Publications by authors named "Rene Wiezer"

13 Publications

  • Page 1 of 1

Implications for IV posaconazole dosing in the era of obesity.

J Antimicrob Chemother 2020 04;75(4):1006-1013

Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

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.
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http://dx.doi.org/10.1093/jac/dkz546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069473PMC
April 2020

Fixed Dosing of Liposomal Amphotericin B in Morbidly Obese Individuals.

Clin Infect Dis 2020 05;70(10):2213-2215

Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nieuwegein, The Netherlands.

In this prospective study, we examined the pharmacokinetics of 1 and 2 mg/kg liposomal amphotericin B in 16 morbidly obese individuals (104-177 kg). Body size had no effect on clearance. We recommend a fixed dose in patients ≥100 kg (ie, 300 or 500 mg rather than the current dose of 3 and 5 mg/kg, respectively). Clinical Trials Registration NCT02320604.
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http://dx.doi.org/10.1093/cid/ciz885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201409PMC
May 2020

Pharmacokinetics and probability of target attainment for micafungin in normal-weight and morbidly obese adults.

J Antimicrob Chemother 2019 04;74(4):978-985

Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Objectives: The rising pandemic of obesity means an increasing number of obese patients who require antimicrobial therapy for serious infections. Micafungin is an echinocandin drug frequently used as therapy or prophylaxis for fungal infections, predominantly with Candida species. In order to maximize the efficacy of micafungin in obese patients, the dose that corresponds to optimal exposure for each obese individual needs to be identified.

Methods: We performed a prospective study in 16 obese and 8 normal-weight healthy subjects with a weight ranging from 61.5-184 kg (ClinicalTrials.gov Identifier: NCT03102658). A population pharmacokinetic model was developed and used to simulate several dosing regimens to evaluate the PTA for relevant MICs to define the optimal dose using the pharmacokinetic/pharmacodynamic target of an AUC/MIC ratio above 5000.

Results: Total body weight was found to be most predictive for CL and V. Simulations showed that a 100 mg dose results in a PTA of >90% in patients weighing ≤125 kg infected with a Candida species having an MIC of 0.016 mg/L. The maintenance dose should be increased to 200 mg in patients >125 kg infected with a Candida species with an MIC of 0.016 mg/L. For an MIC of 0.032 mg/L, a 300 mg maintenance dose is recommended above 125 kg weight. Furthermore, we demonstrate that patients can benefit from a loading dose (i.e. twice the maintenance dose).

Conclusions: We present easy-to-use dose recommendations for obese patients, based on both weight and target MIC, that result in adequate exposure in patients with body weight up to 190 kg.
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http://dx.doi.org/10.1093/jac/dky554DOI Listing
April 2019

Failed Sleeve Gastrectomy: Single Anastomosis Duodenoileal Bypass or Roux-en-Y Gastric Bypass? A Multicenter Cohort Study.

Obes Surg 2018 12;28(12):3834-3842

Department of Surgery, Rijnstate Hospital/Vitalys Clinics, Arnhem, Netherlands.

Background: Sleeve gastrectomy (SG) has become the most performed bariatric procedure to induce weight loss worldwide. Unfortunately, a significant portion of patients show insufficient weight loss or weight regain after a few years.

Objective: To investigate the effectiveness of the single anastomosis duodenoileal (SADI) bypass versus the Roux-en-Y gastric bypass (RYGB) on health outcomes in morbid obese patients who had undergone SG previously, with up to 2 years of follow-up.

Methods: From 2007 to 2017, 140 patients received revisional laparoscopic surgery after SG in four specialized Dutch bariatric hospitals. Data was analyzed retrospectively and included comparisons for indication of surgery, vitamin/mineral deficiencies, and complications; divided into short-, medium-term. To compare weight loss, linear regression and linear mixed models were used.

Results: Conversion of a SG to SADI was performed in 66 patients and to RYGB in 74 patients. For patients in which additional weight loss was the main indication for surgery, SADI achieved 8.7%, 12.4%, and 19.4% more total body weight loss at 6, 12, and 24 months compared to RYGB (all p < .001). When a RYGB was indicated in case of gastroesophageal reflux or dysphagia, it greatly reduced complaints almost directly after surgery. Furthermore, a similar amount of complications and nutritional deficiencies was observed for both groups. There was no intra- or post-operative mortality.

Conclusion: Conversion into a SADI resulted in significantly more weight loss while complications rates and nutritional deficiencies were similar and may therefore be considered the recommended operation for patients in which only additional weight loss is required.
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http://dx.doi.org/10.1007/s11695-018-3429-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223754PMC
December 2018

Magnetic resonance enterography findings of a gastrocolic fistula in Crohn's disease.

Quant Imaging Med Surg 2016 Aug;6(4):482-485

Department of Radiology, Sint Antonius Ziekenhuis, Nieuwegein, The Netherlands.

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http://dx.doi.org/10.21037/qims.2016.08.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009107PMC
August 2016

Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint.

Eur J Clin Pharmacol 2015 Jan 12;71(1):25-34. Epub 2014 Oct 12.

Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.

Purpose: In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI>40 kg/m(2)) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non-obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters.

Methods: Twenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72-252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM.

Results: In a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL=23.0 mL/min × (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1=7.0 L × (LBW/60)).

Conclusions: A pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively.
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http://dx.doi.org/10.1007/s00228-014-1760-4DOI Listing
January 2015

Midazolam pharmacokinetics in morbidly obese patients following semi-simultaneous oral and intravenous administration: a comparison with healthy volunteers.

Clin Pharmacokinet 2014 Oct;53(10):931-41

Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.

Background: While in vitro and animal studies have shown reduced cytochrome P450 (CYP) 3A activity due to obesity, clinical studies in (morbidly) obese patients are scarce. As CYP3A activity may influence both clearance and oral bioavailability in a distinct manner, in this study the pharmacokinetics of the CYP3A substrate midazolam were evaluated after semi-simultaneous oral and intravenous administration in morbidly obese patients, and compared with healthy volunteers.

Methods: Twenty morbidly obese patients [mean body weight 144 kg (range 112-186 kg) and mean body mass index 47 kg/m(2) (range 40-68 kg/m(2))] participated in the study. All patients received a midazolam 7.5 mg oral and 5 mg intravenous dose (separated by 159 ± 67 min) and per patient 22 samples over 11 h were collected. Data from 12 healthy volunteers were available for a population pharmacokinetic analysis using NONMEM(®).

Results: In the three-compartment model in which oral absorption was characterized by a transit absorption model, population mean clearance (relative standard error %) was similar [0.36 (4 %) L/min], while oral bioavailability was 60 % (13 %) in morbidly obese patients versus 28 % (7 %) in healthy volunteers (P < 0.001). Central and peripheral volumes of distribution increased substantially with body weight (both P < 0.001) and absorption rate (transit rate constant) was lower in morbidly obese patients [0.057 (5 %) vs. 0.130 (14 %) min(-1), P < 0.001].

Conclusions: In morbidly obese patients, systemic clearance of midazolam is unchanged, while oral bioavailability is increased. Given the large increase in volumes of distribution, dose adaptations for intravenous midazolam should be considered. Further research should elucidate the exact physiological changes at intestinal and hepatic level contributing to these findings.
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http://dx.doi.org/10.1007/s40262-014-0166-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171595PMC
October 2014

Anti-Xa Levels 4 h After Subcutaneous Administration of 5,700 IU Nadroparin Strongly Correlate with Lean Body Weight in Morbidly Obese Patients.

Obes Surg 2012 Feb 1. Epub 2012 Feb 1.

Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435, CM, Nieuwegein, Netherlands.

BACKGROUND: Morbidly obese patients (BMI > 40 kg/m(2)) are at increased risk for venous thromboembolism, especially after surgery. Despite limited evidence, morbidly obese patients are often administered a double dose of nadroparin for thromboprophylaxis compared to non-obese patients. The aim of this study was to evaluate the influence of different body size descriptors on anti-Xa levels after a double dose of nadroparin (5,700 IU) in morbidly obese patients. METHODS: In 27 morbidly obese patients with a mean total body weight of 148 kg (range 107-260 kg), anti-Xa levels were determined peri-operatively until 24 h after administration of a subcutaneous dose of 5,700 IU of nadroparin. RESULTS: Anti-Xa level 4 h after administration (A(4h), mean 0.22 ± 0.07 IU/ml) negatively correlated strongly with lean body weight (r = -0.66 (p < 0.001)) and moderately with total body weight (r = -0.56 (p = 0.003)) and did not correlate with body mass index (r = -0.26 (p = 0.187)). The area under the anti-Xa level-time curve from 0 to 24 h (AUA(0-24h), mean 2.80 ± 0.97 h IU/ml) correlated with lean body weight (r = -0.63 (p = 0.007)), but did not correlate with total body weight (r = -0.44 (p = 0.075)) or body mass index (r = -0.10 (p = 0.709)). CONCLUCIONS: Following a subcutaneous dose of nadroparin 5,700 IU, A(4h) and AUA(0-24h) were found to negatively correlate strongly with lean body weight. From these results, individualized dosing of nadroparin based on lean body weight should be considered in morbidly obese patients.
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http://dx.doi.org/10.1007/s11695-012-0602-7DOI Listing
February 2012

Preoperative very low-calorie diet and operative outcome after laparoscopic gastric bypass: a randomized multicenter study.

Arch Surg 2011 Nov;146(11):1300-5

Department of Gastrointestinal Surgery, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium.

Hypothesis: A 14-day very low-calorie diet (VLCD) regimen before a laparoscopic gastric bypass procedure will improve perioperative and postoperative outcomes.

Design: Multicenter, randomized, single-blind study.

Setting: Five high-volume bariatric centers in Sweden, the Netherlands, Lithuania, Spain, and Belgium.

Patients: Two hundred ninety-eight morbidly obese patients undergoing laparoscopic gastric bypass from March 1, 2009, through December 5, 2010.

Intervention: Patients were randomly allocated to a 2-week preoperative VLCD regimen or no preoperative dietary restriction (control group).

Main Outcome Measures: Operating time, surgeon's perceived difficulty of the operation, liver lacerations, intraoperative bleeding and complications, 30-day weight loss, and morbidity.

Results: Mean (SD) preoperative weight change was -4.9 (3.6) kg in the VLCD group vs -0.4 (3.2) kg in the control group (P < .001). Although the surgeon's perceived difficulty of the procedure was lower in the VLCD group (median [interquartile range], 26 [15-42] vs 35 [18-50] mm on a visual analog scale; P = .04), no differences were found regarding mean (SD) operating time (81 [21] vs 80 [23] min; P = .53), estimated blood loss (P = .62), or intraoperative complications (P = .88). At the 30-day follow-up, the number of complications was greater in the control compared with the VLCD group (18 vs 8; P = .04).

Conclusions: Although weight reduction with a 14-day VLCD regimen before laparoscopic gastric bypass performed in high-volume centers seems to reduce the perceived difficulty of the procedure, only minor effects on operating time, intraoperative complications, and short-term weight loss could be expected. However, the finding of reduced postoperative complication rates suggests that such a regimen should be recommended before bariatric surgery.
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http://dx.doi.org/10.1001/archsurg.2011.273DOI Listing
November 2011

Population pharmacokinetics and pharmacodynamics of propofol in morbidly obese patients.

Clin Pharmacokinet 2011 Nov;50(11):739-50

Department of Anesthesiology and Intensive Care, St Antonius Hospital, Nieuwegein, the Netherlands.

Background And Objectives: In view of the increasing prevalence of morbidly obese patients, the influence of excessive total bodyweight (TBW) on the pharmacokinetics and pharmacodynamics of propofol was characterized in this study using bispectral index (BIS) values as a pharmacodynamic endpoint.

Methods: A population pharmacokinetic and pharmacodynamic model was developed with the nonlinear mixed-effects modelling software NONMEM VI, on the basis of 491 blood samples from 20 morbidly obese patients (TBW range 98-167 kg) and 725 blood samples from 44 lean patients (TBW range 55-98 kg) from previously published studies. In addition, 2246 BIS values from the 20 morbidly obese patients were available for pharmacodynamic analysis.

Results: In a three-compartment pharmacokinetic model, TBW proved to be the most predictive covariate for clearance from the central compartment (CL) in the 20 morbidly obese patients (CL 2.33 L/min × [TBW/70]^[0.72]). Similar results were obtained when the morbidly obese patients and the 44 lean patients were analysed together (CL 2.22 L/min × [TBW/70]^[0.67]). No covariates were identified for other pharmacokinetic parameters. The depth of anaesthesia in the morbidly obese patients was adequately described by a two-compartment biophase-distribution model with a sigmoid maximum possible effect (E(max)) pharmacodynamic model (concentration at half-maximum effect [EC(50)] 2.12 mg/L) without covariates.

Conclusion: We developed a pharmacokinetic and pharmacodynamic model of propofol in morbidly obese patients, in which TBW proved to be the major determinant of clearance, using an allometric function with an exponent of 0.72. For the other pharmacokinetic and pharmacodynamic parameters, no covariates could be identified. Trial registration number (clinicaltrials.gov): NCT00395681.
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http://dx.doi.org/10.2165/11592890-000000000-00000DOI Listing
November 2011

[Endoscopic posterior adrenalectomy; results of 100 procedures in University Medical Center Utrecht].

Ned Tijdschr Geneeskd 2009 ;153:B399

Universitair Medisch Centrum Utrecht, Afd. Chirurgie, Utrecht, The Netherlands.

Objective: To describe the results of 100 endoscopic posterior retroperitoneal adrenalectomies performed in the University Medical Center Utrecht, the Netherlands.

Design: Descriptive, retrospective.

Method: In the period August 1997-March 2008 100 endoscopic posterior retroperitoneal adrenalectomies were performed in the University Medical Center Utrecht. Data were collected retrospectively on patients, operations, complications and course following the procedure.

Results: In this period 88 unilateral and 6 bilateral EPRA procedures were performed in 94 patients. The most common indications for unilateral EPRA were pheochromocytoma (33), Cushing's syndrome (16) and Conn's syndrome (20). Preoperative diagnosis involved clinical examination, hormonal analysis and radiological imaging. Mean operative time was 110 min and showed a clear learning curve. The mean intraoperative blood loss was 30 ml. The median size of the lesions was 2.8 cm (range: 0.4-7.5). Conversion to open surgery was necessary in 2 patients. No major intraoperative complications occurred. Postoperative complications occurred in 7 patients, of which 2 were severe and 5 were mild. Surgical reintervention was required in 1 patient. Median postoperative stay was 3 days.

Conclusion: In experienced hands endoscopic posterior retroperitoneal adrenalectomy appears to be a safe and effective treatment for adrenal gland lesions.
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February 2010

Recurrent left-sided colon volvulus leading to mediastinal shift.

Clin Gastroenterol Hepatol 2007 Jul 4;5(7):A34. Epub 2007 Jun 4.

Department of Gastroenterology, St Antonius Hospital, Nieuwegein, The Netherlands.

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http://dx.doi.org/10.1016/j.cgh.2007.03.026DOI Listing
July 2007