The History of Clotting Factor Concentrates Pharmacokinetics

Abstract

Clotting factor concentrates (CFCs) underwent tremendous modifications during the last forty years. Plasma-derived concentrates made the replacement therapy feasible not only in the hospital but also at patients’ home by on-demand or prophylactic regimen. Virucidal methods, implemented soon after hepatitis and AIDS outbreak, and purification by Mabs made the plasma-derived concentrates safer and purer. CFCs were considered equivalent to the other drugs and general rules and methods of pharmacokinetics (PK) were applied to their study. After the first attempts by graphical methods and calculation of In Vivo Recovery, compartment and non-compartment methods were applied also to the study of PK of CFCs. The bioequivalence of the new concentrates produced by means of recombinant DNA biotechnology was evaluated in head-to-head PK studies. Since the beginning, the large inter-patient variability of dose/response of replacement therapy was realized. PK allowed tailoring haemophilia therapy and PK driven prophylaxis resulted more cost effective. Unfortunately, the need of several blood samples and logistic difficulties made the PK studies very demanding. Recently, population PK (PopPK) has been applied to the prediction of CFCs dosing by Bayesian methodology. By PopPK also sparse data may allow evaluating the appropriateness of replacement therapy.

Recommendations on multidisciplinary management of elective surgery in people with haemophilia

“…Less‐invasive procedures, such as radio‐ and chemical synovectomy, typically require smaller amounts of clotting factor concentrates. Prior to major elective procedures, an in vivo recovery and half‐life study should be considered when the patient is not bleeding, using either a standard or a Bayesian approach to pharmacokinetic analysis …”

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

“…However, there are several challenges in conducting and evaluating clinical pharmacology studies for plasma‐derived and related recombinant protein products. These challenges are in part attributed to their macromolecular size and their complex and diverse physicochemical properties . Most of these products are naturally produced in the body and the PK/PD characteristics of exogenously administered therapeutic proteins can be influenced by the endogenous level.…”

“…The development of neutralizing or non‐neutralizing antibodies against the therapeutic proteins (risk of immunogenicity) can alter the PK/PD profiles. The mechanism of clearance and tissue biodistribution is not completely understood, and hence, mechanistic characterization of PK/PD relationship is largely unknown …”

“…Despite these challenges, clinical pharmacology studies of plasma‐derived and related recombinant protein products have significantly contributed to regulatory decisions and safe and effective utilization of biologics in clinics. For example, clinical pharmacology studies including population PK modelling of coagulation FVIII and FIX products have provided quantitative data on the inter‐individual variability in the PK and PD characteristics . Quantitative knowledge on inter‐individual variability derived from population PK analysis can be utilized for individualized dosing of FVIII and FIX products to maximize efficacy in preventing bleeding .…”

“…Furthermore, thorough understanding of the clinical pharmacology aspect of protein therapeutic products stimulates product innovation. In this regard, a key aspect of protein engineering and product discovery in the past decade revolves around extending the plasma half‐life of coagulation factors through Fc‐fusion, albumin‐fusion and PEGylation …”