risk score and Landefeld bleeding risk index were evaluated prospectively. Results: Major bleeding occurred in 4 patients (2.1%) and minor bleeding in 101 patients (53.7%). For all (major and minor combined) bleeding, body surface area ≤2 m2 (odds ratio 2.3, 95% Cl 1.2-4.4; p = 0.01), and malignancy (odds ratio 2.4, 95% Cl 1.1-4.9; p = 0.02) were confirmed to be independent risk factors. An increased treatment-related risk of bleeding was observed in patients treated with high doses of heparin, independent of the concomitant activated partial thromboplastin time ratios. Both bleeding risk scores had low diagnostic value for bleeding in this sample of mainly minor bleeders. Conclusions: A small body surface area and malignancy were associated with a higher frequency of bleeding. The bleeding risk scores merely offer the clinician a general estimation of the risk of bleeding. In patients with a small body surface area or in patients with malignancy, it may be of interest to study whether limited dose reduction of the anticoagulant drug may cause less bleeding without affecting efficacy.

Sign in / Sign up

Export Citation Format

Share Document