The History of Clotting Factor Concentrates Pharmacokinetics.

Massimo Morfini

doi:10.3390/jcm6030035

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.

Highlights

The absorption and elimination of drugs attracted the attention of scientists and physicians since the beginning of modern medicine, but the pharmacokinetics developed during the second half of last century [1]
Apart from the inaccuracy of evaluating plasma volume by means of haematocrit, because of the plasma trapped within red cells, the assumption that Volume of distribution (Vd) of FVIII is limited to the plasma pool is inaccurate
During the last 30 years, pharmacokinetics has become a very popular tool to study the in vivo behaviour of Clotting factor concentrates (CFCs)

Summary

Introduction

The absorption and elimination of drugs attracted the attention of scientists and physicians since the beginning of modern medicine, but the pharmacokinetics developed during the second half of last century [1]. The advent of personal computers allowed for sophisticated and iterative procedures for best fitting and modelling. Pharmacokinetics (PK) deals with the Adsorption, Distribution, Elimination and Metabolism (ADEM) of drugs into the recipient’s body. The in vivo behaviour and decay of drugs depends on the body anatomical and functional characteristics of recipients. Pharmacodynamics studies the effects of drug on the body of recipients. Pharmacokinetics and pharmacodynamics are strictly related to each other, but they are two different aspects of drug therapy

The Beginning of Haemophilia Therapy

Plasma-Derived Clotting Factor Concentrates and Their Pharmacokinetics

DNA-Recombinant Clotting Factor Concentrates and Their Pharmacokinetics

Population Pharmacokinetics

Findings

Conclusions