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Swen, J., van der Wouden, C. H., Manson, L. E. N., Abdullah-Koolmees, H., Blagec, K., Blagus, T., . . . Guchelaar, H.-J. (2023). A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study. The Lancet, 401(10374), 347-356
Open this publication in new window or tab >>A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study
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2023 (English)In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 401, no 10374, p. 347-356Article in journal (Refereed) Published
Abstract [en]

Background: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed.

Methods: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants.

Findings: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51.4 % female, 48.6% male; 97.7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1.6%] of the study group and 47 [1.3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11.0%] in the study group and 285 [7.9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21 center dot 0%) of 725 patients in the study group and 231 (27.7%) of 833 patients in the control group (odds ratio [OR] 0 center dot 70 [95% CI 0 center dot 54-0 center dot 91]; p=0.0075), whereas for all patients, the incidence was 628 (21.5%) of 2923 patients in the study group and 934 (28. 6%) of 3270 patients in the control group (OR 0.70 [95% CI 0.61-0.79]; p <0.0001).

Interpretation: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe.

Place, publisher, year, edition, pages
Elsevier, 2023
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-501626 (URN)10.1016/S0140-6736(22)01841-4 (DOI)000970309800001 ()36739136 (PubMedID)
Funder
EU, Horizon 2020, 668353
Available from: 2023-05-10 Created: 2023-05-10 Last updated: 2023-05-10Bibliographically approved
Bukkems, L. H., Versloot, O., Cnossen, M. H., Jönsson, S., Karlsson, M. O., Mathot, R. A. A. & Fischer, K. (2023). Association between Sports Participation, Factor VIII Levels and Bleeding in Hemophilia A. Thrombosis and Haemostasis, 123(03), 317-325
Open this publication in new window or tab >>Association between Sports Participation, Factor VIII Levels and Bleeding in Hemophilia A
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2023 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, E-ISSN 2567-689X, Vol. 123, no 03, p. 317-325Article in journal (Refereed) Published
Abstract [en]

Background

Little is known on how sports participation affects bleeding risk in hemophilia. This study aimed to examine associations between sports participation, factor VIII (FVIII) levels and bleeding in persons with hemophilia A.

Methods

In this observational, prospective, single-center study, persons with hemophilia A who regularly participated in sports were followed for 12 months. The associations of patient characteristics, FVIII levels, and type/frequency of sports participation with bleeding were analyzed by repeated time-to-event modelling.

Results

One hundred and twelve persons (median age: 24 years [interquartile range:16-34], 49% severe, 49% on prophylaxis) were included. During follow-up, 70 bleeds of which 20 sports-induced were observed. FVIII levels were inversely correlated with the bleeding hazard; a 50% reduction of the baseline bleeding hazard was observed at FVIII levels of 3.1 and a 90% reduction at 28.0 IU/dL. The bleeding hazard did not correlate with sports participation. In addition, severe hemophilia, prestudy annual bleeding rate, and presence of arthropathy showed a positive association with the bleeding hazard.

Conclusions

This analysis showed that FVIII levels were an important determinant of the bleeding hazard, but sports participation was not. This observation most likely reflects the presence of adequate FVIII levels during sports participation in our study. Persons with severe hemophilia A exhibited a higher bleeding hazard at a similar FVIII levels than nonsevere, suggesting that the time spent at lower FVIII levels impacts overall bleeding hazard. These data may be used to counsel persons with hemophilia regarding sports participation and the necessity of adequate prophylaxis.

Place, publisher, year, edition, pages
Georg Thieme Verlag KG, 2023
Keywords
bleeding, hemophilia A, prophylaxis, repeated time-to-event, sports
National Category
Hematology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-501898 (URN)10.1055/a-1983-0594 (DOI)000906393500003 ()36402130 (PubMedID)
Available from: 2023-05-16 Created: 2023-05-16 Last updated: 2023-08-28Bibliographically approved
Bukkems, L., Jönsson, S., Cnossen, M. O., Karlsson, M. & Mathot, R. A. A. (2023). Relationship between factor VIII levels and bleeding for rFVIII-SingleChain in severe hemophilia A: A repeated time-to-event analysis. CPT: Pharmacometrics and Systems Pharmacology (PSP), 12(5), 706-718
Open this publication in new window or tab >>Relationship between factor VIII levels and bleeding for rFVIII-SingleChain in severe hemophilia A: A repeated time-to-event analysis
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2023 (English)In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 12, no 5, p. 706-718Article in journal (Refereed) Published
Abstract [en]

Publications on the exposure-effect relationships of factor concentrates for hemophilia treatment are limited, whereas such analyses give insight on treatment efficacy. Our objective was to examine the relationship between the dose, factor VIII (FVIII) levels and bleeding for rFVIII-SingleChain (lonoctocog alfa, Afstyla). Data from persons with severe hemophilia A on rFVIII-SingleChain prophylaxis from three clinical trials were combined. The published rFVIII-SingleChain population pharmacokinetic (PK) model was evaluated and expanded. The probability of bleeding was described with a parametric repeated time-to-event (RTTE) model. Data included 2080 bleeds, 2545 chromogenic stage assay, and 3052 one-stage assay FVIII levels from 241 persons (median age 19 years) followed for median 1090 days. The majority of the bleeds occurred in joints (65%) and the main bleeding reason was trauma (44%). The probability of bleeding decreased during follow-up and a FVIII level of 8.9 IU/dL (95% confidence interval: 6.9-10.9) decreased the bleeding hazard by 50% compared to a situation without FVIII in plasma. Variability in bleeding hazard between persons with similar FVIII levels was large, and the pre-study annual bleeding rate explained part of this variability. When a FVIII trough level of 1 or 3 IU/dL is targeted during prophylaxis, simulations predicted two (90% prediction interval [PI]: 0-17) or one (90% PI: 0-11) bleeds per year, respectively. In conclusion, the developed PK-RTTE model adequately described the relationship between dose, FVIII levels and bleeds for rFVIII-SingleChain. The obtained estimates were in agreement with those published for the FVIII concentrates BAY 81-8973 (octocog alfa) and BAY 94-9027 (damoctocog alfa pegol), indicating similar efficacy to reduce bleeding.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2023
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-504049 (URN)10.1002/psp4.12938 (DOI)000992153800017 ()36965157 (PubMedID)
Available from: 2023-06-26 Created: 2023-06-26 Last updated: 2023-06-26Bibliographically approved
Swartling, M., Tängdén, T., Lipcsey, M., Jönsson, S. & Nielsen, E. I. (2023). Therapeutic drug monitoring of vancomycin and meropenem: Illustration of the impact of inaccurate information in dose administration time. International Journal of Antimicrobial Agents, 63(1), Article ID 107032.
Open this publication in new window or tab >>Therapeutic drug monitoring of vancomycin and meropenem: Illustration of the impact of inaccurate information in dose administration time
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2023 (English)In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 63, no 1, article id 107032Article in journal (Refereed) Published
Abstract [en]

Objectives: To illustrate the impact of errors in documented dose administration time on therapeutic drug monitoring (TDM)-based target attainment evaluation for vancomycin and meropenem, and to explore the influence of drug and patient characteristics, and TDM sampling strategies.

Methods: Bedside observations of errors in documented dose administration times were collected. Population pharmacokinetic simulations were performed for vancomycin and meropenem, evaluating different one- and two-sampling strategies for populations with estimated creatinine clearance (CLcr) of 30, 80 or 130 mL/min. The impact of errors was evaluated as the proportion of individuals incorrectly considered to have reached the target.

Results: Of 143 observed dose administrations, 97% of doses were given within ±30 min of the documented time. For vancomycin, a +30 min error was predicted to result in a 0.1-3.9 percentage point increase of cases incorrectly evaluated as reaching area under the concentration-time curve during a 24-hour period (AUC24)/minimum inhibitory concentration (MIC) >400, with the largest increase for patients with augmented renal clearance and peak and trough sampling. For meropenem, a +30 min error resulted in a 1.3-6.4 and 0-20 percentage point increase of cases incorrectly evaluated as reaching 100% T>MIC, and 50% T>MIC, respectively. Overall, mid-dose and trough sampling was most favourable for both antibiotics.

Conclusions: For vancomycin, simulations indicate that TDM-based target attainment evaluation is robust with respect to the observed errors in dose administration time of ±30 min; however, the errors had a potentially clinically important impact in patients with augmented renal clearance. For meropenem, extra measures to promote correct documentation are warranted when using TDM, as the impact of errors was evident even in patients with normal renal function.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Documentation, Meropenem, Model-informed precision dosing, Therapeutic drug monitoring, Vancomycin
National Category
Social and Clinical Pharmacy
Research subject
Pharmacology
Identifiers
urn:nbn:se:uu:diva-519941 (URN)10.1016/j.ijantimicag.2023.107032 (DOI)001151170700001 ()37956952 (PubMedID)
Funder
Vinnova, 2018-03340Vinnova, 2021-02699Swedish Research Council, 2019-05911Swedish Research Council, 2020-02320
Available from: 2024-01-10 Created: 2024-01-10 Last updated: 2024-02-21Bibliographically approved
Grisic, A.-M., Xiong, W., Tanneau, L., Jönsson, S., Friberg, L., Karlsson, M., . . . Khandelwal, A. (2022). Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab. Clinical Cancer Research, 28(7), 1363-1371
Open this publication in new window or tab >>Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab
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2022 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 28, no 7, p. 1363-1371Article in journal (Refereed) Published
Abstract [en]

Purpose: Empirical time-varying clearance models have been reported for several immune checkpoint inhibitors, including avelumab (anti-programmed death ligand 1). To investigate the exposure response relationship for avelumab, we explored semimechanistic pharmacokinetic (PK)-tumor growth dynamics (TGD) models.

Patients and Methods: Plasma PK data were pooled from three phase I and II trials (JAVELIN Merkel 200, JAVELIN Solid Tumor, and JAVELIN Solid Tumor JPN); tumor size (TS) data were collected from patients with metastatic Merkel cell carcinoma (mMCC) enrolled in JAVELIN Merkel 200. A PK model was developed first, followed by TGD modeling to investigate interactions between avelumab exposure and TGD. A PK-TGD feedback loop was evaluated with simultaneous fitting of the PK and TGD models.

Results: In total, 1,835 PK observations and 338 TS observations were collected from 147 patients. In the final PK-TGD model, which included the bidirectional relationship between PK and TGD, avelumab PK was described by a two-compartment model with a positive association between clearance and longitudinal TS, with no additional empirical time-varying clearance identified. TGD was described by first-order tumor growth/shrinkage rates, with the tumor shrinkage rate decreasing exponentially over time; the exponential time-decay constant decreased with increasing drug concentration, representing the treatment effect through tumor shrinkage inhibition.

Conclusions: We developed a TGD model that mechanistically captures the prevention of loss of antitumor immunity (i.e., T-cell suppression in the tumor microenvironment) by avelumab, and a bidirectional interaction between PK and TGD in patients with mMCC treated with avelumab, thus mechanistically describing previously reported time variance of avelumab elimination.

Place, publisher, year, edition, pages
American Association for Cancer Research (AACR), 2022
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-473698 (URN)10.1158/1078-0432.CCR-21-2662 (DOI)000783284400001 ()34921021 (PubMedID)
Available from: 2022-05-05 Created: 2022-05-05 Last updated: 2022-05-05Bibliographically approved
Swartling, M., Smekal, A.-K., Furebring, M., Lipcsey, M., Jönsson, S. & Nielsen, E. I. (2022). Population pharmacokinetics of cefotaxime in intensive care patients. European Journal of Clinical Pharmacology, 78(2), 251-258
Open this publication in new window or tab >>Population pharmacokinetics of cefotaxime in intensive care patients
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2022 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 78, no 2, p. 251-258Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates.

METHODS: This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000-3000 mg given 2-6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis.

RESULTS: A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%.

CONCLUSION: A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.

Keywords
Cefotaxime, Critically ill, Modelling, Population pharmacokinetics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-459348 (URN)10.1007/s00228-021-03218-6 (DOI)000702582700001 ()34596726 (PubMedID)
Funder
Vinnova, 2018-03340Stiftelsen Familjen Olinder-Nielsens fond för infektionsmedicinsk forskning
Available from: 2021-11-23 Created: 2021-11-23 Last updated: 2022-04-11Bibliographically approved
Chen, C., Jönsson, S., Yang, S., Plan, E. L. & Karlsson, M. (2021). Detecting placebo and drug effects on Parkinson's disease symptoms by longitudinal item-score models. CPT: Pharmacometrics and Systems Pharmacology (PSP), 10(4), 309-317
Open this publication in new window or tab >>Detecting placebo and drug effects on Parkinson's disease symptoms by longitudinal item-score models
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2021 (English)In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 10, no 4, p. 309-317Article in journal (Refereed) Published
Abstract [en]

This study tested the hypothesis that analyzing longitudinal item scores of the Unified Parkinson's Disease Rating Scale could allow a smaller trial size and describe a drug's effect on symptom progression. Two historical studies of the dopaminergic drug ropinirole were analyzed: a cross-over formulation comparison trial in 161 patients with early-stage Parkinson's disease, and a 24-week, parallel-group, placebo-controlled efficacy trial in 393 patients with advanced-stage Parkinson's disease. We applied item response theory to estimate the patients' symptom severity and developed a longitudinal model using the symptom severity to describe the time course of the placebo response and the drug effect on the time course. Similarly, we developed a longitudinal model using the total score. We then compared sample size needs for drug effect detection using these two different models. Total score modeling estimated median changes from baseline at 24 weeks (90% confidence interval) of -3.7 (-5.4 to -2.0) and -9.3 (-11 to -7.3) points by placebo and ropinirole. Comparable changes were estimated (with slightly higher precision) by item-score modeling as -2.0 (-4.0 to -1.0) and -9.0 (-11 to -8.0) points. The treatment duration was insufficient to estimate the symptom progression rate; hence the drug effect on the progression could not be assessed. The trial sizes to detect a drug effect with 80% power on total score and on symptom severity were estimated (at the type I error level of 0.05) as 88 and 58, respectively. Longitudinal item response analysis could markedly reduce sample size; it also has the potential for assessing drug effects on disease progression in longer trials.

Place, publisher, year, edition, pages
John Wiley & SonsWiley, 2021
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-444919 (URN)10.1002/psp4.12601 (DOI)000647254700007 ()33951753 (PubMedID)
Funder
Swedish Research Council
Available from: 2021-06-15 Created: 2021-06-15 Last updated: 2024-01-15Bibliographically approved
Minichmayr, I. K., Karlsson, M. O. & Jönsson, S. (2021). Pharmacometrics-Based Considerations for the Design of a Pharmacogenomic Clinical Trial Assessing Irinotecan Safety. Pharmaceutical research, 38(4), 593-605
Open this publication in new window or tab >>Pharmacometrics-Based Considerations for the Design of a Pharmacogenomic Clinical Trial Assessing Irinotecan Safety
2021 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 38, no 4, p. 593-605Article in journal (Refereed) Published
Abstract [en]

Purpose Pharmacometric models provide useful tools to aid the rational design of clinical trials. This study evaluates study design-, drug-, and patient-related features as well as analysis methods for their influence on the power to demonstrate a benefit of pharmacogenomics (PGx)-based dosing regarding myelotoxicity. Methods Two pharmacokinetic and one myelosuppression model were assembled to predict concentrations of irinotecan and its metabolite SN-38 given different UGT1A1 genotypes (poor metabolizers: CLSN-38: -36%) and neutropenia following conventional versus PGx-based dosing (350 versus 245 mg/m(2) (-30%)). Study power was assessed given diverse scenarios (n = 50-400 patients/arm, parallel/crossover, varying magnitude of CLSN-38, exposure-response relationship, inter-individual variability) and using model-based data analysis versus conventional statistical testing. Results The magnitude of CLSN-38 reduction in poor metabolizers and the myelosuppressive potency of SN-38 markedly influenced the power to show a difference in grade 4 neutropenia (<0.5 center dot 10(9) cells/L) after PGx-based versus standard dosing. To achieve >80% power with traditional statistical analysis (chi(2)/McNemar's test, alpha = 0.05), 220/100 patients per treatment arm/sequence (parallel/crossover study) were required. The model-based analysis resulted in considerably smaller total sample sizes (n = 100/15 given parallel/crossover design) to obtain the same statistical power. Conclusions The presented findings may help to avoid unfeasible trials and to rationalize the design of pharmacogenetic studies.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2021
Keywords
irinotecan model, neutropenia, pharmacogenomics, study design
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-445470 (URN)10.1007/s11095-021-03024-w (DOI)000629928000001 ()33733372 (PubMedID)
Available from: 2021-06-15 Created: 2021-06-15 Last updated: 2024-01-15Bibliographically approved
Abrantes, J. A., Solms, A., Garmann, D., Nielsen, E. I., Jönsson, S. & Karlsson, M. (2020). Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients. Haematologica, 105(5), 1443-1453
Open this publication in new window or tab >>Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients
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2020 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 105, no 5, p. 1443-1453Article in journal (Refereed) Published
Abstract [en]

Pharmacokinetic-based prophylaxis of replacement factor VIII products has been encouraged in the past years, but the exposure (factor VIII activity)-response (bleeding frequency) relationship remains unclear. The aim of this study was to characterize the relationship between factor VIII dose, plasma factor VIII activity, bleeding patterns and individual characteristics in severe hemophilia A patients. Pooled pharmacokinetic and bleeding data during prophylactic treatment with BAY 81-8973 (octocog alfa) were obtained from the three LEOPOLD trials. The population pharmacokinetics of factor VIII activity and longitudinal bleeding frequency, as well as bleeding severity, were described using nonlinear mixed effects modelling in NONMEM. In total, 183 patients (median age 22 years [range, 1-61]; weight 60 kg [11-124]) contributed with 1535 plasma factor VIII activity observations, 633 bleeds and 11 patient/study characteristics (median observation period 12 months [3.1-13.1]). A parametric repeated time-to-categorical bleed model, guided by plasma factor VIII activity from a 2-compartment population pharmacokinetic model, described the time to the occurrence of bleeds and their severity. Bleeding probability decreased with time of study, and a bleed was not found to affect the time of the next bleed. Several covariate effects were identified, including the bleeding history in the 12-month pre-study period increasing the bleeding hazard. However, unexplained inter-patient variability for the phenotypic bleeding pattern remained large (111%CV). Further studies to translate the model into a tool for dose individualization that considers the individual bleeding risk are required. Research based on a post-hoc analysis of the LEOPOLD studies (ClinicalTrials.gov identifiers NCT01029340, NCT01233258 and NCT01311648).

Place, publisher, year, edition, pages
Ferrata Storti Foundation, 2020
Keywords
Hemophilia, clinical trials, population pharmacokinetics, recombinant factor VIII, repeated time-to-event
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-399996 (URN)10.3324/haematol.2019.217133 (DOI)000530645400048 ()31371418 (PubMedID)
Available from: 2019-12-17 Created: 2019-12-17 Last updated: 2020-06-29Bibliographically approved
Abrantes, J. A., Solms, A., Garmann, D., Nielsen, E. I., Jönsson, S. & Karlsson, M. (2019). Bayesian Forecasting Utilizing Bleeding Information to Support Dose Individualization of Factor VIII. CPT: Pharmacometrics and Systems Pharmacology (PSP), 8(12), 894-903
Open this publication in new window or tab >>Bayesian Forecasting Utilizing Bleeding Information to Support Dose Individualization of Factor VIII
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2019 (English)In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 8, no 12, p. 894-903Article in journal (Refereed) 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.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-381217 (URN)10.1002/psp4.12464 (DOI)000493314600001 ()31668021 (PubMedID)
Available from: 2019-04-05 Created: 2019-04-05 Last updated: 2020-12-17Bibliographically approved
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