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• W2600156320 abstract "In this issue of the Journal of Thrombosis and Haemostasis, Zhang et al. 1.Zhang Y.R. Robers J. Tortorici M. Veldman A. St Ledger K. Feussner A. Sidhu J. Population pharmacokinetics of recombinant coagulation factor VIII‐SingleChain in patients with severe hemophilia A.J Thromb Haemost. 2017; 15: 1106-14Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar describe the population pharmacokinetics of a new recombinant factor VIII product. They conclude that their model ‘can be utilized to simulate FVIII activity–time profiles for various dosing scenarios’. The beauty of having a robust population pharmacokinetic (PK) model, as described here, for a specific factor concentrate is that the model is based on many PK curves (in this case 130) created by the use of rich sampling (in this case, nine samples taken after infusion for up to 72 h in patients aged ≥ 12 years, and for some subjects even for up to 96 h). For patients aged < 12 years, five samples were taken, for practical reasons. If the model is robust, then, theoretically, one sample is enough from a single patient (provided that information about previous few infusions is available). From this single sample, a full PK curve can be constructed for the single patient. As one sample is ‘no sample’, the accuracy, for obvious reasons (preanalytic and analytic), will increase if several samples are taken within a certain time window (Fig. 1) after factor infusion, as described for FVIII 2.Bjorkman S. Collins P. Project on Factor VIII/Factor IX Pharmacokinetics of the Factor VIII/Factor IX Scientific and Standardization Committe of the ISTH. Measurement of factor VIII pharmacokinetics in routine clinical practice.J Thromb Haemost. 2013; 11: 180-2Crossref PubMed Scopus (48) Google Scholar. Whereas rich sampling typically needs 48 h for FVIII and 72 h for FIX, the possibility of sparse sampling by using population pharmacokinetics makes it feasible to collect samples during the day of a routine patient visit. This was not possible before the era of population pharmacokinetics. The population PK model also provides the possibility of simulating factor levels in a patient at different, predefined, theoretical dosing regimens with different doses and dose intervals. Population pharmacokinetics may open new avenues for hemophilia prophylaxis, regarding both FVIII and FIX, although the pharmacokinetics for FIX are more complicated than those for FVIII, and may need to be studied further 3.Bjorkman S. Population pharmacokinetics of recombinant factor IX: implications for dose tailoring.Haemophilia. 2013; 19: 753-7Crossref PubMed Scopus (35) Google Scholar. It has long been recognized that interindividual pharmacokinetics are quite stable with over time, with the exception that clearance is higher, and hence biological half‐life shorter, at younger ages, at least for FVIII, whereas clearance increases with body weight for FIX but decreases if corrected for body weight 4.Bjorkman S. Oh M. Spotts G. Schroth P. Fritsch S. Ewenstein B.M. Casey K. Fischer K. Blanchette V.S. Collins P.W. Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight.Blood. 2012; 119: 612-18Crossref PubMed Scopus (163) Google Scholar. What is the advantage of using pharmacokinetics in prophylactic treatment for hemophilia? The simple answer is: ‘if you know, you will also see’. Knowing the plasma levels of the infused factor at the time of a clinical event, e.g. a joint bleed, is in fact a prerequisite for proper adjustment of the dosing schedule during prophylaxis. The opposite situation may also occur; that is, in a patient who never bleeds, the dose may perhaps be adjusted to reduce the annual factor consumption, in the interests of economy. Fine‐tuned tailoring of dose and dosing schedules is almost impossible without knowing: (i) the pharmacokinetics of the patient (ii); the exact clinical bleeding phenotype, with careful recording of events; and (iii) when challenge to the hemostatic capacity will occur (e.g. physical activity) in relation to factor level. Today's clinical practice at most hemophilia treatment centers does not allow such dose tailoring in a controlled way, because rich plasma sampling for PK evaluation is too demanding for the patients, especially children, and for the healthcare organization. With the application of population pharmacokinetics, these hurdles will be easily overcome. Full PK curves can easily be constructed, and modeling of dosing schedules can be performed, whereby levels are adjusted in the computer according to the needs of the patient. Such studies have been published already, and many of the early fundamentals were given by Björkman et al. at the Malmö center during the 1990s. Dose modeling using Baysian analysis was implemented in clinical practice for both FVIII and FIX, and the validity of the models could be successfully confirmed via control plasma sampling 5.Carlsson M. Berntorp E. Bjorkman S. Lindvall K. Pharmacokinetic dosing in prophylactic treatment of hemophilia A.Eur J Haematol. 1993; 51: 247-52Crossref PubMed Scopus (105) Google Scholar. Cost savings were substantial, and, in hemophilia A, going from standard dosing, i.e. two or three times weekly, to dosing every second day reduced FVIII consumption by 43%, with maintained or increased trough levels. Shortening intervals to daily dosing, maintaining trough levels, would reduce factor consumption by 82%, at least theoretically. Certainly, theoretical modeling with clinical implementation for a relatively short period will not show whether the modeled regimen will have the same clinical efficacy in the long term as the standard one. In a later, prospective cross‐over 2 × 12‐month study in 10 patients, standard dosing was compared with daily dosing 6.Lindvall K. Astermark J. Bjorkman S. Ljung R. Carlsson K.S. Persson S. Berntorp E. Daily dosing prophylaxis for haemophilia: a randomized crossover pilot study evaluating feasibility and efficacy.Haemophilia. 2012; 18: 855-9Crossref PubMed Scopus (40) Google Scholar. Substantial concentrate savings were again shown, but a few patients experienced more occasional bleeds, and the quality of life decreased slightly. When doses are adjusted downwards and intervals are shortened, maintaining similar trough levels as with standard dosing, peak levels will also decrease, and this must be considered. The importance of different factor levels during the entire interval between infusions remains to be elucidated. The question of which level is the most important to protect patients from bleeding cannot be easily answered, and it might turn out that all levels between dose intervals are of importance, i.e. peak, trough, and the total factor level depicted as area under the curve (AUC) 7.Fischer K. Berntorp E. Targeting factor replacement therapy in severe hemophilia: which level is important?.Semin Thromb Hemost. 2015; 41: 860-3Crossref PubMed Scopus (10) Google Scholar. The importance of trough levels in the prevention of bleeding during prophylaxis were established decades ago 8.Nilsson I.M. Berntorp E. Lofqvist T. Pettersson H. Twenty‐five years’ experience of prophylactic treatment in severe haemophilia A and B.J Intern Med. 1992; 232: 25-32Crossref PubMed Scopus (823) Google Scholar, and the importance of both peak levels and AUC was more recently described for every‐third‐day pharmacokinetics‐guided prophylaxis. Prophylaxis/long‐term replacement therapy/continuous prophylaxis have evolved since the 1950s. The earliest, long‐term follow‐up of a large cohort of patients (hemophilia A, n = 52; and hemophilia B, n = 8) of different ages (3–32 years) was described by Nilsson et al. in 1992 8.Nilsson I.M. Berntorp E. Lofqvist T. Pettersson H. Twenty‐five years’ experience of prophylactic treatment in severe haemophilia A and B.J Intern Med. 1992; 232: 25-32Crossref PubMed Scopus (823) Google Scholar. Typical dosing was 25–40 IU of FVIII/FIX per kg body weight three times or twice weekly for hemophilia A and B, respectively. The authors concluded that it was possible to prevent the development of hemophilic arthropathy if prophylaxis was started early and if factor levels usually did not fall below 1%. This regimen is often known as ‘the Swedish high‐dose regimen’. Although it is seemingly effective, the consequent high factor consumption is extremely costly, which has raised concerns. Other regimens, with lower costs, have therefore been implemented, such as the Dutch intermediate dose and the Canadian dose‐escalation regimens (for a summary, see 9.Berntorp E. Shapiro A.D. Modern haemophilia care.Lancet. 2012; 379: 1447-56Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). The use of prophylaxis is expensive, and for many years has been a privilege of wealthy countries. However, recent results from well‐controlled studies 10.Manco‐Johnson M.J. Abshire T.C. Shapiro A.D. Riske B. Hacker M.R. Kilcoyne R. Ingram J.D. Manco‐Johnson M.L. Funk S. Jacobson L. Valentino L.A. Hoots W.K. Buchanan G.R. DiMichele D. Recht M. Brown D. Leissinger C. Bleak S. Cohen A. Mathew P. et al.Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.N Engl J Med. 2007; 357: 535-44Crossref PubMed Scopus (1462) Google Scholar, 11.Gringeri A. Lundin B. von Mackensen S. Mantovani L. Mannucci P.M. ESPRIT Study GroupA randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study).J Thromb Haemost. 2011; 9: 700-10Crossref PubMed Scopus (371) Google Scholar and obvious results from cohort studies have been convincing, and have prompted the implementation of less costly, low‐dose protocols in low‐economy countries. The overall trend also seems to be shortening of interval; today, a common interval is every second day 12.Berntorp E. Dolan G. Hay C. Linari S. Santagostino E. Tosetto A. Castaman G. Alvarez‐Roman M.T. Parra Lopez R. Oldenburg J. Albert T. Scholz U. Holmstrom M. Schved J.F. Trossaert M. Hermans C. Boban A. Ludlam C. Lethagen S. European retrospective study of real‐life haemophilia treatment.Haemophilia. 2017; 23: 105-14Crossref PubMed Scopus (43) Google Scholar, which could be interpreted as a result of more PK thinking when dosing regimens are implemented. Obviously, there is no international consensus on how to dose for prophylaxis in hemophilia, and there are reasons for this. One important reason is economy, which must be considered when the cost of factor concentrate takes a share of > 90% of the cost of treatment of severe hemophilia. Another important reason is the variation in bleeding phenotype among patients. This has been highlighted in several studies, and the traditional thinking that 1% is enough can be abandoned. In fact, there are reasons to believe that some patients may develop joint problems at much higher factor levels, and the need for improved tools for monitoring joint disease is vital, as even subclinical bleeds probably occur 10.Manco‐Johnson M.J. Abshire T.C. Shapiro A.D. Riske B. Hacker M.R. Kilcoyne R. Ingram J.D. Manco‐Johnson M.L. Funk S. Jacobson L. Valentino L.A. Hoots W.K. Buchanan G.R. DiMichele D. Recht M. Brown D. Leissinger C. Bleak S. Cohen A. Mathew P. et al.Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.N Engl J Med. 2007; 357: 535-44Crossref PubMed Scopus (1462) Google Scholar. In the World Federation of Hemophilia treatment guidelines, the advice regarding prophylaxis is to individualize treatment, but no single specific dosing regimen is recommended. The introduction of products with extended half‐lives will be a challenge for dosing. The knowledge gained with standard FVIII and FIX products cannot directly be transferred to products with new properties, as the PK profile differs and becomes more flat, especially for FIX, for which the half‐life extension is more pronounced than for FVIII. If long intervals are aimed for, in the interests of convenience and adherence, peak levels will become less frequent, and the time span at relatively low factor levels may be longer than for standard products, depending on how the treater decides to dose. To achieve successful results with prophylaxis, careful monitoring of the patient and plasma levels is of utmost importance. The only feasible way to manage the new era of hemophilia prophylaxis is to implement population pharmacokinetics, not only if one is about switch to new products, but also if one is to continue to use a more conservative treatment approach. If plasma factor levels in the patient are known and connected to clinical response and outcome, the patient and the treater can have greater understanding, and see what events happen and why. The educational impact of this knowledge and its potential to help in the development of prophylaxis cannot be overestimated. The great potential of population pharmacokinetics is now widely appreciated, and several recent publications have addressed this topic, regarding both specific concentrate issues 13.Zhang Y. Roberts J. Bensen‐Kennedy D. Jacobs I. Santagostino E. Voigt C. Feussner A. Morfini M. Sidhu J. Population pharmacokinetics of a new long‐acting recombinant coagulation factor IX albumin fusion protein for patients with severe hemophilia B.J Thromb Haemost. 2016; 14: 2132-40Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 1.Zhang Y.R. Robers J. Tortorici M. Veldman A. St Ledger K. Feussner A. Sidhu J. Population pharmacokinetics of recombinant coagulation factor VIII‐SingleChain in patients with severe hemophilia A.J Thromb Haemost. 2017; 15: 1106-14Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 14.Nestorov I. Neelakantan S. Ludden T.M. Li S. Jiang H. Rogge M. Population pharmacokinetics of recombinant factor VIII Fc fusion protein.Clin Pharmacol Drug Dev. 2015; 4: 163-74Crossref PubMed Scopus (39) Google Scholar, 15.Brekkan A. Berntorp E. Jensen K. Nielsen E.I. Jonsson S. Population pharmacokinetics of plasma‐derived factor IX: procedures for dose individualization.J Thromb Haemost. 2016; 14: 724-32Crossref PubMed Scopus (29) Google Scholar and modeling of dosing regimens 16.Diao L. Li S. Ludden T. Gobburu J. Nestorov I. Jiang H. Population pharmacokinetic modelling of recombinant factor IX Fc fusion protein (rFIXFc) in patients with haemophilia B.Clin Pharmacokinet. 2014; 53: 467-77Crossref PubMed Scopus (31) Google Scholar. For implementation in clinical routine practice, practical software packages are needed, and these have been developed 17.McEneny‐King A. Foster G. Iorio A. Edginton A.N. Data analysis protocol for the development and evaluation of population pharmacokinetic models for incorporation into the Web‐Accessible Population Pharmacokinetic Service – Hemophilia (WAPPS‐Hemo).JMIR Res Protoc. 2016; 5: e232Crossref PubMed Google Scholar, 18.Iorio A. Keepanasseril A. Foster G. Navarro‐Ruan T. McEneny‐King A. Edginton A.N. Thabane L. network WA‐Hc‐iDevelopment of a Web‐Accessible Population Pharmacokinetic Service‐Hemophilia (WAPPS‐Hemo): study protocol.JMIR Res Protoc. 2016; 5: e239Crossref PubMed Google Scholar, 19.Alvarez‐Roman M.T. Fernandez‐Bello I. de la Corte‐Rodriguez H. Hernandez‐Moreno A.L. Martin‐Salces M. Butta‐Coll N. Rivas‐Pollmar M.I. Rivas‐Munoz S. Jimenez‐Yuste V. Experience of tailoring prophylaxis using factor VIII pharmacokinetic parameters estimated with myPKFiT(R) in patients with severe haemophilia A without inhibitors.Haemophilia. 2017; 23: e50-4Crossref PubMed Scopus (30) Google Scholar. A paradigm shift in hemophilia prophylaxis is about to happen, to the benefit of patients, treatment centers, and society. E. Berntorp reports receiving grants, personal fees, non‐financial support and consultancy from Bayer, Shire, and Sobi; grants and personal fees from CSL Behring; grants, personal fees and non‐financial support from Octapharma; personal fees, non‐financial support and consultancy from LFB; grants and non‐financial support from Novo Nordisk; and grants from Grifols, outside the submitted work." @default.
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• W2600156320 title "If you know you will also see: population pharmacokinetics is the way to personalize and optimize prophylaxis in hemophilia" @default.
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