Correlation between FIX genotype and pharmacokinetics of Nonacog alpha according to a multicentre Italian study

Abstract

Introduction: Pharmacokinetic (PK) studies on recombinant FIX concentrate, Nonacog alpha, were conducted with different sampling time designs which gave rise to not complete and homogenous outcomes. In addition, patient's FIX genotype/PK relationship has never been investigated. Aim: Investigate how different sampling times may affect PK parameters and try to find a FIX genotype/PK relationship. Patients and Methods: A cohort pharmacokinetic, Nonacog Alpha single-dose, open-label, non-comparative study was conducted in eight Comprehensive Care Haemophilia Centres in Italy. Seventeen previously treated moderate or severe haemophilia B patients were enrolled. Factors IX:C one-stage clotting assay, FIX genotype and PK analysis were centralized. Results: The evaluation of PK outcomes showed a quite long half-life, smaller clearance and volume of distribution of Nonacog Alpha in comparison with the results from previously reported studies, where blood sampling was stopped too early. The relationship between PK outcomes and FIX genotype showed that small deletions displayed the higher clearance and shorter half-life, the nonsense mutations (the lower and the longer respectively), and missense mutations were in between. Conclusions: It is evident that area under the curve (AUC) and other PK parameters depend from the sampling time design. In order to have a complete evaluation of clotting factors in vivo decay, blood samples must be collected until the baseline factor concentration has been achieved again. Due to the relationship between FIX genotype and clearance, tailored prophylaxis of HB patients could be partially predicted by genotyping.

Weekly recombinant FIX prophylaxis for severe haemophilia B in normal clinical practice: data from UKHCDO and Finland

“…The limited PK data available showed trough levels of <0.01-0.12 IU mL À1 , 5 to 7-days post-infusion in eight patients; in keeping with the longer terminal rFIX half-life recently reported [2,5]. Morfini observed long half-lives of 33.8-57.5 h in patients with missense and nonsense mutations, but very short half-lives of 5.02 and 9.69 h in two patients with FIX deletions [5]. Although the genotype was known for 17/20 of our patients, no obvious link could be shown between genotype, weekly dosage or ABR.…”

“…Although EHL-IX has a longer terminal half-life than rFIX, this is not consistently reflected in an improved clinical outcome and the annualized bleedrates (ABR) reported for standard and EHL-products are surprisingly similar [2][3][4]. These studies have also demonstrated a median terminal half-life for rFIX of 35-hmuch longer than previously reported [2,5]. These observations suggest that OWP with standard rFIX may have wider utility than previously recognized.…”

Pharmacokinetics and the transition to extended half‐life factor concentrates: communication from the SSC of the ISTH

“…No significant differences in elimination HL are recognized between plasma‐derived and recombinant FVIII concentrate bioequivalence studies, but small differences between their alpha‐HL distributions exist . Although FVIII genotype does not affect FVIII concentrate PK, FIX genotype may interfere with nonacog alpha PK, because FIX mutations may produce non‐active or truncated proteins that compete with infused concentrate for binding to collagen type IV or filling the extravascular space . Blood group O and low VWF concentration are well‐known covariates interfering with FVIII HL, but not protein C and LRP1; other plasma proteins or cell receptor polymorphisms are under investigation (Morfini and Bernardi, unpublished data).…”

The History of Clotting Factor Concentrates Pharmacokinetics

“…Only in phase 3 head-to-head study of rFIX-Fc, the PK of pdFIX and rFIX have been prolonged up to 72 and 96 h [74]. It is easy to understand how prolonged sample timing causes a larger AUC, a smaller Cl, and a longer HL, as shown by a recent Italian multicentre PK study [75]. Similar findings have been observed in a PK study of nonacog alfa conducted in China [76].…”