Predicting Individual Changes in Terminal Half-Life After Switching to Extended Half-Life Concentrates in Patients With Severe Hemophilia

Versloot, Olav; Iserman, Emma; Chelle, Pierre; Germini, Federico; Edginton, Andrea N.; Schutgens, Roger E.G.; Iorio, Alfonso; Fischer, Kathelijn

doi:10.1097/hs9.0000000000000694

Cited by 2 publications

(7 citation statements)

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“…A recent study containing data from 688 patients with severe haemophilia A showed large inter-individual differences in patients' terminal half-life after switching to various EHL products. 25,26 This study, performed using the Web-Accessible Population Pharmacokinetic Service (WAPPS) database, showed a median 1.4-fold increase in half-life after switching to EHL FVIII products. However, 10% of patients had a decrease in median terminal half-life after the switch to an EHL FVIII product.…”

Section: Discussionmentioning

confidence: 99%

“…However, 10% of patients had a decrease in median terminal half-life after the switch to an EHL FVIII product. 26 Thus, individual responses to EHL FVIII products can be variable, and may be influenced by factors such as age and blood groups. [25][26][27] Less-than-expected FVIII activity was also reported in the PRO-TECT VIII Kids trial, investigating the safety and efficacy of the PEGylated recombinant FVIII damoctocog alfa pegol in paediatric PTPs with severe haemophilia A.…”

Section: Discussionmentioning

confidence: 99%

“…26 Thus, individual responses to EHL FVIII products can be variable, and may be influenced by factors such as age and blood groups. [25][26][27] Less-than-expected FVIII activity was also reported in the PRO-TECT VIII Kids trial, investigating the safety and efficacy of the PEGylated recombinant FVIII damoctocog alfa pegol in paediatric PTPs with severe haemophilia A. 28,29 Out of 73 paediatric PTPs in the study, 12 patients (11 under 6 years of age) discontinued the product due to a perceived loss of efficacy and/or due to severe hypersensitivity, indicating that loss of efficacy occurred in ∼16% of paediatric PTPs exposed to damoctocog alfa pegol.…”

Section: Discussionmentioning

confidence: 99%

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Cases of less‐than‐expected FVIII activity in previously treated patients during post‐marketing surveillance of N8‐GP

Oldenburg,

Benson,

Chowdary

et al. 2023

Haemophilia

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IntroductionTuroctocog alfa pegol (N8‐GP) is a glycoPEGylated, extended half‐life (EHL), human recombinant factor VIII (FVIII) approved for the treatment and prevention of bleeding episodes in patients with haemophilia A. Since its launch in August 2019, > 800 patients have been treated worldwide.AimTo present data from identified post‐marketing cases of less‐than‐expected FVIII activity in previously treated patients (PTPs) without inhibitors after switching to N8‐GP.MethodsThe post‐marketing safety database was searched using keywords such as ‘coagulation FVIII level decreased’. Identified cases reported prior to 13 October 2021 were included in this report. Cases in which patients had FVIII inhibitors were excluded.ResultsHere we report 14 cases of less‐than‐expected FVIII activity. Details varied greatly amongst the cases. At presentation, FVIII activity ranged from 1% (15 min post‐dose) to 51% (2 days post‐dose). Seven patients experienced bleeding episodes after switching to N8‐GP with heterogeneity in bleeding presentations. Six out of seven patients who were tested for anti‐PEG IgG and/or IgM antibodies were positive. In all known cases, FVIII activity returned to the expected range when switched to an alternative FVIII replacement product.ConclusionIn conclusion, the 14 reported cases of less‐than‐expected FVIII activity, without presence of detectable FVIII inhibitors, presented with heterogenous characteristics, and wide variations in FVIII activity and anti‐PEG antibody titre. FVIII activity returned to the expected range after switching to alternative FVIII products. In line with WFH guidelines, monitoring of FVIII activity can ensure FVIII activity in the expected range. The safety surveillance of N8‐GP continues.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cases of less‐than‐expected FVIII activity in previously treated patients during post‐marketing surveillance of N8‐GP

Oldenburg,

Benson,

Chowdary

et al. 2023

Haemophilia

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“…Infusion logs included bleeding data and were completed mostly by parents.. Sports was defined as "all forms of physical activity which, through casual or organized participation aim at expressing or improving physical fitness and mental well-being, forming social relationships or obtaining results in competition at all levels." 78 . Participation in school physical education classes was not considered.…”

Section: Data Collectedmentioning

confidence: 99%

“…However, the pharmacokinetic responses vary in people with severe haemophilia A and are hard to predict. (chapter 11), making it important to actually measure pharmacokinetic factors such as terminal half-life to base any decisions on existing patient data, rather than on modelled data 78 . This clearly shows once more that counselling people with haemophilia requires an individually tailored approach, in which pharmacokinetic of extended half-life products should be taken into account as well.…”

Section: Pharmacokinetics Of Factor Levelsmentioning

confidence: 99%

Sports participation, Injuries and Bleeds in People with Haemophilia

Versloot¹

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Around 1,700 men and boys in the Netherlands suffer from haemophilia, which is characterized by prolonged bleeding after trauma or surgery and an increased risk of (spontaneous) muscle and joint bleeds. People with haemophilia require lifelong prophylactic treatment and have traditionally been discouraged to participate in sport because of the anticipated increased bleeding risk. With the introduction of prophylactic treatment options, possibilities for sports participation have increased but the debate about the safety of sports participation continues. The aim of this study was to describe sports participation, sports injuries and sports-induced bleeds in people with haemophilia, with a special emphasis on the role of factor levels in the risk of sports-induced bleeds and to identify physical risk factors for sports injuries and sports-induced bleeds. Sports participation in people with haemophilia is currently similar to the general population across all age groups. Although sports participation decreased in older people with haemophilia, this was less pronounced than in the general population. Sports participation was associated with severity in adults, but not in children. Sports participation was similar in people with haemophilia with high-dose (Sweden) and intermediate-dose (The Netherlands) treatment strategies. However, Dutch people with haemophilia showed an age-related decrease, unlike their Swedish counterparts. Furthermore, sports participation was not associated with bleeds or clotting factor consumption. A retrospective study showed high sports-participation (including high-risk sports) and low injury rates in 102 Dutch boys with haemophilia and similar injury rates in boys with severe and non-severe haemophilia. Sports participation and sports injuries were similar to the general population. Sports participation in people with haemophilia decreased as a result of the imposed restriction during the COVID-19 pandemic, just as in the general population, although more pronounced and mainly showed a shift from high-risk sports to safe sports and from team sports to individual sports. Sports injuries and sports-induced bleeds were rare in people with haemophilia and sports-induced bleeds were associated with factor levels at the time of injury, but not with severity. Factor levels ≥10 IU/dl showed a 50% reduction in bleeding risk when sustaining a sports injury. The current selection of motor proficiency and endurance tests could not predict sports injuries or sports-induced bleeds, most likely due to a low number of injuries and bleeds. A repeated time-to-event analysis of the association between sports participation and sports-induced bleeds showed an inverse association between FVIII levels and bleeding hazard, but no association between sports participation and bleeding hazard, confirming that FVIII levels are the most important determinant for bleeding hazard. Extended half-life concentrates have recently been developed to provide longer terminal half-life and limit patient burden by decreasing the infusion frequency, while maintaining sufficient factor VIII/IX levels. Reference values for FVIII and FIX extended half-life concentrates based on patient characteristics and concentrate types are provided. Furthermore, an age-related increase in terminal half-life in both FVIII (all ages) and FIX (until 30, remaining stable in older ages) and a shorter FVIII half-life in subjects with blood group O and people with haemophilia with a positive inhibitor history was reported. Not all people with haemophilia A benefited from switching to extended half-life concentrates. A clinically meaningful extension in half-life in people with haemophilia A was predicted by short half-life at baseline and blood group non-O. (High-risk) sport participation, was assumed to improve therapeutic adherence as we assumed that people with haemophilia make deliberate choices to participate in sports. However, no association between (high-risk) sports participation and adherence to prophylactic treatment was reported.

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Predicting Individual Changes in Terminal Half-Life After Switching to Extended Half-Life Concentrates in Patients With Severe Hemophilia

Cited by 2 publications

References 42 publications

Cases of less‐than‐expected FVIII activity in previously treated patients during post‐marketing surveillance of N8‐GP

Cases of less‐than‐expected FVIII activity in previously treated patients during post‐marketing surveillance of N8‐GP

Sports participation, Injuries and Bleeds in People with Haemophilia

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