A clinical study assessing the pharmacokinetics, efficacy and safety of AlphaNine®, a high-purity factor IX concentrate, in patients with severe haemophilia B

Abstract

Effective treatment with factor IX (FIX) requires a thorough consideration of the properties of the concentrate to be used as replacement therapy, to date, the only available treatment for haemophilia B. The aim of the study was to determine the pharmacokinetics, clinical efficacy and safety in routine clinical use of AlphaNine(®) , a high-purity human FIX concentrate. This open, single-arm, multicentre, non-randomized trial included 25 subjects (age ≥ 12) with moderate/severe haemophilia B. Pharmacokinetics was assessed at baseline and after a 6-month follow-up. The degree of haemostasis control achieved was evaluated during a 12-month follow-up. Safety was evaluated in terms of tolerance, thrombogenicity, immunogenicity and viral safety. Mean recovery was 1.01 ± 0.19 IU dL(-1) per IU kg(-1) at baseline and 1.23 ± 0.34 IU dL(-1) per IU kg(-1) 6 months later. Terminal half-life was 34.5 ± 6.2 h and 33.7 ± 5.4 h, respectively. Ratios of each parameter between the two pharmacokinetic studies were all close to 1. A total of 1,576,890 IU AlphaNine(®) were administered in 889 infusions (mean dose per infusion: 1774 IU; 3.2 infusions per month per patient). The main reasons for infusion were mild/moderate bleeding (62.3%) and prophylaxis (20.5% continuous, 15.6% intermittent). Overall, 93.0% of the efficacy assessments were rated as excellent/good and 88.8% of bleedings resolved after the first infusion. Twenty-one adverse events were reported in eight patients, none of which was considered related to the study medication. AlphaNine(®) showed a pharmacokinetic profile in agreement with that of other plasma-derived FIX concentrates and provides safe and clinically effective substitution therapy for patients with haemophilia B.

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.…”