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.

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.

Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer.

1997 ◽  
Vol 15 (7) ◽  
pp. 2691-2700 ◽  
Author(s):  
M J McKeage ◽  
F Raynaud ◽  
J Ward ◽  
C Berry ◽  
D O'Dell ◽  
...  
Keyword(s):  
Phase I ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Platinum Complex ◽  
Maximum Tolerated Dose ◽  
Phase Ii Trials ◽  
Time Curve ◽  
Once Daily ◽  
Plasma Ultrafiltrate

PURPOSE We aimed to determine the maximum-tolerated dose (MTD) clinical toxicities, pharmacokinetics, and pharmacodynamics of oral JM216 given once daily for 5 days to cancer patients. PATIENTS AND METHODS Patients who fulfilled standard phase I trial criteria were enrolled. Oral JM216 was given at doses based on patient body-surface area, on an empty stomach, once daily for 5 consecutive days, as 10-, 50-, and 200-mg hard gelatin capsules and with oral antiemetics. The pharmacokinetics of platinum were studied on days 1 and 5 of the first treatment course using atomic absorption spectrophotometry (AAS). RESULTS Thirty-two patients received 94 courses of oral JM216 at doses that ranged from 30 to 140 mg/m2 body-surface area for 5 consecutive days. The MTD was 140 mg/m2/d. The dose-limiting toxicities were thrombocytopenia and neutropenia. Hematotoxicity was reversible (nadir, 17 to 21 days; recovery, 28 days), noncumulative, and dependent on the dose and history of previous therapy. There were two instances of neutropenic sepsis. Two-thirds of patients experienced mild nausea, vomiting, or diarrhea. There was no ototoxicity, neurotoxicity, nephrotoxicity, or objective tumor responses. There was a significant correlation between JM216 dose and the day 1 and 5 plasma ultrafiltrate area under the concentration-time curve (AUC; r = .78), which indicates linear pharmacokinetics. There was considerable intersubject pharmacokinetic and pharmacodynamic variability, but a significant sigmoidal relationship between the plasma ultrafiltrate AUC and severity of thrombocytopenia (R2 = .83). CONCLUSION We recommend JM216 doses of 100 and 120 mg/m2/d x 5 for previously treated and untreated patients, respectively, for phase II trials.

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.

Correlation Between Docetaxel Clearance and Estimated Cytochrome P450 Activity by Urinary Metabolite of Exogenous Cortisol

2000 ◽  
Vol 18 (11) ◽  
pp. 2301-2308 ◽  
Author(s):  
Noboru Yamamoto ◽  
Tomohide Tamura ◽  
Yoshikazu Kamiya ◽  
Ikuo Sekine ◽  
Hideo Kunitoh ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Practical Method ◽  
Interpatient Variability ◽  
Cyp3a4 Activity ◽  
Time Curve ◽  
Glycoprotein P ◽  
Cytochrome P450 Activity ◽  
Free Cortisol ◽  
Cyp3a4 Enzyme ◽  
The Individual

PURPOSE: There is no simple and practical method for the estimation of the interpatient variability of cytochrome P450 (CYP3A4) enzyme activity. Cortisol is metabolized by this enzyme and excreted as 6-beta-hydroxycortisol (6β-OHF) and free-cortisol (FC) in urine, and docetaxel is also metabolized by hepatic CYP3A4 enzyme. We developed a new method for the estimation of CYP3A4 activity by measuring urinary cortisol metabolite after administration of exogenous cortisol. This study was aimed at assessing the predictability of the individual activity of CYP3A4 estimated by this method. PATIENTS AND METHODS: Thirty patients with advanced non–small-cell lung cancer were entered onto this study. Hydrocortisone 300 mg was administered intravenously, and urinary 6β-OHF and FC were measured. More than 2 days later, 60 mg/m2 of docetaxel was administered intravenously with pharmacokinetic sampling. The correlation between docetaxel pharmacokinetics and estimated interpatient variability of CYP3A4 activity with the application of our method was assessed. RESULTS: After cortisol administration, the total amount of 24-hour urinary 6β-OHF (T6β-OHF) increased about 60-fold compared with pretreatment levels, averaging 12,273 ± 4,076 μg/d (mean ± SD). Docetaxel clearance (CL) and area under the concentration-time curve averaged 24.5 ± 6.4 L/h/m2 and 2.66 ± 0.91 mg/L 8729· h, respectively. An excellent correlation between docetaxel CL and T6β-OHF was observed (r = .867). In multivariate analysis, T6β-OHF (P < .001), alpha-1-acid glycoprotein (P < .004), AST (P = .007), and age (P = .022) significantly correlated with docetaxel CL. CONCLUSION: The interpatient variability of CYP3A4 activity and docetaxel CL could be predicted by measuring T6β-OHF after cortisol administration.

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.

The use of Body Surface Index as a Better Clinical Health indicators Compare to Body Mass Index and Body Surface Area for Clinical Application

2018 ◽  
pp. 131-136
Author(s):  
Shirazu I. ◽  
Theophilus. A. Sackey ◽  
Elvis K. Tiburu ◽  
Mensah Y. B. ◽  
Forson A.
Keyword(s):  
Surface Area ◽  
Body Surface Area ◽  
Clinical Application ◽  
Body Surface ◽  
Body Height ◽  
Health Indicators ◽  
The Body ◽  
Body Parameters ◽  
The Relationship ◽  
Individual Body

The relationship between body height and body weight has been described by using various terms. Notable among them is the body mass index, body surface area, body shape index and body surface index. In clinical setting the first descriptive parameter is the BMI scale, which provides information about whether an individual body weight is proportionate to the body height. Since the development of BMI, two other body parameters have been developed in an attempt to determine the relationship between body height and weight. These are the body surface area (BSA) and body surface index (BSI). Generally, these body parameters are described as clinical health indicators that described how healthy an individual body response to the other internal organs. The aim of the study is to discuss the use of BSI as a better clinical health indicator for preclinical assessment of body-organ/tissue relationship. Hence organ health condition as against other body composition. In addition the study is `also to determine the best body parameter the best predict other parameters for clinical application. The model parameters are presented as; modeled height and weight; modelled BSI and BSA, BSI and BMI and modeled BSA and BMI. The models are presented as clinical application software for comfortable working process and designed as GUI and CAD for use in clinical application.

Oxygen Fraction Adjustment According to Body Surface Area during Extracorporeal Circulation

2015 ◽  
Vol 18 (3) ◽  
pp. 098
Author(s):  
Cem Arıtürk ◽  
Serpil Ustalar Özgen ◽  
Behiç Danışan ◽  
Hasan Karabulut ◽  
Fevzi Toraman
Keyword(s):  
Body Temperature ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Extracorporeal Circulation ◽  
Group Iii ◽  
Oxygen Fraction ◽  
Arterial Blood ◽  
Group I ◽  
Group Ii

<p class="p1"><span class="s1"><strong>Background:</strong> The inspiratory oxygen fraction (FiO<sub>2</sub>) is usually set between 60% and 100% during conventional extracorporeal circulation (ECC). However, this strategy causes partial oxygen pressure (PaO<sub>2</sub>) to reach hyperoxemic levels (&gt;180 mmHg). During anesthetic management of cardiothoracic surgery it is important to keep PaO<sub>2</sub> levels between 80-180 mmHg. The aim of this study was to assess whether adjusting FiO<sub>2</sub> levels in accordance with body temperature and body surface area (BSA) during ECC is an effective method for maintaining normoxemic PaO<sub>2</sub> during cardiac surgery.</span></p><p class="p1"><span class="s1"><strong>Methods:</strong> After approval from the Ethics Committee of the University of Acıbadem, informed consent was given from 60 patients. FiO<sub>2</sub> adjustment strategies applied to the patients in the groups were as follows: FiO<sub>2</sub> levels were set as 0.21 × BSA during hypothermia and 0.21 × BSA + 10 during rewarming in Group I; 0.18 × BSA during hypothermia and 0.18 × BSA + 15 during rewarming in Group II; and 0.18 × BSA during hypothermia and variable with body temperature during rewarming in Group III. Arterial blood gas values and hemodynamic parameters were recorded before ECC (T1); at the 10th minute of cross clamp (T2); when the esophageal temperature (OT) reached 34°C (T3); when OT reached 36°C (T4); and just before the cessation of ECC (T5).</span></p><p class="p1"><span class="s1"><strong>Results:</strong> Mean PaO<sub>2</sub> was significantly higher in Group I than in Group II at T2 and T3 (<em>P</em> = .0001 and <em>P</em> = .0001, respectively); in Group I than in Group III at T1 (<em>P</em> = .02); and in Group II than in Group III at T2, T3, and T4 <br /> (<em>P</em> = .0001 for all). </span></p><p class="p1"><span class="s1"><strong>Conclusion: </strong>Adjustment of FiO<sub>2</sub> according to BSA rather than keeping it at a constant level is more appropriate for keeping PaO<sub>2</sub> between safe level limits. However, since oxygen consumption of cells vary with body temperature, it would be appropriate to set FiO<sub>2</sub> levels in concordance with the body temperature in the <br /> rewarming period.</span></p>

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