scholarly journals Comparing Predictions of a PBPK Model for Cyclosporine With Drug Levels From Therapeutic Drug Monitoring

2021 ◽  
Vol 12 ◽  
Author(s):  
Sonja E. Zapke ◽  
Stefan Willmann ◽  
Scott-Oliver Grebe ◽  
Kristin Menke ◽  
Petra A. Thürmann ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Pbpk Model ◽  
Clinical Population ◽  
Pbpk Modeling ◽  
Additional Patient ◽  
Therapeutic Drug ◽  
Model Parameters ◽  
Drug Levels ◽  
Trough Levels

This study compared simulations of a physiologically based pharmacokinetic (PBPK) model implemented for cyclosporine with drug levels from therapeutic drug monitoring to evaluate the predictive performance of a PBPK model in a clinical population. Based on a literature search model parameters were determined. After calibrating the model using the pharmacokinetic profiles of healthy volunteers, 356 cyclosporine trough levels of 32 renal transplant outpatients were predicted based on their biometric parameters. Model performance was assessed by calculating absolute and relative deviations of predicted and observed trough levels. The median absolute deviation was 6 ng/ml (interquartile range: 30 to 31 ng/ml, minimum = −379 ng/ml, maximum = 139 ng/ml). 86% of predicted cyclosporine trough levels deviated less than twofold from observed values. The high intra-individual variability of observed cyclosporine levels was not fully covered by the PBPK model. Perspectively, consideration of clinical and additional patient-related factors may improve the model’s performance. In summary, the current study has shown that PBPK modeling may offer valuable contributions for pharmacokinetic research in clinical drug therapy.

scholarly journals Feasibility of Extrapolating Randomly Taken Plasma Samples to Trough Levels for Therapeutic Drug Monitoring Purposes of Small Molecule Kinase Inhibitors

2021 ◽  
Vol 14 (2) ◽  
pp. 119
Author(s):  
Ruben A. G. van Eerden ◽  
Esther Oomen-de Hoop ◽  
Aad Noordam ◽  
Ron H. J. Mathijssen ◽  
Stijn L. W. Koolen
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Small Molecule ◽  
Trough Concentration ◽  
Drug Monitoring ◽  
Half Life ◽  
Kinase Inhibitors ◽  
Therapeutic Drug ◽  
Blood Samples ◽  
Elimination Half ◽  
Trough Levels

Small molecule kinase inhibitors (SMKIs) are widely used in oncology. Therapeutic drug monitoring (TDM) for SMKIs could reduce underexposure or overexposure. However, logistical issues such as timing of blood withdrawals hamper its implementation into clinical practice. Extrapolating a random concentration to a trough concentration using the elimination half-life could be a simple and easy way to overcome this problem. In our study plasma concentrations observed during 24 h blood sampling were used for extrapolation to trough levels. The objective was to demonstrate that extrapolation of randomly taken blood samples will lead to equivalent estimated trough samples compared to measured Cmin values. In total 2241 blood samples were analyzed. The estimated Ctrough levels of afatinib and sunitinib fulfilled the equivalence criteria if the samples were drawn after Tmax. The calculated Ctrough levels of erlotinib, imatinib and sorafenib met the equivalence criteria if they were taken, respectively, 12 h, 3 h and 10 h after drug intake. For regorafenib extrapolation was not feasible. In conclusion, extrapolation of randomly taken drug concentrations to a trough concentration using the mean elimination half-life is feasible for multiple SMKIs. Therefore, this simple method could positively contribute to the implementation of TDM in oncology.

scholarly journals P152 Low rates of subtherapeutic drug levels are observed with proactive therapeutic drug monitoring of adalimumab

2021 ◽  
Author(s):  
Stephanie Shields ◽  
John Paul Seenan ◽  
Allan Dunlop ◽  
Peter Galloway ◽  
Jonathan Macdonald
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Drug Levels

scholarly journals Viral load Guided Immunosuppression after Lung Transplantation (VIGILung) – study protocol for a randomized controlled trial

2020 ◽  
Author(s):  
Jens Gottlieb ◽  
Alexander Reuss ◽  
Konstantin Mayer ◽  
Karin Weide ◽  
Carmen Schade-Brittinger ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Lung Transplantation ◽  
Drug Monitoring ◽  
Lung Transplant ◽  
Controlled Trial ◽  
Therapeutic Drug ◽  
Transplant Recipients ◽  
Randomized Controlled ◽  
Lung Transplant Recipients ◽  
Trough Levels

Abstract Background:Immunosuppression including high dose calcineurin-inhibitors (CNI) is essential after lung transplantation. Dosing is usually guided by therapeutic drug monitoring adjusted to target trough levels of CNIs to keep the balance between over-dose causing severe toxicity and increased risk of infections or under-dose with risk of graft-injury.Adaptation of CNI-based immunosuppression by monitoring of Torque-Teno-Virus (TTV) – a latent nonpathogenic DNA virus, measured in whole blood in addition to conventional therapeutic drug monitoring may reduce toxicity of immunosuppression with similar efficacy.Methods/Design:An open-label, randomized, controlled, parallel-group, multicenter trial in lung transplant recipients will be conducted to investigate the safety and efficacy of immunosuppression guided by TTV monitoring as add-on to conventional therapeutic drug monitoring. Adult lung transplant recipients 21 - 42 days after transplantation are eligible to participate. Patients (N = 144) will be randomized 1:1 to the experimental intervention (Arm 1: Immunosuppression guided by TTV monitoring in addition to conventional therapeutic drug monitoring of tacrolimus trough levels) and control intervention (Arm 2: conventional therapeutic drug monitoring). Outcomes will be assessed 12 months after randomization with the change in glomerular filtration rate as the primary endpoint. Secondary endpoints will be additional measurements on renal function, allograft function, incidence of acute rejections, incidence of chronic lung allograft dysfunction, graft loss and infections.Discussion:The results of this randomized controlled trial may reduce toxicity of immunosuppression after lung transplantation while maintaining efficacy of immunosuppression. Study results are transferable to all other solid organ transplantations.Trial registration: ClinicalTrials.gov, NCT04198506. Registered 12 December 2019, https://www.clinicaltrials.gov/show/NCT04198506

scholarly journals P050 Analysis of posaconazole therapeutic drug monitoring in paediatric haematology and oncology patients

2019 ◽  
Vol 104 (7) ◽  
pp. e2.55-e2 ◽  
Author(s):  
Natalie Donald ◽  
Ruth Edwards ◽  
Alison Thomson
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Fungal Infection ◽  
Broad Spectrum ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Paediatric Cancer ◽  
Oncology Patients ◽  
Paediatric Haematology ◽  
Paediatric Patients ◽  
Trough Levels

Posaconazole is a broad spectrum triazole antifungal with activity against a range of invasive fungal pathogens including Candida and Aspergillus species.1 Due to its range of activity it has been shown, by randomised controlled trials, to be superior to fluconazole and itraconazole for prevention of fungal infection in neutropenic patients,2 as well as being cost saving.1 Fungal prophylaxis with posaconazole has become the drug of choice within a paediatric cancer unit due to its broad spectrum of activity however there are significant differences in bioavailability of the suspension and tablet preparations and there is limited data relating to its use in the paediatric population.ObjectiveTo determine if the paediatric cancer unit is undertaking effective dosing and appropriate therapeutic drug monitoring (TDM) of posaconazole in paediatric haematology and oncology patients.MethodsA retrospective analysis of clinical data from 38 paediatric patients treated with posaconazole was undertaken. Patients received either 18–24-mg/kg/day posaconazole suspension in divided doses (maximum 800-mg/day,3 or 6–8-mg/kg/day posaconazole tablets (maximum 300-mg/day). Compliance with this guidance, initial and subsequent levels, efficacy and tolerability were analysed.SettingThe study was undertaken within the XXXX cancer unit; data for patients treated with posaconazole between January 2016 and August 2017 was reviewed.Key findingsThere was good compliance with the dosing advice for liquid and tablet posaconazole with 82% of patients dosed correctly. Due to this, the initial trough level of ≥0.7 mg/L was achieved in 82% of patients within 14 days of treatment initiation; there were no significant differences between formulations. Trough levels were monitored on a monthly basis for 71% of patients but dose adjustments were necessary in 34% of patients. Posaconazole had a good tolerability profile during the study with most side effects resolving on continuation of treatment however one patient had to discontinue the drug due to widespread rash. No patients developed a fungal infection whilst on posaconazole.ConclusionSafe and effective dosing and monitoring of posaconazole suspension and tablet formulations has been undertaken at the XXXX. Trough levels attained the desired target concentration of ≥0.7 mg/L in the majority of patients but dose adjustments were required with both formulations emphasising the need for regular TDM. Posaconazole was well tolerated and clinically effective in preventing fungal infection indicating its appropriateness in this patient group. From this review, a guideline for initiation and appropriate TDM of posaconazole can be developed.ReferencesDranitsaris G, Khoury H. Posaconazole versus fluconazole or itraconazole for prevention of invasive fungal infections in patients undergoing intensive cytotoxic therapy for acute myeloid leukemia or myelodysplasia: a cost effectiveness analysis. Supportive Care in Cancer. 2011; 19(11): 1807–1813.Cornely O, Maertens J, Winston D, et al. Posaconazole vs. Fluconazole or Itraconazole in Patients with Neutropenia. New England Journal of Medicine. 2007; 356(4): 348–359.Bernardo V, Cross S, Crews K, et al. Posaconazole Therapeutic Drug Monitoring in Paediatric Patients and Young Adults with Cancer. The Annals of Pharmacotherapy. 2013; 47: 976–983.

scholarly journals N22 Nurse led therapeutic drug monitoring (TDM) of Infliximab in IBD

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S667-S668
Author(s):  
S Gleeson ◽  
K Sugrue ◽  
M Buckley ◽  
J McCarthy
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Trough Concentration ◽  
Drug Monitoring ◽  
Response Assessment ◽  
Symptom Improvement ◽  
Therapeutic Drug ◽  
Serum Samples ◽  
Drug Concentrations ◽  
Biologic Response ◽  
Trough Levels

Abstract Background Therapeutic drug monitoring (TDM) is the clinical practice of measuring serum drug concentrations to guide clinical decision making. Achieving therapeutic drug concentrations has been associated with clinical, endoscopic and histological outcomes in IBD. The use of TDM offers a more personalised treatment approach and is associated with sustained clinical remission. Proactive TDM was introduced to the Mercy University Hospital in 2014 for all patients on biologics. Methods One hundred patients receiving biologic infusion (Infliximab) were evaluated post induction (week 12) for therapeutic drug trough concentration and for clinical response. Serum samples were taken from all IBD patients at week 12. Biologic response assessment forms were complete for all patients to assess symptom improvement. Results Thirty-five per cent of patients had sub therapeutic trough levels at week 12. They subsequently received 3 increased doses of 10mgs/kg and levels were rechecked. Of these 90% achieved therapeutic levels after the dose escalation. 65% of patients had therapeutic levels at week 12. There was a correlation between therapeutic trough levels and patient reported improvement of clinical symptoms in 85% of respondents. Conclusion TDM in our unit facilitates appropriate dose 100 patients receiving biologic infusion (Infliximab) were evaluated post induction (week 12) for therapeutic drug trough concentration and for clinical response. Serum samples were taken from all IBD patients at week 12. Biologic response assessment forms were complete for all patients to assess symptom improvement.

scholarly journals Vancomycin prophylaxis in paediatric patients following cardiac surgery: a retrospective evaluation of trough levels and associated variables

2020 ◽  
Vol 31 (5) ◽  
pp. 667-673
Author(s):  
Leonardo Vallesi ◽  
Tiziana Fragasso ◽  
Simona Benegni ◽  
Giulia Insom ◽  
Luca Di Chiara ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Clinical Predictors ◽  
Paediatric Patients ◽  
Number Of Patients ◽  
Vancomycin Trough ◽  
Optimal Target ◽  
Independent Association ◽  
Trough Levels

Abstract OBJECTIVES Therapeutic drug monitoring during vancomycin administration is recommended. However, little information is available in case of paediatric vancomycin prophylaxis. The aim of this study was to analyse vancomycin trough levels on postoperative day (POD) 2 and 3 after paediatric cardio-surgery to assess the clinical predictors and outcomes associated with vancomycin concentrations and to evaluate whether adjustments are effective to target optimal levels. METHODS A retrospective study was conducted in paediatric patients receiving vancomycin prophylaxis after elective cardio-surgery. Adjustments were made if levels between 20 and 30 (halving subsequent dose) or ˃30 mg/l (dose withheld) were found. RESULTS Vancomycin doses of the 100 examined children (3.7–6.4 years) were 12.8 (2.5), 9.4 (5.4) and 9.7 (4.5) mg/kg, on POD1, 2 and 3, respectively (P = 0.0001). The 200 vancomycin trough levels decreased from 16.9 (11.4) on POD2 to 14.6 (8.5) on POD3 (P = 0.003). Overall, 66 troughs were sub-target, 68 reached the optimal target and 66 were supra-target. On POD2 and 3, 32 and 27 dose adjustments were required, leading to a reduced number of patients with supra-target troughs. Neonates showed a higher number of supra-target levels with respect to non-neonatal patients on both POD2 (P = 0.003) and 3 (P = 0.0001). At multivariable regression analysis, vancomycin levels showed independent association with weight and creatinine levels on both POD2 and 3. Vancomycin levels correlated with ventilation days (P = 0.31, P = 0.039), but not with methicillin-resistant Staphylococcus aureus positivity (P = 0.69). CONCLUSIONS Vancomycin prophylaxis in paediatric cardio-surgery requires strict therapeutic drug monitoring and several dosage adjustments. Supra-target troughs are frequent and neonatal age, weight and creatinine levels significantly affect vancomycin concentrations.

scholarly journals Therapeutic Drug Monitoring of Piperacillin-Tazobactam Using Spent Dialysate Effluent in Patients Receiving Continuous Venovenous Hemodialysis

2010 ◽  
Vol 55 (2) ◽  
pp. 557-560 ◽  
Author(s):  
Michael J. Connor ◽  
Charbel Salem ◽  
Seth R. Bauer ◽  
Christina L. Hofmann ◽  
Joseph Groszek ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Kidney Injury ◽  
Therapeutic Drug ◽  
Plasma Drug ◽  
Drug Dosing ◽  
Drug Levels ◽  
Drug Concentrations ◽  
Continuous Venovenous Hemodialysis ◽  
Dosing Strategies

ABSTRACTSepsis and multisystem organ failure are common diagnoses affecting nearly three-quarters of a million Americans annually. Infection is the leading cause of death in acute kidney injury, and the majority of critically ill patients who receive continuous dialysis also receive antibiotics. Dialysis equipment and prescriptions have gradually changed over time, raising concern that current drug dosing recommendations in the literature may result in underdosing of antibiotics. Our research group directed its attention toward antibiotic dosing strategies in patients with acute renal failure (ARF), and we sought data confirming that patients receiving continuous dialysis and antibiotics actually were achieving therapeutic plasma drug levels during treatment. In the course of those investigations, we explored “fast-track” strategies to estimate plasma drug concentrations. As most antimicrobial antibiotics are small molecules and should pass freely through modern high-flux hemodialyzer filters, we hypothesized that continuous renal replacement therapy (CRRT) effluent could be used as the medium for drug concentration measurement by reverse-phase high-pressure liquid chromatography (HPLC). Here we present the first data demonstrating this approach for piperacillin-tazobactam. Paired blood and dialysate trough-peak-trough samples were drawn from 19 patients receiving piperacillin-tazobactam and continuous venovenous hemodialysis (CVVHD). Total, free, and dialysate drug concentrations were measured by HPLC. Dialysate drug levels predicted plasma free drug levels well (r2= 0.91 and 0.92 for piperacillin and tazobactam, respectively) in all patients. These data suggest a strategy for therapeutic drug monitoring that minimizes blood loss from phlebotomy and simplifies analytic procedures.

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