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.

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.

Rituximab Exhibits a Long Half-Life Based on a Population Pharmacokinetic Analysis in Non-Hodgkin’s Lymphoma (NHL) Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2371-2371 ◽  
Author(s):  
Jing Li ◽  
Micha Levi ◽  
Jean-Eric Charoin ◽  
Nicolas Frey ◽  
Thian Kheoh ◽  
...  
Keyword(s):  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Half Life ◽  
Tumor Burden ◽  
Individual Variability ◽  
Hodgkin's Lymphoma ◽  
Population Pharmacokinetic ◽  
Non Hodgkin's Lymphoma ◽  
Chop Therapy

Abstract The mean serum half life of rituximab reported in the current approved package insert (February 2007) is 76.3 and 205.8 hours following the first and fourth infusions, respectively. This results is based on data from 14 Non-Hodgkin’s Lymphoma (NHL) patients treated with a dose of 375 mg/m2 weekly × 4 analyzed using non-compartmental analysis (NCA). The aims of the current analysis were: to develop a population pharmacokinetic (POP PK) model using a large NHL patient population to investigate possible mechanisms that may explain the observed increase in half-life with time such as a B-cell/tumor burden mediated clearance to identify covariates as potential predictors of PK variability. The population PK analysis was performed using NONMEM V based on 3739 rituximab serum concentration samples from 298 patients who received rituximab as a single agent or in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy from six clinical studies. Tested covariates evaluated included body surface area (BSA), gender, age, race, WHO status, baseline CD19+ counts, sum of the tumor perpendicular diameters (SPD) of tumor and CHOP therapy. A non-parametric bootstrap procedure was used to estimate the precision of model parameters, and the model performance was assessed using visual predictive check. Rituximab concentration data were best described by a two-compartment model with time-varying clearance. Total clearance comprised of two terms, a non-specific clearance pathway (CL1), which remains unchanged throughout treatment, and a specific clearance pathway (CL2, B cells/tumor burden mediated), which decreased at a first-order decay rate from its initial value following the first infusion. The typical population estimates of rituximab nonspecific clearance (CL1), specific clearance (CL2), and central compartment volume of distribution (V1) were 0.14 L/day, 0.59 L/day, and 2.7 L, respectively. Age, gender, race, and WHO performance status had no effect on the PK of rituximab. Covariate analysis revealed that patients with higher CD19 counts or SPD of tumor burden at baseline had a higher rituximab CL2, while V1 varied by body surface area (BSA) and CHOP chemotherapy. However, unexplained inter-individual variability remained high for CL2 following correction for CD19/SPD. Changes from typical V1 values contributed by extreme BSA (1.53 to 2.32 m2) and concurrent CHOP therapy, were relatively minor (27.1% and 19.0%) and explained 27.3% and 5.75% of the inter-individual variability in V1, respectively. Dose adjustment for the tested covariates is not expected to result in a meaningful reduction in rituximab PK variability. Retrospective analysis of rituximab PK using non linear mixed effect modeling confirmed that rituximab elimination decreased following multiple infusions. The median of individual estimates of rituximab terminal half-life was 22 days (range, 6.1 to 52 days), which is typical for immunoglobulin isotype IgG in human and is longer than that reported for humanized anti-CD20 clinical candidates, IMMU106 and of atumumab of 12.0 and 14.3 days, respectively.

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 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.

scholarly journals Tigecycline Population Pharmacokinetics in Patients with Community- or Hospital-Acquired Pneumonia

2010 ◽  
Vol 54 (12) ◽  
pp. 5180-5186 ◽  
Author(s):  
Christopher M. Rubino ◽  
Alan Forrest ◽  
Sujata M. Bhavnani ◽  
Gary Dukart ◽  
Angel Cooper ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Community Or ◽  
Hospital Acquired Pneumonia ◽  
Hospital Acquired

ABSTRACT Tigecycline is a new-generation of tetracycline (glycylcyclines) and is active in vitro against bacteria that possess any of the classical genes that confer tetracycline resistance through ribosomal protection or efflux pumps. Herein, tigecycline disposition in patients with community- or hospital-acquired pneumonia was described using a population pharmacokinetic model. Additionally, the influence of covariates, such as body surface area, severity of illness, and clinical laboratory measures, on tigecycline disposition was evaluated. An intravenous loading dose of 100 mg was followed by 50 mg of tigecycline every 12 h. The final population pharmacokinetic model was a two-compartment model with linear elimination and with a relationship between tigecycline clearance and body surface area and creatinine clearance. The model was parameterized using total clearance (CL), the volume of the central compartment, distributional clearance from the central to the peripheral compartment, and volumes of distribution at steady state. Relationships between body surface area and creatinine clearance were identified as significant predictors of interindividual variability on CL. This model will serve as the basis for estimating tigecycline exposure for pharmacokinetic-pharmacodynamic analyses for efficacy and safety among patients with community- or hospital-acquired pneumonia.

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.

scholarly journals Population Pharmacokinetic Study of Cefazolin Dosage Adaptation in Bacteremia and Infective Endocarditis Based on a Nomogram

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Ronan Bellouard ◽  
Colin Deschanvres ◽  
Guillaume Deslandes ◽  
Éric Dailly ◽  
Nathalie Asseray ◽  
...  
Keyword(s):  
Body Weight ◽  
Infective Endocarditis ◽  
Continuous Infusion ◽  
Population Pharmacokinetics ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Daily Dose

ABSTRACT Optimal dosing of continuous-infusion cefazolin can be challenging in patients being treated for bacteremia or infective endocarditis. The aim of this work is to describe and analyze the pharmacokinetics of cefazolin in those patients using a population pharmacokinetics modeling approach and to establish a nomogram to determine the optimal daily dose. Population pharmacokinetics were modeled using the Pmetrics package for R. Plasma concentrations were collected retrospectively from patients treated with continuous-infusion cefazolin for bacteremia or infective endocarditis. The influence of multiple parameters, including renal function, total body weight, body mass index, body surface area (BSA), ideal weight, lean body weight, height, and age, was tested. The probabilities of target attainment for selected target concentrations (40, 60, and 80 mg/liter) were calculated. A dosing nomogram was then developed, using the absolute value of the glomerular filtration rate (aGFR), to determine the optimal daily dose required to achieve the target concentrations in at least 90% of patients. In total, 346 cefazolin plasma concentrations from 162 patients were collected. A one-compartment model best described the data set. The only covariate was aGFR, calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and the patient’s body surface area, for the rate of elimination. Using the nomogram, achieving a cefazolin concentration target of 40 mg/liter with a success rate of at least 90% and with an aGFR of 30, 60, 90, and 120 ml/min requires a daily dose of 2.6, 4.3, 6.1, and 8.0 g/day, respectively. These results confirm the interest of posology adaptation of cefazolin according to aGFR.

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