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Plasma Polyethylene Glycol (PEG) Levels Reach Steady State Following Repeated Treatment with N8-GP (Turoctocog Alfa Pegol; Esperoct®).

ABSTRACT: BACKGROUND:Extended half-life (EHL) factor VIII (FVIII)-replacement therapies enable patients with haemophilia A to maintain higher activity levels with fewer injections. N8-GP (turoctocog alfa pegol; Esperoct®) is an EHL product derived from conjugation of polyethylene glycol (PEG) to a recombinant FVIII protein. Upon activation, PEG is released from the active protein and excreted in urine and faeces. While PEG levels are expected to reach steady state with repeated dosing, there has been some discussion regarding whether abnormal accumulation of PEG in plasma and tissues may occur. OBJECTIVE:Our objective was to examine plasma PEG concentrations in rats and humans repeatedly treated with N8-GP for periods of up to 5 years. METHODS:PEG levels were measured using liquid chromatography-tandem mass spectrometry in plasma samples from rats treated with N8-GP as part of a 52-week toxicity study. Human plasma samples from children, adolescents and adults treated with N8-GP as part of the pathfinder programme were also examined (NCT01731600; NCT01480180). These data were compared with steady-state PEG levels predicted by pharmacokinetic modelling of single-dose rat data. RESULTS:PEG levels reached steady state in plasma in both rats and humans after repeated dosing. The timing and degree of PEG increase to steady state were in line with or below model predictions, confirming the utility of the pharmacokinetic model and indicating that rat data can be used to estimate human plasma PEG levels. CONCLUSION:Steady-state PEG levels were reached in plasma from rats and humans repeatedly treated with N8-GP. No unexpected increase in PEG was observed.

SUBMITTER: Bjornsdottir I

PROVIDER: S-EPMC7221073 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Plasma Polyethylene Glycol (PEG) Levels Reach Steady State Following Repeated Treatment with N8-GP (Turoctocog Alfa Pegol; Esperoct<sup>®</sup>).

Bjørnsdottir Inga I Støvring Birgitte B Søeborg Tue T Jacobsen Helene H Sternebring Ola O

Drugs in R&D 20200601 2

<h4>Background</h4>Extended half-life (EHL) factor VIII (FVIII)-replacement therapies enable patients with haemophilia A to maintain higher activity levels with fewer injections. N8-GP (turoctocog alfa pegol; Esperoct<sup>®</sup>) is an EHL product derived from conjugation of polyethylene glycol (PEG) to a recombinant FVIII protein. Upon activation, PEG is released from the active protein and excreted in urine and faeces. While PEG levels are expected to reach steady state with repeated dosing, ...[more]

PMID: 32152818

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Project description:PurposeTo illustrate the benefits of the extended half-life (EHL) recombinant factor VIII product N8-GP (Esperoct®, turoctocog alfa pegol) by describing individual cases of patients with severe hemophilia A treated with N8-GP in the pathfinder clinical trial program.Patients and methodsThis manuscript presents selected patient cases from the pivotal pathfinder clinical trial program, which included a number of clinical studies in adults (pathfinder 2 and 3) and children (pathfinder 5); overall results published previously. Clinical data and outcomes described in this manuscript are more detailed and derived from several interesting patient cases (five adults from pathfinder 2 and two children from pathfinder 5), who received N8-GP as prophylaxis (PPX) for their severe hemophilia A. Three of the five adults described here also underwent multiple major surgeries (for which they moved from pathfinder 2 into pathfinder 3 and later returned to pathfinder 2). New analyses on pediatric joint health from pathfinder 5 are also summarized here. Outcomes assessed included bleeding complications, improvements in quality of life, intraoperative hemostatic response, blood loss during surgery, number of blood transfusions, and annualized bleeding rates. For the pediatric patients, target joint resolution, adverse events, and annualized joint bleeding rate were also assessed, all by the treating physician.ResultsConsiderable improvements in treatment adherence, bleeding rates, and overall physical activity levels were demonstrated in two adult cases from the pathfinder 2 trial. N8-GP demonstrated good or excellent hemostatic coverage in three adult patients undergoing multiple major surgeries. The benefits of N8-GP for joint health and in support of children and adolescents with evolving active lifestyles were reported for several pediatric cases.ConclusionThese patient cases highlight the benefits of EHL products, such as N8-GP, for patients with severe hemophilia A. They include more challenging scenarios relating to improvements in previously poor adherence to PPX, children with active sporting lifestyles, and patients requiring multiple major surgeries.

Dataset Information

Plasma Polyethylene Glycol (PEG) Levels Reach Steady State Following Repeated Treatment with N8-GP (Turoctocog Alfa Pegol; Esperoct®).

Publications

Plasma Polyethylene Glycol (PEG) Levels Reach Steady State Following Repeated Treatment with N8-GP (Turoctocog Alfa Pegol; Esperoct<sup>®</sup>).

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