scholarly journals Implications for IV posaconazole dosing in the era of obesity

2020 ◽  
Vol 75 (4) ◽  
pp. 1006-1013 ◽  
Author(s):  
Roeland E Wasmann ◽  
Cornelis Smit ◽  
Marieke H van Donselaar ◽  
Eric P A van Dongen ◽  
René M J Wiezer ◽  
...  
Keyword(s):  
Body Size ◽  
Fungal Infections ◽  
Oral Treatment ◽  
Total Body Weight ◽  
Normal Weight ◽  
Therapeutic Drug ◽  
Morbidly Obese ◽  
Population Pharmacokinetic ◽  
Antimicrobial Drugs ◽  
Starting Point

Abstract Background The prevalence of obesity has shown a dramatic increase over recent decades. Obesity is associated with underdosing of antimicrobial drugs for prophylaxis and treatment. Posaconazole is a broad-spectrum triazole antifungal drug licensed for prophylaxis and treatment of invasive fungal infections. It is unclear how posaconazole should be dosed in obese patients. Methods We performed a prospective study investigating the pharmacokinetics of posaconazole in morbidly obese (n = 16) and normal-weight (n = 8) subjects, with a weight ranging between 61.4 and 190 kg, after a 300 or 400 mg IV dose. Population pharmacokinetic modelling was used to assess the effect of body size on posaconazole pharmacokinetics. ClinicalTrials.gov Identifier: NCT03246386. Results Total body weight best predicted changes in CL and V. Model-based simulations demonstrated that, for treatment of fungal infections, a daily IV dose of 300 mg will result in a PTA of ≥90% in individuals up to 140 kg, after which both twice daily loading and the daily maintenance dose should be increased to 400 mg. For prophylaxis, a 300 mg IV dose is adequate in patients up to 190 kg. Conclusions Body size has a significant impact on posaconazole CL and V, resulting in a lower exposure in obese subjects compared with normal-weight subjects. For therapeutic use of posaconazole, a dose increase is required in patients above 140 kg. For prophylaxis, a 300 mg IV dose is adequate. For oral treatment, these recommendations can act as a starting point followed by therapeutic drug monitoring.

scholarly journals Pharmacokinetics of Anidulafungin in Obese and Normal-Weight Adults

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Roeland E. Wasmann ◽  
Rob ter Heine ◽  
Eric P. van Dongen ◽  
David M. Burger ◽  
Vincent J. Lempers ◽  
...  
Keyword(s):  
Reference Value ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Normal Weight ◽  
Pharmacokinetic Parameters ◽  
Morbidly Obese ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Obese Subjects

ABSTRACT In 2025, approximately one out of five adults will be obese. Physiological changes associated with obesity have been shown to influence the pharmacokinetics of drugs. Anidulafungin is frequently used in critically ill patients, and to achieve optimal efficacy, it is essential that its dose is appropriate for each patient's characteristics. We combined data from obese subjects with data from normal-weight subjects and determined an optimal dosing regimen for obese patients by population pharmacokinetic modeling. Twenty adults, 12 of which were normal-weight healthy subjects (median weight, 67.7 kg; range, 61.5 to 93.6 kg) and 8 of which were morbidly obese subjects (median weight, 149.7 kg; range, 124.1 to 166.5 kg) were included in the analysis. Subjects received a single dose of 100 mg anidulafungin intravenously over 90 min, upon which blood samples were obtained. Monte Carlo simulations were performed to optimize dosing in obesity. A three-compartment model and equal volumes of distribution described the data best. Total body weight was identified as a descriptor for both clearance and the volume of distribution, but the effect of weight on these parameters was limited. Simulations showed that with the licensed 100-mg dose, more than 97% of subjects with a weight above 140 kg will have an area under the concentration-time curve from 0 to 24 h of less than 99 mg · h/liter (the reference value for normal-weight individuals). We found that in obese and normal-weight subjects, weight influenced both of the anidulafungin pharmacokinetic parameters clearance and volume of distribution, implying a lower exposure to anidulafungin in (morbidly) obese individuals. Consequently, a 25% increase in the loading and maintenance doses could be considered in patients weighing more than 140 kg.

Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis

2021 ◽  
Author(s):  
Antonin Praet ◽  
Laurent Bourguignon ◽  
Florence Vetele ◽  
Valentine Breant ◽  
Charlotte Genestet ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dose Adjustment ◽  
Total Body Weight ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Two Compartment Model ◽  
Total Body

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC 24 /MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC 24 /MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

Influence of Body Weight Category on Outcomes in Candidemia Patients Treated With Anidulafungin

2020 ◽  
pp. 089719002093821
Author(s):  
Mary Hutton ◽  
Rachel M. Kenney ◽  
Jose A. Vazquez ◽  
Susan L. Davis
Keyword(s):  
Body Weight ◽  
Fungal Infections ◽  
Case Reports ◽  
Normal Weight ◽  
Morbidly Obese ◽  
Pharmacokinetic Data ◽  
Obese Patients ◽  
Serum Concentrations ◽  
Weight Category ◽  
Off Label

Background: Case reports and pharmacokinetic data suggest off-label echinocandin dosing may be needed to reach adequate serum concentrations in obese patients. Few outcome studies exist evaluating this population. Objectives: Of this study were to (1) determine the association of body mass index (BMI) with clinical outcomes of candidemia patients on standard doses of anidulafungin and (2) characterize fungal infections by body weight. Methods: A retrospective cohort was conducted to evaluate hospitalized patients treated for candidemia with anidulafungin at Food and Drug Administration–labeled dosing for at least 72 hours from January 1, 2014, through January 31, 2018. Candidemia was diagnosed by blood culture or T2 magnetic resonance (T2MR). Patients were compared according to BMI category. Results: One hundred seventy-three patients were included. Candida albicans and Candida glabrata were identified in 58 (33%) and 57 (33%) patients, respectively. Mortality was comparable according to BMI category: 4 (36.4%) underweight, 8 (25.8%) normal weight, 16 (32.0%) overweight, 20 (33.9%) obese, and 7 (31.8%) morbidly obese, P = .976. Variables associated with mortality included: severe sepsis (adjusted odds ratio [OR] = 5.1, 95% CI: 1.7-14.8) and liver disease (adjusted OR = 3.2, 95% CI: 1.1-9.4). Variables that were protective of mortality included: line removal (adjusted OR = 0.05, 95% CI: 0.02-0.2) and receipt of anidulafungin for at least 5 days (adjusted OR = 0.35, 95% CI: 0.15-0.8). Conclusion: There was no difference detected in mortality among patients with candidemia across BMI category. Larger studies are needed to confirm whether standard doses of anidulafungin are sufficient for candidemia in obese patients.

Voriconazole: an audit of hospital-based dosing and monitoring and evaluation of the predictive performance of a dose-prediction software package

2020 ◽  
Vol 75 (7) ◽  
pp. 1981-1984 ◽  
Author(s):  
Kanika Chaudhri ◽  
Sophie L Stocker ◽  
Kenneth M Williams ◽  
Robert C McLeay ◽  
Deborah J E Marriott ◽  
...  
Keyword(s):  
Prediction Error ◽  
Software Package ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Predictive Performance ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Dose Prediction ◽  
Retrospective Audit ◽  
Trough Concentrations

Abstract Background Therapeutic drug monitoring (TDM) is recommended to guide voriconazole therapy. Objectives To determine compliance of hospital-based voriconazole dosing and TDM with the Australian national guidelines and evaluate the predictive performance of a one-compartment population pharmacokinetic voriconazole model available in a commercial dose-prediction software package. Methods A retrospective audit of voriconazole therapy at an Australian public hospital (1 January to 31 December 2016) was undertaken. Data collected included patient demographics, dosing history and plasma concentrations. Concordance of dosing and TDM with Australian guidelines was assessed. Observed concentrations were compared with those predicted by dose-prediction software. Measures of bias (mean prediction error) and precision (mean squared prediction error) were calculated. Results Adherence to dosing guidelines for 110 courses of therapy (41% for prophylaxis and 59% for invasive fungal infections) was poor, unless oral formulation guidelines recommended a 200 mg dose, the most commonly prescribed dose (56% of prescriptions). Plasma voriconazole concentrations were obtained for 82% (90/110) of courses [median of 3 (range: 1–27) obtained per course]. A minority (27%) of plasma concentrations were trough concentrations [median concentration: 1.5 mg/L (range: <0.1 to >5.0 mg/L)]. Of trough concentrations, 57% (58/101) were therapeutic, 37% (37/101) were subtherapeutic and 6% (6/101) were supratherapeutic. The dose-prediction software performed well, with acceptable bias and precision of 0.09 mg/L (95% CI −0.08 to 0.27) and 1.32 (mg/L)2 (95% CI 0.96–1.67), respectively. Conclusions Voriconazole dosing was suboptimal based on published guidelines and TDM results. Dose-prediction software could enhance TDM-guided therapy.

scholarly journals Comparative Evaluation of the Predictive Performances of Three Different Structural Population Pharmacokinetic Models To Predict Future Voriconazole Concentrations

2016 ◽  
Vol 60 (11) ◽  
pp. 6806-6812 ◽  
Author(s):  
Andras Farkas ◽  
Gergely Daroczi ◽  
Phillip Villasurda ◽  
Michael Dolton ◽  
Midori Nakagaki ◽  
...  
Keyword(s):  
Prediction Error ◽  
Fungal Infections ◽  
Nonlinear Models ◽  
Point Of View ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Cell Transplant ◽  
Concentration Data ◽  
Hematopoietic Stem ◽  
Squared Prediction Error

ABSTRACTBayesian methods for voriconazole therapeutic drug monitoring (TDM) have been reported previously, but there are only sparse reports comparing the accuracy and precision of predictions of published models. Furthermore, the comparative accuracy of linear, mixed linear and nonlinear, or entirely nonlinear models may be of high clinical relevance. In this study, models were coded into individually designed optimum dosing strategies (ID-ODS) with voriconazole concentration data analyzed using inverse Bayesian modeling. The data used were from two independent data sets, patients with proven or suspected invasive fungal infections (n =57) and hematopoietic stem cell transplant recipients (n =10). Observed voriconazole concentrations were predicted whereby for each concentration value, the data available to that point were used to predict that value. The mean prediction error (ME) and mean squared prediction error (MSE) and their 95% confidence intervals (95% CI) were calculated to measure absolute bias and precision, while ΔME and ΔMSE and their 95% CI were used to measure relative bias and precision, respectively. A total of 519 voriconazole concentrations were analyzed using three models. MEs (95% CI) were 0.09 (−0.02, 0.22), 0.23 (0.04, 0.42), and 0.35 (0.16 to 0.54) while the MSEs (95% CI) were 2.1 (1.03, 3.17), 4.98 (0.90, 9.06), and 4.97 (−0.54 to 10.48) for the linear, mixed, and nonlinear models, respectively. In conclusion, while simulations with the linear model were found to be slightly more accurate and similarly precise, the small difference in accuracy is likely negligible from the clinical point of view, making all three approaches appropriate for use in a voriconazole TDM program.

scholarly journals Performance of Population Pharmacokinetic Models in Predicting Polymyxin B Exposures

2020 ◽  
Vol 8 (11) ◽  
pp. 1814
Author(s):  
Vincent Tam ◽  
Lawrence Lee ◽  
Tat-Ming Ng ◽  
Tze-Peng Lim ◽  
Benjamin Cherng ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Area Under The Curve ◽  
Predictive Performance ◽  
Total Body Weight ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Patient Specific ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models

Polymyxin B is the last line of defense in treating multidrug-resistant gram-negative bacterial infections. Dosing of polymyxin B is currently based on total body weight, and a substantial intersubject variability has been reported. We evaluated the performance of different population pharmacokinetic models to predict polymyxin B exposures observed in individual patients. In a prospective observational study, standard dosing (mean 2.5 mg/kg daily) was administered in 13 adult patients. Serial blood samples were obtained at steady state, and plasma polymyxin B concentrations were determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The best-fit estimates of clearance and daily doses were used to derive the observed area under the curve (AUC) in concentration–time profiles. For comparison, 5 different population pharmacokinetic models of polymyxin B were conditioned using patient-specific dosing and demographic (if applicable) variables to predict polymyxin B AUC of the same patient. The predictive performance of the models was assessed by the coefficient of correlation, bias, and precision. The correlations between observed and predicted AUC in all 5 models examined were poor (r2 < 0.2). Nonetheless, the models were reasonable in capturing AUC variability in the patient population. Therapeutic drug monitoring currently remains the only viable approach to individualized dosing.

The Influence of Body Size Descriptors on the Estimation of Kidney Function in Normal Weight, Overweight, Obese, and Morbidly Obese Adults

2012 ◽  
Vol 46 (3) ◽  
pp. 317-328 ◽  
Author(s):  
Eun Jung Park ◽  
Manjunath P Pai ◽  
Ting Dong ◽  
Jialu Zhang ◽  
Chia-Wen Ko ◽  
...  
Keyword(s):  
Body Size ◽  
Kidney Function ◽  
Normal Weight ◽  
Morbidly Obese ◽  
Obese Adults

scholarly journals Population Pharmacokinetic Analysis of Vancomycin in Patients with Hematological Malignancies

2005 ◽  
Vol 49 (12) ◽  
pp. 4934-4941 ◽  
Author(s):  
Dolores Santos Buelga ◽  
María del Mar Fernandez de Gatta ◽  
Emma V. Herrera ◽  
Alfonso Dominguez-Gil ◽  
María José García
Keyword(s):  
Hematological Malignancies ◽  
A Priori ◽  
Total Body Weight ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
High Risk Population ◽  
Prediction Errors ◽  
Concentration Data

ABSTRACT This study determines vancomycin (VAN) population pharmacokinetics (PK) in adult patients with hematological malignancies. VAN serum concentration data (n = 1,004) from therapeutic drug monitoring were collected retrospectively from 215 patients. A one-compartment PK model was selected. VAN pharmacokinetics population parameters were generated using the NONMEM program. A graphic approach and stepwise generalized additive modeling were used to elucidate the preliminary relationships between PK parameters and clinical covariates analyzed. Covariate selection revealed that total body weight (TBW) affected V, whereas renal function, estimated by creatinine clearance, and a diagnosis of acute myeloblastic leukemia (AML) influenced VAN clearance. We propose one general and two AML-specific models. The former was defined by CL (liters/h) = 1.08 × CLCR(Cockcroft and Gault) (liters/h); CVCL = 28.16% and V (liters) = 0.98 × TBW; CV V =37.15%. AML models confirmed this structure but with a higher clearance coefficient (1.17). The a priori performance of the models was evaluated in another 59 patients, and clinical suitability was confirmed. The models were fairly accurate, with more than 33% of the measured concentrations being within ±20% of the predicted value. This therapeutic precision is twofold higher than that of a noncustomized population model (16.1%). The corresponding standardized prediction errors included zero and a standard deviation close to unity. The models could be used to estimate appropriate VAN dosage guidelines, which are not clearly defined for this high-risk population. Their simple structure should allow easy implementation in clinical software and application in dosage individualization using the Bayesian approach.

scholarly journals Body size throughout the life-course and incident benign prostatic hyperplasia-related outcomes and nocturia

BMC Urology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Saira Khan ◽  
K. Y. Wolin ◽  
R. Pakpahan ◽  
R. L. Grubb ◽  
G. A. Colditz ◽  
...  
Keyword(s):  
Body Size ◽  
Benign Prostatic Hyperplasia ◽  
Life Course ◽  
Early Life ◽  
Prostate Volume ◽  
Late Life ◽  
Later Life ◽  
Normal Weight ◽  
Prostatic Hyperplasia ◽  
The Life Course

Abstract Background Existing evidence suggests that there is an association between body size and prevalent Benign Prostatic Hyperplasia (BPH)-related outcomes and nocturia. However, there is limited evidence on the association between body size throughout the life-course and incident BPH-related outcomes. Methods Our study population consisted of men without histories of prostate cancer, BPH-related outcomes, or nocturia in the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (n = 4710). Associations for body size in early- (age 20), mid- (age 50) and late-life (age ≥ 55, mean age 60.7 years) and weight change with incident BPH-related outcomes (including self-reported nocturia and physician diagnosis of BPH, digital rectal examination-estimated prostate volume ≥ 30 cc, and prostate-specific antigen [PSA] concentration > 1.4 ng/mL) were examined using Poisson regression with robust variance estimation. Results Men who were obese in late-life were 25% more likely to report nocturia (Relative Risk (RR): 1.25, 95% Confidence Interval (CI): 1.11–1.40; p-trendfor continuous BMI < 0.0001) and men who were either overweight or obese in late-life were more likely to report a prostate volume ≥ 30 cc (RRoverweight: 1.13, 95% CI 1.07–1.21; RRobese: 1.10, 95% CI 1.02–1.19; p-trendfor continuous BMI = 0.017) as compared to normal weight men. Obesity at ages 20 and 50 was similarly associated with both nocturia and prostate volume ≥ 30 cc. Considering trajectories of body size, men who were normal weight at age 20 and became overweight or obese by later-life had increased risks of nocturia (RRnormal to overweight: 1.09, 95% CI 0.98–1.22; RRnormal to obese: 1.28, 95% CI 1.10–1.47) and a prostate volume ≥ 30 cc (RRnormal to overweight: 1.12, 95% CI 1.05–1.20). Too few men were obese early in life to examine the independent effect of early-life body size. Later-life body size modified the association between physical activity and nocturia. Conclusions We found that later-life body size, independent of early-life body size, was associated with adverse BPH outcomes, suggesting that interventions to reduce body size even late in life can potentially reduce the burden of BPH-related outcomes and nocturia.

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