Sjoerd F. Koopman, MSc (1), Marjon H. Cnossen, MD, PhD (2), Ron A.A. Mathôt (1), PharmD, PhD1, for the OPTI-CLOT study group and SYMPHONY consortium.
(1) Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center, Amsterdam, The Netherlands. (2) Department of Pediatric Hematology, Erasmus University Medical Center – Sophia Children’s Hospital Rotterdam, Rotterdam, The Netherlands.
Introduction: In haemophilia, the vast majority of the existing population pharmacokinetic (PK) models use weight (WT) to normalize the PK parameters instead of other morphometric parameters [1]. When specifically evaluating population PK models in haemophilia B, not a single model has assessed or included fat-free mass (FFM) as covariate, even though FFM seemed to correlate better to plasma volume than WT in haemophilia A [2], [3]. For recombinant fusion protein linking recombinant coagulation factor IX (FIX) with recombinant albumin (rIX-FP), an extended half-life (EHL)-clotting factor concentrate administered to haemophilia B patients, one population PK model has been published [4]. In this model, clearance (CL) and central and peripheral volume (V1 and V2, respectively) were normalized by WT. Since rIX-FP is expected to remain in the plasma [5], one would assume that FFM would better explain its pharmacokinetic behaviour. Of further interest in the published model, a relationship between the administered dose and V1 is described, which cannot be explained on basis of pharmacological principles.
Objectives: Our objective was to create a revised population PK model for rIX-FP with normalization of PK parameters to FFM instead of WT and without the inclusion of the relationship between dose and V1.
Methods: Data collected from the PROLONG-9FP studies (CSL654_2001, CSL654_2004, CSL654_3001, CSL654_3002 and CSL654_3003) was re-evaluated. In these studies, severe haemophilia B patients (FIX activity level ≤2 IU/dL) were treated with a median starting dose of 50 IU/kg (range: 19-102) intravenous rIX-FP as decided by the treating physician. Studies were considered complete when 50 patients achieved over 50 days of rIX-FP exposure. In our study, the annual bleeding rate (ABR) was calculated per patient by dividing the amount of registered bleeds by the follow-up time (FUT). FFM was calculated based on height (HT) and WT [6]. To evaluate both models’ performances, the mean prediction error (MPE) as well as the required dose to yield a FIX activity level > 3 IU/dL (Dose3%) after two weeks were assessed for a typical patient (following the dataset medians).
Results: We included 113 unique participants with a total of 2424 FIX activity levels. At baseline, the median age was 25 years (range: 1-61), median HT 172 cm (range: 78-190) and median WT 63.1 kg (range: 11-130), resulting in a median FFM of 51.2 kg (range: 9-72). A two-compartment model with a central and peripheral compartment adequately described our data. Normalization of PK parameters to FFM resulted in a better fit to the data than normalization to WT with a ΔOFV of -30.0. Patients receiving an initial dose of ≥70 IU/kg (n=11) appeared to have a higher baseline ABR than patients receiving <70 IU/kg rIX-FP (n=102) with respective median values of 7.0 year-1 (IQR: 1-13) and 3.0 year-1 (IQR: 1-8), respectively (p>0.05). For the published and revised model, the MPE was 17.6% (95% CI: 0-36) and 15.7% (95% CI: 0-34), respectively. The Dose3% for a typical patient was calculated to be 30 IU/kg with both models.
Conclusion: This study was set out to construct a population PK model for rIX-FP with its PK parameters normalized to FFM and without the inclusion of a relationship between dose and central volume of distribution. Normalization to FFM showed an improved fit of the model when compared to WT, yet the revised model showed similar parameter estimates and performance. In the trial design, the treating physician was able to select a pre-specified rIX-FP starting dose. The lack of randomization in starting dose allocation makes the model susceptible for treatment selection bias [7], [8]. In essence, after administration of a standard dose, patients with a relatively high volume of distribution (V) may have a relatively low activity levels and, consequently, a higher bleeding risk than patients with a relatively low V. To conclude, this study poses an alternative and pharmacologically-sound population PK model which may be employed to perform PK-guided dosing.
References:
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Reference: PAGE 32 (2024) Abstr 10960 [www.page-meeting.org/?abstract=10960]
Poster: Clinical Applications