Pharmacokinetic study of a high‐purity factor IX concentrate (Factor IX Grifols^®) with a 6‐month follow up in previously treated patients with severe haemophilia B

Abstract

Optimal replacement treatment in haemophilia B patients requires a good understanding of the pharmacokinetics of factor IX (FIX). The aim of this study was to compare the pharmacokinetic profile of Factor IX Grífols, a highly purified human FIX concentrate with two specific pathogen inactivation/removal steps, to that of available FIX preparations. The study was an open, non-randomized trial including 25 male subjects older than 12 years of age with severe haemophilia B. Pharmacokinetic profile of the FIX preparation regularly used by the subjects was determined as control. Pharmacokinetic profile of Factor IX Grifols was determined twice, one 7-15 days after control assessment and second after a 6 months period had elapsed. Results showed that all products had peak plasma levels of FIX:C within 30 min. Mean recovery was 1.3 +/- 0.3 IU dL(-1) per IU kg(-1) for Factor IX Grifols and 1.0 +/- 0.3 IU dL(-1) per IU kg(-1) for control products (P < 0.001). The mean terminal half-life (t(1/2)) for Factor IX Grifols was 26.7 h and 26.8 h for control product. Pharmacokinetic parameters after 6 months of treatment with Factor IX Grifols did not statistically differ from the parameters obtained with the first infusion. There were no adverse events related to Factor IX Grifols for the duration of the study. In conclusion, Factor IX Grifols has adequated pharmacokinetic properties comparable to the control plasma-derived FIX and these parameters remain stable after 6 months of treatment. Factor IX Grifols can be an effective and safe plasma-derived FIX concentrate for replacement therapy in haemophilia B patients.

Population pharmacokinetics of plasma-derived factor IX in adult patients with haemophilia B: implications for dosing in prophylaxis

“…Differences in study methodology and difficulties to fit a model to individual FIX:C curves may also explain part of the variation in reported PK parameter values. Elimination CL (easily determined from the area under the curve) ranged between 3.8 and 6.3 mL/h per kilogram in six studies [9,12,13,[15][16][17]. Together with the results from the present study, these values confirm that the CL of plasma-derived FIX is substantially lower than the 7.5-9.1 mL/h per kilogram normally reported for recombinant FIX [8].…”

“…In the three-compartment model, the typical [9] "physiological" interpretation of V2 as one extravascular compartment could thus be modified to V2 and V3 representing extravascular compartments characterized by fast and slow exchange of FIX, respectively, with the general circulation. The elimination half-life of plasma-derived FIX has previously been found to average 29-34 h [9,11,12,14,16,17]; however, mean values of 18 [13] or 43 h [15] have also been reported after a complete 72 h of blood sampling. Our study establishes that the average elimination half-life of plasma-derived FIX is approximately 30 h, thereby confirming that the average half-life is longer for plasma-derived FIX than the 18-24 h generally found [8] for recombinant FIX.…”

“…It is also the first one in which FIX has been found to follow three-compartment PK. Distinguishing threecompartment from two-compartment PK with the conventional separate curve-fitting on FIX:C data from each patient, as in previous studies [9,[11][12][13][14][15][16][17], may be virtually impossible, since a few data points deviating from the twocompartment curve are not sufficient to reject the simpler model in favour of the more complex one. Adequate statistical power is more easily obtained with a population model-in our case with a disposition pattern made up from 893 data points.…”

“…Our study establishes that the average elimination half-life of plasma-derived FIX is approximately 30 h, thereby confirming that the average half-life is longer for plasma-derived FIX than the 18-24 h generally found [8] for recombinant FIX. Incremental in vivo recovery, a parameter traditionally used in coagulation factor PK and ubiquitously [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]22] estimated or discussed, was also calculated. It represents the FIX:C level observed immediately after infusion in relationship to the administered dose, that is, recovery equals C 0 (IU/dL) divided by dose (IU/kg).…”

“…It has been shown that adequate blood sampling for at least 56 and most preferably 72 h is required to yield reliable estimates of the PK of plasma-derived FIX [6,9] (European regulatory guidelines [10] stipulate sampling up to 50 h, with an optional 72-h sample). To date, eight studies with sampling for at least 72 h have been reported in the literature [9,[11][12][13][14][15][16][17]. Compilation of these findings reveals a fragmentary description of the PK of FIX [8], with conflicting values reported for even such a basic parameter as elimination halflife.…”