Laura H. Bukkems (1), Siv Jönsson (2), Marjon H. Cnossen (3), Mats O. Karlsson (2), Ron A.A. Mathôt (1)
(1) Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center, the Netherlands; (2) Department of Pharmacy, Uppsala University, Uppsala, Sweden; (3) Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children’s Hospital Rotterdam, Rotterdam, the Netherlands.
Objectives: Severe and some moderate severe patients with hemophilia A are often prophylactically treated with factor VIII (FVIII) concentrates. Publications on the exposure-effect relation of the available factor concentrates are limited, while such analyses give insight on the efficacy of treatment and its potential to reduce bleeding. Therefore, our objective was to examine the relationship between the dose, FVIII activity levels and occurrence of bleeding for rFVIII-SingleChain (Afstyla®).
Methods: Pharmacokinetic and bleeding data from patients with severe hemophilia A on prophylaxis from three rFVIII-SingleChain clinical trials were pooled.[1–3] The predictive performance of the published rFVIII-SingleChain population PK model was evaluated, and the model was expanded to include FVIII levels measured with the one-stage assay (OSA) and chromogenic assay (CSA).[4] The probability of bleeding was described with a parametric repeated time-to-event (RTTE) model. Exponential, Gompertz and Weibull hazard functions were examined. The effect of FVIII activity levels measured by CSA was evaluated on the bleeding hazard using a Imax model. Time-dependency between successive bleeds was evaluated using a Markov dependence hazard function in which the time was described as the time since previous bleed. The models were developed by means of non-linear mixed effects modelling using NONMEM v7.4.1.[5]
Results: Data included 3,052 OSA FVIII activity levels, 2,545 CSA FVIII activity levels and 2,080 bleeds from 241 patients (median age 19 years, range: 1-58) followed for median 1,090 days (range: 29-1,910). The majority of the bleeds occurred in joints (65%), were spontaneous (43%) or trauma-related (44%) and were treated with factor concentrate in 91% of cases. The previously published population PK model showed adequate predictive performance, but was improved by inclusion of estimation of the residual FVIII level of a previous dose and inter-individual variability (IIV) on residual error (p<0.01). FVIII levels measured by OSA were estimated to be a factor 0.52 (95% CI: 0.36-0.69) lower than CSA FVIII levels.
The probability of bleeding decreased during the study observation time and was best described by a Weibull hazard function. As expected, low FVIII activity levels were related to a higher bleeding risk compared to high FVIII activity levels, and the FVIII activity level at which 50% of the inhibitory effect was observed was 9.5 IU/dL (95%CI: 7.4-11.6). A typical patient with a constant FVIII activity level of 1 IU/dL after 1 year of follow-up experienced 2.8 bleeds per year (95%CI: 2.0-3.9), while a patient with a constant FVIII activity level of 20 IU/dL experienced 1.0 bleeds per year (95%CI: 0.6-1.5). Large differences were observed in the bleeding hazard between patients achieving the same FVIII activity level, as the coefficient of variation of the IIV on the overall bleeding hazard was 360%. No time-dependency between successive bleeds was identified with the Markov hazard function.
Conclusion: The developed model described the relation between dose, FVIII activity levels and bleeds for rFVIII-SingleChain. The obtained estimates were similar to estimates of the developed RTTE model for BAY 81-8973[6], indicating similar efficacy and potential to reduce bleeding between BAY 81-8973 and rFVIII-SingleChain.
Acknowledgment: We would like to thank CSL Behring for providing the data for this study.
References:
[1] Mahlangu J, Kuliczkowski K, Karim FA, et al. Efficacy and safety of rVIII-Singlechain: Results of a phase 1/3 multicenter clinical trial in severe hemophilia A. Blood. 2016; 128:630–637.
[2] Stasyshyn O, Djambas Khayat C, Iosava G, et al. Safety efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial. J Thromb Haemost. 2017; 15:636–644.
[3] Mahlangu J, Karim FA, Stasyshyn O, et al. Recombinant single-chain factor VIII in severe hemophilia: Long- term safety and efficacy in previously treated patients in the AFFINITY extension study. Res Pract Thromb Haemost. 2022; 6:e12665.
[4] Zhang Y, Roberts J, Tortorici M, et al. Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A. J Thromb Haemost. 2017; 15:1106–1114.
[5] Beal S, Sheiner L, Boeckmann A, et al. NONMEM 7.4 Users Guides. (1989–2017). Gaithersburg, MD: ICON plc; 2017. Available from: https://nonmem.iconplc.com/nonmem741.
[6] Abrantes JA, Solms A, Garmann D, et al. Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients. Haematologica. 2020; 105:1443–1453.
Reference: PAGE 30 (2022) Abstr 9954 [www.page-meeting.org/?abstract=9954]
Poster: Drug/Disease Modelling - Other Topics