Perioperative pharmacokinetic-guided factor VIII concentrate dosing in haemophilia (OPTI-CLOT trial): an open-label, multicentre, randomised, controlled trial

Moort, Iris van; Preijers, Tim; Bukkems, Laura H.; Hazendonk, H. C. A. M.; Bom, Johanna G. van der; Gorkom, Britta A P Laros-van; Beckers, Erik A.M.; Nieuwenhuizen, Laurens; Meer, F. J. M. Van Der; Ypma, Paula F.; Coppens, Michiel; Fijnvandraat, Karin; Schutgens, Roger E.G.; Meijer, Karina; Leebeek, Frank W.G.; Mathôt, Ron A. A.; Cnossen, Marjon H.; Kruip, Marieke J.H.A.; Polinder, Suzanne; Lock, Janske; Heijdra, Jessica M.; Goedhart, Marie C.H.J.; Arashi, Wala Al; Jager, Nico C. B. de; Cloesmeijer, M. E.; Janssen, Alexander; Tamminga, R. Y. J.; Brons, Paul; Schols, Saskia E. M.; Eikenboom, Jeroen; Fischer, K. M.; Galen, Karin P M van; Heubel‐Moenen, Floor C. J. I.; Driessens, M. H. E.; Vliet, Ineke van; Collins, Peter William; Liesner, Ri; Chowdary, Pratima; Millar, Carolyn M.; Hart, Dan; Keeling, David

doi:10.1016/s2352-3026(21)00135-6

Cited by 11 publications

(26 citation statements)

References 26 publications

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“…35 However, a recent randomized controlled perioperative trial was not able to show a decrease in FVIII concentrate consumption, although achievement of FVIII target ranges was clearly more optimal. 36 We hypothesize PK-guided dosing leads to individualization of prophylaxis which is in accordance with the recommendations of the subcommittee on FVIII, FIX, and rare bleeding disorders of the International Society on Thrombosis and Haemostasis (ISTH). 37 PK-guided dosing may help achieve higher trough levels more efficiently when clinically indicated, as well as provide guidance when patients switch to alternative replacement factor concentrates, while taking cost and benefit of treatment into account.…”

Section: Pharmacokinetic-guided Dosingmentioning

confidence: 77%

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Design of a Prospective Study on Pharmacokinetic-Guided Dosing of Prophylactic Factor Replacement in Hemophilia A and B (OPTI-CLOT TARGET Study)

Goedhart

Bukkems

Coppens

et al. 2022

TH Open

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In resource rich countries, almost all severe hemophilia patients receive prophylactic replacement therapy with factor concentrates to prevent spontaneous bleeding in joints and muscles, to decrease the development of arthropathy and risk of long-term disability. Pharmacokinetic (PK)-guided dosing can be applied to individualize factor replacement therapy, as inter-individual differences in PK parameters influence factor VIII (FVIII) and factor IX (FIX) activity levels. PK-guided dosing may therefore lead to more optimal safeguarding of FVIII/FIX levels during prophylaxis and on demand treatment. The OPTI-CLOT TARGET study is a multicenter, non-randomized, prospective cohort study that aims to investigate the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B patients in daily clinical practice. At least 50 patients of all ages on prophylactic treatment using standard half-life (SHL) and extended half-life (EHL) factor concentrates will be included during nine months and will receive PK guided treatment. As primary endpoint, a minimum of four FVIII/FIX levels will be compared to FVIII/FIX levels as predicted by Bayesian forecasting. Secondary endpoints are the association of FVIII and FIX levels with bleeding episodes and physical activity, expectations and experiences, economic analyses and optimization of population PK models. This study will lead to more insight in the reliability and feasibility of PK-guided dosing in hemophilia patients. Moreover, it will contribute to personalization of treatment by greater knowledge of dosing regimens needed to prevent and treat bleeding in the individual patient and provide evidence to more clearly associate factor activity levels with bleeding risk.

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Section: Pharmacokinetic-guided Dosingmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Design of a Prospective Study on Pharmacokinetic-Guided Dosing of Prophylactic Factor Replacement in Hemophilia A and B (OPTI-CLOT TARGET Study)

Goedhart

Bukkems

Coppens

et al. 2022

TH Open

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“…Detailed information on this trial can be found in the trial design paper 11 and recent publication. 12 In brief, this perioperative trial included patients with severe or moderate haemophilia A from Haemophilia Treatment Centres in the Netherlands to compare PK-guided iterative perioperative FVIII concentrate dosing with standard treatment. Following a bolus of 50 IU/kg FVIII concentrate, the preoperative PK profiles were constructed using three blood samples.…”

Section: Methodsmentioning

confidence: 99%

“…We analyzed patient data from the individual preoperative PK profiles from the OPTI‐CLOT randomized controlled trial. Detailed information on this trial can be found in the trial design paper 11 and recent publication 12 . In brief, this perioperative trial included patients with severe or moderate haemophilia A from Haemophilia Treatment Centres in the Netherlands to compare PK‐guided iterative perioperative FVIII concentrate dosing with standard treatment.…”

Section: Methodsmentioning

confidence: 99%

Does difference between label and actual potency of factor VIII concentrate affect pharmacokinetic‐guided dosing of replacement therapy in haemophilia A?

et al. 2022

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Background: To account for interindividual variability in the pharmacokinetics (PK) of factor concentrates, PK-guided dosing is increasingly implemented in haemophilia patients. Calculations are based on provided label potency, but legislation allows a potency difference of ±20% between label and actual potency. It is unknown if these differences affect PK guidance.Aim: Explore the effects of potency differences on individual factor VIII (FVIII) PK parameters and the prediction of FVIII trough levels of dosing regimens. Methods:We analyzed individual preoperative PK profiling data from severe and moderate haemophilia A patients included in the OPTI-CLOT randomized controlled trial.Label and actual potency were compared, with data on potency provided by pharmaceutical companies. For both potencies, individual PK parameters were estimated and concentration-time curves were constructed by nonlinear mixed-effects modelling. Finally, we explored the effect of both the identified and the maximum legislated potency difference on predicted FVIII trough levels infused in a low and high dose regimen. Results:In 45/50 included patients, actual potency was higher than its label potency.The median potency difference was 6.0% (range -9.2% to 18.4%) and resulted in varying individual PK parameter estimates but practically identical FVIII concentrationtime curves. As expected, predicted FVIII trough levels were linearly correlated to the actual dose. Conclusion:It is not necessary to take potency differences into account when applying PK guidance of FVIII concentrates in haemophilia A patients. However, when the patient is switched to another FVIII batch after PK-guided dosing, trough levels may deviate ±20% from calculations based on label dose.

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“…Both models will be fit on a retrospective data set, 5 and will be validated on data collected during the OPTI‐CLOT randomized controlled trial. 6 …”

Section: Introductionmentioning

confidence: 99%

Deep compartment models: A deep learning approach for the reliable prediction of time‐series data in pharmacokinetic modeling

Janssen¹,

Leebeek

Cnossen

et al. 2022

CPT Pharmacom & Syst Pharma

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Nonlinear mixed effect (NLME) models are the gold standard for the analysis of patient response following drug exposure. However, these types of models are complex and time‐consuming to develop. There is great interest in the adoption of machine‐learning methods, but most implementations cannot be reliably extrapolated to treatment strategies outside of the training data. In order to solve this problem, we propose the deep compartment model (DCM), a combination of neural networks and ordinary differential equations. Using simulated datasets of different sizes, we show that our model remains accurate when training on small data sets. Furthermore, using a real‐world data set of patients with hemophilia A receiving factor VIII concentrate while undergoing surgery, we show that our model more accurately predicts a priori drug concentrations compared to a previous NLME model. In addition, we show that our model correctly describes the changing drug concentration over time. By adopting pharmacokinetic principles, the DCM allows for simulation of different treatment strategies and enables therapeutic drug monitoring.

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Perioperative pharmacokinetic-guided factor VIII concentrate dosing in haemophilia (OPTI-CLOT trial): an open-label, multicentre, randomised, controlled trial

Cited by 11 publications

References 26 publications

Design of a Prospective Study on Pharmacokinetic-Guided Dosing of Prophylactic Factor Replacement in Hemophilia A and B (OPTI-CLOT TARGET Study)

Design of a Prospective Study on Pharmacokinetic-Guided Dosing of Prophylactic Factor Replacement in Hemophilia A and B (OPTI-CLOT TARGET Study)

Does difference between label and actual potency of factor VIII concentrate affect pharmacokinetic‐guided dosing of replacement therapy in haemophilia A?

Deep compartment models: A deep learning approach for the reliable prediction of time‐series data in pharmacokinetic modeling

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