Pharmacokinetic-based prediction of real-life dosing of extended half-life clotting factor concentrates on hemophilia

Abstract

The improvement of clotting factor concentrates (CFCs) has undergone an impressive boost during the last six years. Since 2010, several new recombinant factor (rF)VIII/IX concentrates entered phase I/II/III clinical trials. The improvements are related to the culture of human embryonic kidney (HEK) cells, post-translational glycosylation, PEGylation, and co-expression of the fragment crystallizable (Fc) region of immunoglobulin (Ig)G1 or albumin genes in the manufacturing procedures. The extended half-life (EHL) CFCs allow an increase of the interval between bolus administrations during prophylaxis, a very important advantage for patients with difficulties in venous access. Although the inhibitor risk has not been fully established, phase III studies have provided standard prophylaxis protocols, which, compared with on-demand treatment, have achieved very low annualized bleeding rates (ABRs). The key pharmacokinetics (PK) parameter to tailor patient therapy is clearance, which is more reliable than the half-life of CFCs; the clearance considers the decay rate of the drug concentration-time profile, while the half-life considers only the half concentration of the drug at a given time. To tailor the prophylaxis of hemophilia patients in real-life, we propose two formulae (expressed in terms of the clearance, trough and dose interval between prophylaxis), respectively based on the one- and two-compartmental models (CMs), for the prediction of the optimal single dose of EHL CFCs. Once the data from the time decay of the CFCs are fitted by the one- or two-CMs after an individual PK analysis, such formulae provide to the treater the optimal trade-off among trough and time-intervals between boluses. In this way, a sufficiently long time-interval between bolus administration could be guaranteed for a wider class of patients, with a preassigned level of the trough. Finally, a PK approach using repeated dosing is discussed, and some examples with new EHL CFCs are shown.

Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A

“…As patients present with varied clinical phenotypes, tailored patient therapy should be guided by careful consideration of the overall improved PK profile of an EHL rFVIII product [24,30]. Besides half-life, PK parameters such as AUC, CL, and time above FVIII threshold level are important contributors to protection from bleeds and, thus, are of clinical significance [31]. In patients with severe hemophilia A, time spent with very low FVIII levels potentially carries the risk of spontaneous joint bleeds [3].…”

Model‐Based Evaluation of Linear Limited and Bayesian Sparse Sampling for Therapeutic Monitoring of Recombinant Coagulation Factor IX

“…Because coagulation factor trough values are generally used for the management of hemophilia, 8,14‐16 we also developed an indirect method to project the factor IX trough value(s). In our analysis we used AUC as an intermediate step for prediction of factor IX trough values because we found that AUC has strong statistical relationships with both the concentration at 24 hours and trough values (Table 1 and Figure 3).…”

“…For coagulation factors, a trough level above 1 IU/dL is often considered clinically relevant for the prevention of bleeding in patients with hemophilia 8,14‐16 . Because there is no established target FIX AUC level that corresponds to trough level, we define target AUC as the minimum AUC value that corresponds with FIX trough level ≥ 1 IU/dL.…”

“…Clinical pharmacology studies such as clearance prediction and exposure analysis (AUC) assist therapeutic dose individualization. For coagulation factors, a target AUC that correspond with efficacy has not been established; instead prophylactic treatment often aims to maintain a trough level above 1 IU/dL 8,14‐16 . Thus, it remains unknown whether one can employ AUC from limited sampling models for dose individualization of coagulation factors.…”

Clinical Pharmacology Review of Plasma‐derived and Recombinant Protein Products: CBER Experience and Perspectives on Model‐Informed Drug Development

“…The concept of clearance as a key parameter for selecting appropriate dosing regimen and therapeutic individualization is now being appreciated in haemophilia research community. 3,13 Currently, limited PK studies are submitted for licensing of biological products used for rare coagulation disorders. For example, the FDA package insert for COAGADEX (Coagulation Factor X) provides clearance data only for >12 years old subjects.…”