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Pharmacometric Approaches to Improve Dose Individualization Methods in Hemophilia A
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
2019 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Hemophilia A is a bleeding disorder caused by the lack of functional coagulation factor VIII (FVIII). The overall aim of this thesis was to improve dose individualization of FVIII replacement therapy in hemophilia A using pharmacometric approaches.

A population pharmacokinetic (PK) model of FVIII activity following the administration of moroctocog alfa was developed based on data from a large heterogeneous cohort of moderate to severe hemophilia A patients. Body weight, age, neutralizing anti-FVIII inhibitors, race, and analytical assay were found to be significant predictors of FVIII activity PK. In addition, large inter-individual variability (IIV) and inter-occasion variability (IOV) was identified highlighting the need for dose individualization.

High magnitudes of IOV are known to impair model-based therapeutic drug monitoring. Using a population PK model of FVIII activity, several approaches to handle IOV in Bayesian forecasting of individual PK parameters were assessed across a wide range of features. Considering IOV in Bayesian forecasting, but ignoring IOV in dose calculation, led to the most precise individualized doses, in particular, when sparse data was used.

The dose-exposure-response relationship of FVIII replacement therapy remains unclear. A parametric repeated time-to-categorical event (RTTCE) model was developed to characterize the relationship between the dose of octocog alfa, plasma FVIII activity, bleeding frequency and severity, and covariates, using data from clinical trials. The bleeding hazard was found to decrease throughout time and to be affected by plasma FVIII activity and number of previous bleeds. Unexplained IIV in the bleeding hazard was found to be large.

Bayesian forecasting based on the RTTCE model was used to predict the future occurrence of bleeds, and to contrast the predicted outcome using individual i) PK, ii) bleeding, and iii) PK, bleeding and covariate information, from data collected in clinical trials. The results support that individual bleed information can inform the optimization of prophylactic dosing regimens in severe hemophilia A patients.

In summary, the pharmacometric approaches presented provide a valuable quantitative framework to improve dose individualization in hemophilia A. Furthermore, enhanced dosing has the potential to reduce bleeding frequency and to lower the high costs associated to treatment.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2019. , s. 70
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 270
Emneord [en]
Bayesian forecasting, coagulation factor VIII, dose adaptation, hemophilia/haemophilia A, inter-occasion variability, NONMEM, pharmacodynamics, pharmacokinetics, pharmacometrics, therapeutic drug monitoring
HSV kategori
Forskningsprogram
Farmaceutisk vetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-381218ISBN: 978-91-513-0631-5 (tryckt)OAI: oai:DiVA.org:uu-381218DiVA, id: diva2:1302635
Disputas
2019-05-29, B41, Biomedicinskt centrum, Husargatan 3, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2019-05-06 Laget: 2019-04-05 Sist oppdatert: 2019-06-17
Delarbeid
1. Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa
Åpne denne publikasjonen i ny fane eller vindu >>Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa
Vise andre…
2017 (engelsk)Inngår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, nr 6, s. 977-988Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-342208 (URN)10.1002/cpt.716 (DOI)000414921800026 ()28437834 (PubMedID)
Tilgjengelig fra: 2018-02-20 Laget: 2018-02-20 Sist oppdatert: 2019-04-05bibliografisk kontrollert
2. Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data
Åpne denne publikasjonen i ny fane eller vindu >>Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data
2019 (engelsk)Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 85, nr 6, s. 1326-1336Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

AIMS: This study aims to assess approaches to handle interoccasion variability (IOV) in a model-based therapeutic drug monitoring (TDM) context, using a population pharmacokinetic model of coagulation factor VIII as example.

METHODS: We assessed five model-based TDM approaches: empirical Bayes estimates (EBEs) from a model including IOV, with individualized doses calculated based on individual parameters either (i) including or (ii) excluding variability related to IOV; and EBEs from a model excluding IOV by (iii) setting IOV to zero, (iv) summing variances of interindividual variability (IIV) and IOV into a single IIV term, or (v) re-estimating the model without IOV. The impact of varying IOV magnitudes (0-50%) and number of occasions/observations was explored. The approaches were compared with conventional weight-based dosing. Predictive performance was assessed with the prediction error (PE) percentiles.

RESULTS: When IOV was lower than IIV, the accuracy was good for all approaches (50th percentile of the PE [P50] <7.4%), but the precision varied substantially between IOV magnitudes (P97.5 61-528%). Approach (ii) was the most precise forecasting method across a wide range of scenarios, particularly in case of sparse sampling or high magnitudes of IOV. Weight-based dosing led to less precise predictions than the model-based TDM approaches in most scenarios.

CONCLUSIONS: Based on the studied scenarios and theoretical expectations, the best approach to handle IOV in model-based dose individualisation is to include IOV in the generation of the EBEs, but exclude the portion of unexplained variability related to IOV in the individual parameters used to calculate the future dose.

sted, utgiver, år, opplag, sider
John Wiley & Sons, 2019
Emneord
NONMEM, pharmacokinetics, population analysis, therapeutic drug monitoring
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-381215 (URN)10.1111/bcp.13901 (DOI)000468974200029 ()30767254 (PubMedID)
Tilgjengelig fra: 2019-04-05 Laget: 2019-04-05 Sist oppdatert: 2019-06-24bibliografisk kontrollert
3. Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients
Åpne denne publikasjonen i ny fane eller vindu >>Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients
Vise andre…
(engelsk)Inngår i: Artikkel i tidsskrift (Fagfellevurdert) Submitted
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-381216 (URN)
Tilgjengelig fra: 2019-04-05 Laget: 2019-04-05 Sist oppdatert: 2019-04-05
4. Bayesian Forecasting Utilizing Bleeding Information to Support Dose Individualization of Factor VIII
Åpne denne publikasjonen i ny fane eller vindu >>Bayesian Forecasting Utilizing Bleeding Information to Support Dose Individualization of Factor VIII
Vise andre…
2019 (engelsk)Inngår i: CPT: Pharmacometrics & Systems Pharmacology, ISSN 2163-8306, Vol. 8, nr 12, s. 894-903Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Bayesian forecasting for dose individualization of prophylactic factor VIII replacement therapy using pharmacokinetic samples is challenged by large interindividual variability in the bleeding risk. A pharmacokinetic‐repeated time‐to‐event model‐based forecasting approach was developed to contrast the ability to predict the future occurrence of bleeds based on individual (i) pharmacokinetic, (ii) bleeding, and (iii) pharmacokinetic, bleeding and covariate information using observed data from the Long‐Term Efficacy Open‐Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trials (172 severe hemophilia A patients taking prophylactic treatment). The predictive performance assessed by the area under receiver operating characteristic (ROC) curves was 0.67 (95% confidence interval (CI), 0.65–0.69), 0.78 (95% CI, 0.76–0.80), and 0.79 (95% CI, 0.77–0.81) for patients ≥ 12 years when using pharmacokinetics, bleeds, and all data, respectively, suggesting that individual bleed information adds value to the optimization of prophylactic dosing regimens in severe hemophilia A. Further steps to optimize the proposed tool for factor VIII dose adaptation in the clinic are required.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-381217 (URN)10.1002/psp4.12464 (DOI)000493314600001 ()31668021 (PubMedID)
Tilgjengelig fra: 2019-04-05 Laget: 2019-04-05 Sist oppdatert: 2020-04-20bibliografisk kontrollert

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