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  • 1. Berntorp, E
    et al.
    Astermark, J
    Baghaei, F
    Bergqvist, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    Holmström, M
    Ljungberg, B
    Norlund, A
    Palmblad, J
    Petrini, P
    Stigendal, L
    Säwe, J
    Treatment of haemophilia A and B and von Willebrand's disease: summary and conclusions of a systematic review as part of a Swedish health-technology assessment2012Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 18, nr 2, s. 158-165Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    In an ongoing health-technology assessment of haemophilia treatment in Sweden, performed by the governmental agency Dental and Pharmaceutical Benefits Agency (TLV; tandvårds-och läkemedelsförmånsverket), the Swedish Council on Health Technology Assessment (SBU; statens beredning för medicinsk utvärdering) was called upon to evaluate treatment of haemophilia A and B and von Willebrand's disease (VWD) with clotting factor concentrates. To evaluate the following questions: What are the short-term and long-term effects of different treatment strategies? What methods are available to treat haemophilia patients that have developed inhibitors against factor concentrates? Based on the questions addressed by the project, a systematic database search was conducted in PubMed, NHSEED, Cochrane Library, EMBASE and other relevant databases. The literature search covered all studies in the field published from 1985 up to the spring of 2010. In most instances, the scientific evidence is insufficient for the questions raised in the review. Concentrates of coagulation factors have good haemostatic effects on acute bleeding and surgical intervention in haemophilia A and B and VWD, but conclusions cannot be drawn about possible differences in the effects of different dosing strategies for acute bleeding and surgery. Prophylaxis initiated at a young age can prevent future joint damage in persons with haemophilia. The available treatment options for inhibitors have been insufficiently assessed. The economic consequences of various treatment regimens have been insufficiently analysed. Introduction of national and international registries is important.

  • 2.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A commentary on the differences in pharmacokinetics between recombinant and plasma-derived factor IX and their implications for dosing2011Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 17, nr 2, s. 179-184Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    This commentary aims to summarize all aspects of the difference in pharmacokinetics (PK) between recombinant factor IX (rFIX) and plasma-derived factor IX (pdFIX) and their implications for dosing. PK data were compiled from 17 published studies. The average clearance (CL) of rFIX normally ranged between 7.5 and 9.1 mL h-1 kg-1, whereas that of pdFIX was 3.8-5.4 mL h-1 kg-1. The average terminal half-life was 18-24 h among all 72-h studies on rFIX, in contrast to (normally) 29-43 h for pdFIX. In vivo recovery was more variable. Judging from the pooled data, the typical recovery of rFIX is around two-third that of pdFIX. The difference in PK between rFIX and pdFIX is thus clear-cut and has implications for dosing. As estimated from the compiled data, the dose required to reach any peak level of FIX immediately after administration would be 1.5 times higher for rFIX than for pdFIX, most probably with considerable individual variation. Calculated doses for a patient on a twice weekly prophylactic treatment to achieve a predetermined trough FIX level depended markedly on CL and were about twice as high with rFIX as with pdFIX. In summary, conversion factors between rFIX and pdFIX of 1.5 for single doses and 2 for prophylactic dosing can tentatively be applied; however, the interindividual variance both in recovery and CL of rFIX and pdFIX and the unknown variance in ratios between these PK parameters call for careful monitoring if a switch of treatment is made.

  • 3.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Clinical pharmacokinetic studies on factor VIII and factor IX - experiences from the Malmo centre2006Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 12, s. 12-14Artikel i tidskrift (Refereegranskat)
  • 4.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Comparative pharmacokinetics of factor VIII and recombinant factor IX: for which coagulation factors should half-life change with age?2013Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 19, nr 6, s. 882-886Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The half-life of factor VIII (FVIII) increases with the age of the patient, while studies on recombinant factor IX (rFIX) and factor VIIa (rFVIIa) have not demonstrated corresponding age-related changes. The purpose of this analysis was to relate the changes in FVIII and rFIX pharmacokinetics (PK) with age to developmental changes in body size and fluid volumes and explain why the elimination half-life of FVIII, but not of rFIX, would change with age, and to consider how the findings could be applied prospectively to other coagulation factors. Published PK data for FVIII from 186 patients aged 1-74years and for rFIX from 56 patients aged 4-56years were used. The relationships of FVIII and rFIX clearance (CL) with body weight could be described by allometric expressions. Relative changes in CL with age or weight were similar for FVIII and rFIX. The age-related change in volume of distribution at steady state (V-ss) of rFIX was parallel to the change in CL in the children while for FVIII the change was much less pronounced. Elimination half-life was clearly age-dependent for FVIII while only a very weak trend could be seen for rFIX. Limited data suggest that rFVIIa in this respect resembles rFIX, with parallel changes in CL and V-ss producing insignificant change in half-life. To what extent the elimination half-life of a coagulation factor would show a correlation with age can in principle be predicted from the characteristics of its CL and distribution.

  • 5.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Evaluation of the TCIWorks Bayesian computer program for estimation of individual pharmacokinetics of FVIII2011Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 17, nr 1, s. E239-E240Artikel i tidskrift (Refereegranskat)
  • 6.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Limited blood sampling for pharmacokinetic dose tailoring of FVIII in the prophylactic treatment of haemophilia A2010Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 16, nr 4, s. 597-605Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Summary. The aim of this study was to evaluate the use of limited blood sampling and Bayesian analysis to estimate the pharmacokinetics (PK) and tailor the dose of factor VIII (FVIII) in an individual patient. In a Bayesian analysis, PK parameters are estimated from only a few plasma concentration measurements, using a previously established PK model. First the necessary model was created using intense blood sampling FVIII data from 10 patients. Then FVIII data from another 21 patients were used for 'clinical' evaluation. Three scenarios were created retrospectively by reduction of the original 7-sample data set; blood sampling at 4, 24 and 48 h, at 8 and 30 h and at 24 h after the infusion. PK parameters were estimated for each individual using Bayesian analysis and compared with those obtained using conventional methods from the full data. The accuracy of predictions of FVIII levels during prophylactic treatment 5-17 months later and implications for dose tailoring were also investigated. Blood sampling at 4, 24 and 48 h was found to give practically the same PK information as a full, conventional (7-10-sample) study. Even a single 24-h FVIII level provided adequate data for initial dose tailoring and gave predictions of FVIII levels 5-17 months later that were not appreciably worse than predictions based on the full PK analysis. By contrast, dose tailoring based on body weight failed completely. In conclusion, PK-based dose tailoring of FVIII can be performed using limited blood sampling during prophylactic treatment.

  • 7.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Pharmacokinetics of PDFIX and RFIX concentrates - implications for prophylaxis and on-demand therapy2013Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 19, nr S2, s. 7-7Artikel i tidskrift (Refereegranskat)
  • 8.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Pharmacokinetics of plasma-derived and recombinant factor IX - implications for prophylaxis and on-demand therapy2013Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 19, nr 6, s. 808-813Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Plasma-derived (pd) and recombinant (r) factor IX (FIX) differ in pharmacokinetic (PK) properties. These differences and their clinical implications have been debated since the introduction of rFIX. The aim of this review was to describe the comparative disposition of pdFIX and rFIX and will for this purpose begin with an overview of population PK modelling. In contrast to the model-independent method, a population PK model can analyse sparse data sets obtained in various settings, provide parameter values that can be used to predict coagulation factor levels with any kind of single or multiple dosing and include statistical analysis of variation between individuals. Population modelling has also clearly demonstrated the difference in PK between pdFIX and rFIX. Their distribution characteristics influence the FIX coagulant activity (FIX:C) level vs. time curve during the early hours after infusion. In vivo recovery and elimination half-life are consequently not adequate descriptors of the effective PK of FIX, and for new analogues with modified PK, differences in distribution might be clinically important. Calculated doses to maintain 1% trough levels during twice-weekly prophylactic treatment are considerably higher with rFIX than with pdFIX and roughly correspond to dosing in clinical studies. However, the putative relationship between FIX:C trough level and therapeutic outcome has never been confirmed in a clinical trial. Comparative studies on prophylaxis with different types of FIX are needed.

  • 9.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Population pharmacokinetics of recombinant factor IX: implications for dose tailoring2013Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 19, nr 5, s. 753-757Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The principles of pharmacokinetic (PK) dose tailoring in clinical practice, using limited blood sampling and Bayesian PK analysis, have been described for factor VIII (FVIII). This study applied the same procedure to recombinant FIX (rFIX), i.e. population PK modelling and the use of a simplified (one-compartment) model to describe only the terminal part of the coagulation factor vs. time curve. Data from a previous study on rFIX in 56 patients (4-56years, 18-133kg) were used to define a three-compartment population PK model. The average FIX clearance was 8.4mLh(-1)kg(-1). Elimination half-life ranged between 14 and 27h. Data obtained from 24h after the infusion were found to define the terminal phase of FIX disposition. Doses to produce a target trough FIX level (set at 0.01IUmL(-1)) at 72h predicted by the Bayesian analysis, with blood sampling at either 24, 48 and 72h or at only 24 and 48h, were within -40% to +67% of those predicted using the three-compartment model, and within -57% to +125% for targeting a level at 96h. These errors were lower than the overall interindividual variance in dose requirements. As three-compartment models are needed to characterize the PK of both plasma-derived FIX and rFIX, simplification to a one-compartment model is less straightforward than for FVIII, and the methodology should be investigated further before clinical application. Limited blood sampling and Bayesian analysis could still, however, be potentially useful for targeting rFIX trough levels during prophylaxis.

  • 10.
    Björkman, Sven E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Folkesson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Berntorp, E.
    In vivo recovery of factor VIII and factor IX: intra- and interindividual variance in a clinical setting2007Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 13, nr 1, s. 2-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In vivo recovery (IVR) is traditionally used as a parameter to characterize the pharmacokinetic properties of coagulation factors. It has also been suggested that dosing of factor VIII (FVIII) and factor IX (FIX) can be adjusted according to the need of the individual patient, based on an individually determined IVR value. This approach, however, requires that the individual IVR value is more reliably representative for the patient than the mean value in the population, i.e. that there is less variance within than between the individuals. The aim of this investigation was to compare intra- and interindividual variance in IVR (as U dL−1 per U kg−1) for FVIII and plasma-derived FIX in a cohort of non-bleeding patients with haemophilia. The data were collected retrospectively from six clinical studies, yielding 297 IVR determinations in 50 patients with haemophilia A and 93 determinations in 13 patients with haemophilia B. For FVIII, the mean variance within patients exceeded the between-patient variance. Thus, an individually determined IVR value is apparently no more informative than an average, or population, value for the dosing of FVIII. There was no apparent relationship between IVR and age of the patient (1.5–67 years). For FIX, the mean variance within patients was lower than the between-patient variance, and there was a significant positive relationship between IVR and age (13–69 years). From these data, it seems probable that using an individual IVR confers little advantage in comparison to using an age-specific population mean value. Dose tailoring of coagulation factor treatment has been applied successfully after determination of the entire single-dose curve of FVIII:C or FIX:C in the patient and calculation of the relevant pharmacokinetic parameters. However, the findings presented here do not support the assumption that dosing of FVIII or FIX can be individualized on the basis of a clinically determined IVR value.

  • 11.
    Brekkan, Ari
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Degerman, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jönsson, Siv
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Model-based evaluation of low dose factor VIII prophylaxis in haemophilia A2019Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 25, nr 3, s. 408-415Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction The optimal treatment modality for haemophilia A is lifelong prophylaxis which is expensive and may not be implementable everywhere where factor VIII (FVIII) availability is limited. A less costly alternative to prophylaxis is low-dose prophylaxis (LDP) which was compared to conventional prophylaxis in this model-based simulation study. Aim To explore whether LDP is motivated where standard prophylaxis is not implementable, including evaluating LDP efficacy compared to high-dose prophylaxis and investigating the potential economic benefit of individualized dosing. Methods For a virtual adult haemophilia A population, FVIII activity levels were simulated following alternative treatment regimens, based on a published population PK model. The regimens included very LDP, LDP and conventional prophylaxis twice and thrice weekly. The annual probability of bleeding was predicted based on the weekly time spent below 1 IU/dL, using a previously published relationship. Additionally, PK-based dose individualization was evaluated to determine FVIII savings using Bayesian forecasting. Results A treatment regimen of 10 IU/kg administered thrice weekly cost 75% less than a standard high-dose regimen and was predicted to have a 5% higher median probability of annual bleeds. PK-based dose individualization may result in further cost-savings, but implementation needs benefit versus feasibility consideration. Conclusion Based on simulations, a promising LDP regimen was identified that decreased treatment costs compared with standard high-dose prophylaxis at a small increase in bleeding risk. The results indicate that LDP is advocated where the standard-of-care is on-demand treatment; however, the results should be considered in the context of any limitations of the applied models.

  • 12. Collins, P. W.
    et al.
    Fischer, K.
    Morfini, M.
    Blanchette, V. S.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia2011Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 17, nr 1, s. 2-10Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The pharmacokinetic (PK) response to factor VIII (FVIII) and factor IX varies between patients and this has important clinical implications for treatment. Although PK is affected by patient characteristics, this relationship is too weak to infer a result for an individual and, if required, PK must be measured. An important determinant of the efficacy of prophylaxis is the length of time an individual spends with a low level of coagulation factor. This time is more dependent on the patient's coagulation factor half-life and the frequency of dosing than in vivo recovery and dose infused. Improved understanding of the effect of PK and dose frequency on factor levels in patients on prophylaxis will help tailor regimens to individuals better and allow more cost effective use of coagulation factor concentrates. Calculations suggest that adults need less FVIII per kg body weight than children. The effect of half-life on trough levels questions the logic of Monday, Wednesday, Friday dosing and suggests a role for innovative regimens including low-dose daily treatment which leads to either higher trough levels or decreased FVIII requirement. This may expand access to prophylaxis in healthcare systems with limited resources and potentially improve patient outcomes. The ideal trough level will vary between individuals and at different times of their lives and may be <1 IU dL(-1). If PK is to be used in routine clinical practice, a simplified method for its measurement is required and this methodology is becoming available.

  • 13. Fischer, K.
    et al.
    Collins, P.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Blanchette, V.
    Oh, M.
    Fritsch, S.
    Schroth, P.
    Spotts, G.
    Ewenstein, B.
    Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials2011Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 17, nr 3, s. 433-438Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Replacement therapy or prophylaxis, has become the standard of care for the treatment of severe haemophilia A. To describe bleeding patterns in children, adolescents and adults on prophylaxis and their observed relationships to times of infusion (during the week and during the day) as well as season of the year. Data from Advate pre-licensure prospective clinical trials from 145 patients with factor VIII (FVIII) < 1%, were used. All patients underwent a 48-h pharmacokinetic study. The 10-65 year group had >= 75 exposure days on fixed prophylaxis (25-40 IU kg-1 3-4x per week). Prophylaxis was not fixed but similar for 1-6 year olds. Bleeding patterns were analysed. Overall, 700 bleeds were observed in 110/145 patients. All were treated with prophylaxis, mean dose 108 IU kg-1 week-1 in on average 2.9 infusions (1-6 years), 86 IU kg -1week-1 in 2.7 infusions (10-17 years),and 75 IU kg -1week-1 in 2.6 infusions (18-65 years), respectively. On prophylaxis, median total bleeds per year were low at 3.1 for patients aged 1-6 years, 3.3 for those aged 10-17 years and 2.1 for patients aged 18-65 years. Patients aged 1-6 years had predominantly soft tissue bleeds (79%). Incidence of joint bleeding was not associated with season, but was significantly lower in patients who infused FVIII in the mornings: median 0 per year (IQR 0.0-0.4) compared to those who infused later [median 1.8 per year (IQR 0.0-5.2)]. Older patients predominantly experienced joint bleeds (50% and 62%, respectively). More joint bleeds occurred during the summer [43 and 46% respectively, (P < 0.01)]. Bleeding patterns in patients on prophylaxis varied according to age. In addition, the 10-65 year olds showed increased bleeding during the summer. After confirmation in prospective studies, this information may be used to improve tailoring of prophylactic treatment.

  • 14. Jensen, Kirsten
    et al.
    Jönsson, Siv
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nielsen, Elisabet I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Berntorp, Erik
    Population pharmacokinetics of plasma-derived factor IX2014Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 20, nr S3, s. 80-80Artikel i tidskrift (Övrigt vetenskapligt)
  • 15. Larsen, Malte Selch
    et al.
    Vestergaard Juul, Rasmus
    Zintner, Shannon M
    T Kristensen, Annemarie
    Margaritis, Paris
    Kjelgaard-Hansen, Mads
    Wiinberg, Bo
    Simonsson, Ulrika S H
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kreilgaard, Mads
    Rotational thromboelastometry can predict the probability of bleeding events in a translational rat model of haemophilia A following gene-based FVIIa prophylaxis.2019Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Monitoring of clinical effectiveness of bypassing agents in haemophilia patients is hampered by the lack of validated laboratory assays. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) have been evaluated for predicting clinical effectiveness of bypassing agents, however, with limited success.

    AIM: Application of a longitudinal model-based approach may allow for a quantitative characterization of the link between ROTEM parameters and the probability of bleeding events.

    METHODS: We analyse longitudinal data from haemophilia A rats receiving gene-based FVIIa prophylaxis in terms of total circulatory levels of FVII/FVIIa, clotting time (CT) measured using ROTEM and the probability of bleeding events.

    RESULTS: Using population pharmacokinetic-pharmacodynamic (PKPD) modelling, a PK-CT-repeated time-to-event (RTTE) model was developed composed of three submodels (a) a FVII/FVIIa PK model, (b) a PK-CT model describing the relationship between predicted FVIIa expression and CT and (c) a RTTE model describing the probability of bleeding events as a function of CT. The developed PK-CT-RTTE model accurately described the vector dose-dependent plasma concentration-time profile of total FVII/FVIIa and the exposure-response relationship between AAV-derived FVIIa expression and CT. Importantly, the developed model accurately described the occurrence of bleeding events over time in a quantitative manner, revealing a linear relationship between predicted change from baseline CT and the probability of bleeding events.

    CONCLUSION: Using PK-CT-RTTE modelling, we demonstrated that ROTEM parameters can accurately predict the probability of bleeding events in a translational animal model of haemophilia A.

  • 16. Lindvall, K.
    et al.
    Astermark, J.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ljung, R.
    Carlsson, K. S.
    Persson, S.
    Berntorp, E.
    Daily dosing prophylaxis for haemophilia: A randomized crossover pilot study evaluating feasibility and efficacy2012Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 18, nr 6, s. 855-859Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Regular replacement therapy (prophylaxis) for haemophilia has been shown to prevent development of disabling arthropathy and to provide a better quality of life compared to treatment on demand; however, at a substantially higher cost. Calculations based on pharmacokinetic principles have shown that shortening dose intervals may reduce cost. The aim of this prospective, randomized, crossover pilot study was to address whether daily dosing is feasible, if it reduces concentrate consumption and is as effective in preventing bleeding as the standard prophylactic dosing regimen. In a 12 + 12 month crossover study, 13 patients were randomized to start either their own previously prescribed standard dose, or daily dosing adjusted to maintain at least the same trough levels as obtained with the standard dose. Ten patients completed the study. A 30% reduction in cost of factor concentrates was achieved with daily prophylaxis. However, the number of bleeding events increased in some patients in the daily dosing arm and patients reported decreased quality of life during daily prophylaxis. Daily treatment had a greater impact on daily life, and the patients found it more stressful.Prophylaxis with daily dosing may be feasible and efficacious in some patients. A substantial reduction of factor consumption and costs can be realized, but larger studies are needed before the introduction of daily prophylaxis into clinical routine can be recommended.

  • 17. Lovdahl, S.
    et al.
    Henriksson, Karin M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Baghaei, F.
    Holmstrom, M.
    Berntorp, E.
    Astermark, J.
    A longitudinal study of family structure in Swedish persons with haemophilia2014Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 20, nr 4, s. 493-499Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Haemophilia is an X-linked inherited rare bleeding disorder affecting mainly men. The treatment consists of replacement therapy that has been associated with severe side effects, such as blood transmitted viral infections, but has markedly improved over the last decades. The aim of this study was to study family structure over time among Swedish persons with haemophilia (PWH), focusing on children, siblings and marital status. PWH A or B were identified from the haemophilia centres and the national Patient Registry. Each PWH was compared to five age- and gender-matched controls. The national Multi-Generation Registry was used to identify children and siblings. A total of 1365 children with a father suffering from haemophilia A or B and 1938 siblings of the PWH were identified. Having one or more children was significantly less common (P=0.003) for PWH than for controls. Significantly lower rates of having a child were also found for the subgroups of persons suffering from severe haemophilia and those infected with HIV (P<0.001). A higher proportion of PWH, with or without HIV and/or viral hepatitis had siblings compared to the controls (P<0.001). However, the mean number of siblings was significantly lower for persons with severe haemophilia (P=0.001). The number of marriages and divorces did not differ between PWH and controls. Our data indicate a negative impact of HIV and viral hepatitis on family structure for PWH despite the relatively good access to treatment in Sweden over the last few decades. This was particularly true for those with a severe form of haemophilia.

  • 18.
    Mangles, S.
    et al.
    Hampshire Hosp NHS Fdn Trust, Haemophilia Haemostasis & Thrombosis Ctr, Basingstoke, Hants, England.
    Rea, C.
    Hampshire Hosp NHS Fdn Trust, Haemophilia Haemostasis & Thrombosis Ctr, Basingstoke, Hants, England.
    Madan, B.
    St Thomas Hosp, Ctr Haemostasis & Thrombosis, London, England.
    Nielsen, Elisabet I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jönsson, Siv
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Needham, J.
    Hampshire Hosp NHS Fdn Trust, Haemophilia Haemostasis & Thrombosis Ctr, Basingstoke, Hants, England.
    Collins, P. W.
    Univ Hosp Wales, Arthur Bloom Haemophilia Ctr, Cardiff, S Glam, Wales.
    Rangarajanl, S.
    Hampshire Hosp NHS Fdn Trust, Haemophilia Haemostasis & Thrombosis Ctr, Basingstoke, Hants, England.
    Real life experiences of a PK dosing study: Challenges and lessons learned2018Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 24, nr 3, s. E145-E148Artikel i tidskrift (Övrigt vetenskapligt)
  • 19. Roy, John
    et al.
    Morfini, Massimo
    Ignas, Dan
    Carcao, Manuel
    Barnes, Chris
    Zhao, Xiu Yan
    Tanashima, Reo
    Ito, Shinya
    Blanchette, Victor
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Validation of a population pharmacokinetic model of recombinant factor VIII in children2014Ingår i: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 20, nr S3, s. 26-26Artikel i tidskrift (Övrigt vetenskapligt)
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