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.

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.

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.

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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