| dc.description.abstract | Hemophilia is a bleeding disorder in which the blood is unable to form clots, and is also classified as severe (defined as having an endogenous factor VIII [FVIII] concentration < 1 IU/dL, or 1%), moderate (1-5%) or mild (5-50%). Those with severe hemophilia may spontaneously bleed without physical trauma. If not treated appropriately, people with hemophilia may develop hemophilic arthropathy, a joint disease commonly showing signs of bleeding in the knees, ankles, or elbows, which not only impairs movement, but significantly impacts life expectancy and quality of life.
The current treatment of hemophilia involves prophylactic administration of factor concentrates. Although prophylactic treatment has improved health outcomes compared to on-demand treatment, there are still some challenges regarding the use of clotting factor concentrates. Generally, clotting factor concentrates are dosed based on international units per weight, but this one size fits all dosing mechanism fails to account for pharmacokinetic variability within this population. Appropriate dosing regimens vary by patient and treatment with hemophilia A patients using FVIII concentrates should be individualized from a therapeutic and economic standpoint.
Population pharmacokinetic (PopPK) models were used as the basis for individualizing dosing regimens for patients with hemophilia while on factor concentrates. PopPK models are built using PK data from multiple participants to quantify the relationships between covariates such as age and weight to PK parameters as well as define variability between and within participants for these same PK parameters. To determine individual PK using only a few clotting factor activity levels and patient covariates, PopPK models are leveraged for Bayesian forecasting. People with hemophilia who have few sampling points are still available to be assessed using prior knowledge available from the patient population. While PopPK models may be helpful in hemophilia, this poses a concern when switching between factor concentrates. Factor concentrate switches may be prompted by the availability of new, improved concentrates by termination of national contracts resulting in a discontinuation of drug coverage, hypersensitivity to their current drug formulation, or adverse drug reactions. The lack of PK-tailored guidance when switching from one product to another may result in a period of time where treatment may increase the risk of inappropriate dosing, leading to either an increased risk of bleeds or waste of expensive factor concentrate. The work presented in this dissertation uses knowledge of an individual’s PK on a prior factor concentrate to better predict an individual’s PK on a new factor concentrate using data available from the Web-Accessible Population Pharmacokinetic Service – Haemophilia (WAPPS-Hemo).
Emicizumab is a bispecific, recombinant, monoclonal antibody that bridges activated factor IX and X, mimics and partially restores the function of clotting FVIII in people with hemophilia A without inhibitors and was approved as routine prophylaxis by Health Canada in 2019. While emicizumab has its advantages over factor concentrates, such as decreased frequency of administration, and subcutaneous route of administration versus intravenous injections, the drug label recommends that any unused solution from a vial must be discarded, thereby wasting expensive resources. The use of a PopPK model of emicizumab was used to explore the implications of dosing based on vial size. This dissertation concludes that administering the entire vial of emicizumab and reducing the frequency may result in a reduction of vials used annually and consequently potential cost-savings.
With high treatment costs and the approval of emicizumab, understanding the pharmacoeconomics of hemophilia is imperative for healthcare systems for reimbursement approval and contributing to commercial success and decision making as to whether emicizumab should be covered or not. Given the lifelong burden of the disease, the high cost of treatment in hemophilia, and the approval of emicizumab, a drug that may change the landscape of how hemophilia is treated, a cost-utility analysis studying the cost and quality-of-life of different prophylactic treatment regimens was presented in this dissertation, concluding that emicizumab is more effective and may be less costly than FVIII for patients with hemophilia A in Canada, conditional on drug cost assumptions.
The method for estimating individual PK using PopPK models developed described in this dissertation may have a high impact for patients with hemophilia taking factor concentrates, who benefit from a safer individualized dosing regimen when switching between factor concentrates, potentially reducing adverse events or medication wastage. For patients with hemophilia on emicizumab, the simulations conducted exploring the use of emicizumab dosed based on vial size may have significant economic implications in cost-savings and provide a more practical dosing regimen. Finally, the economic evaluation conducted in the Canadian healthcare landscape may provide the healthcare system insight regarding the health and economic effects of using emicizumab compared to factor concentrates. | en |
