Personalization of Clotting Factor VIII Replacement Therapy Based on Population Pharmacokinetics in Adult Patients with Severe Hemophilia a Who Frequently Switch Factor VIII Concentrates

Interindividual pharmacokinetic differences in clotting factor VIII (FVIII) metabolism impede the dosing regimen optimization in patients with hemophilia A. The population pharmacokinetic (PK) analysis enables the estimation of FVIII pharmacokinetics in individual patients which is used to personalize dosing regimens. Therefore, we conducted a prospective study on adult patients with severe hemophilia A who received different FVIII concentrates for tertiary prophylaxis and whose dosage of FVIII was adjusted based on individual PK results. We aimed to compare the number of bleeding episodes and FVIII consumption before and after dosing adjustment.

The study, conducted for 18 months for each participant, was divided into 3 phases: (1) pre-PK: assessments before FVIII dosing adjustment, (2) dosing adjustment based on the PK analysis of FVIII, and (3) assessments after FVIII dosing adjustment. All patients gave informed consent before enrolment, and all procedures were carried out according to the Declaration of Helsinki. During the study patients frequently changed FVIII concentrates (each patient used 3-5 different products) which reflects the standard of care in adult patients with hemophilia in Poland.

During phase 1 of the study, over 5-13 months [median: 11.0 months, mean(standard deviation - SD): 10.8(1.9) months], patients recorded FVIII consumption and bleedings using electronic diaries (myPKFiT® licensed for octocog alfa). In phase 2 of the study, a PK analysis (clearance, half-time, time to reach the 1 IU/dl concentration) was performed: following the 72-hour washout period, blood samples were collected, and patients received the infusion of octocog alfa with the mean dose (SD) of 51.1(1.7) IU/kg. Two more blood samples were collected 3-4 h and 24-36 h after the infusion. Plasma FVIII activity was measured with a one-stage clotting assay, and the FVIII inhibitor with the Nijmegen modification of the standard Bethesda method. The myPKFiT® was used to obtain individualized FVIII dosing regimens based on PK analysis results. The dosing adjustment was offered to patients who experienced breakthrough bleeds during phase 1 or in whom the pre-PK treatment did not secure FVIII trough level of >1 IU/dl. In case of favorable PK results and no breakthrough bleeds during phase 1, a less intensive regimen was implemented. In phase 3 of the study (which lasted for 5-13 months, median: 7.7 months, mean(SD): 7.6(1.6) months), patients continued treatment with locally available FVIII concentrates and used electronic diaries to record FVIII consumption and bleedings. All bleeding rates were annualized (annualized bleeding rates - ABR).

The final analysis set included 22 male patients, aged 23-68 years. The clearance of octocog alpha ranged from 0.014 to 0.051 dL/h/kg [mean(SD), 0.030±0.010 dL/h/kg; coefficient of variation (CV)=33%], half-life - from 9.1 to 27.9 h (14.6(4.3) h, CV=29%), and time to reach 1 IU/dl - from 51 to 179 h [91(29) h, CV=32%]. Three individuals were categorized as slow metabolizers (clearance of 0.014, 0.018, and 0.019 dL/h/kg), and 2 as fast metabolizers (clearance of 0.048 and 0.051 dL/kg/h). FVIII inhibitor was undetectable (<0.5 BU/ml) in all patients.

After the PK analysis, 21 of 22 patients met the criteria of FVIII dosing adjustment. Four patients did not agree to change the regimen. Seventeen patients modified it according to the PK results (10 of them had FVIII trough levels of >1 IU/dl and 7 of them of <1 IU/dl in phase 1 of the study). Changing the dosing regimen in the 17 patients resulted in ABR reduction compared to the pre-PK phase: a decrease of 3.1-fold in total ABR (p=0.045 for dependent samples t-test); 3.2-fold in spontaneous ABR (p=0.046); and 3.1-fold in injury-related ABR (p=0.072). The consumption of FVIII due to bleeds had decreased by 77% (p=0.034).

In conclusion, personalizing the FVIII replacement therapy based on population PK models helps to lower bleeding risk and drug consumption in patients with severe hemophilia A. Presented results suggest that prophylaxis regimen based on PK analysis carried out with octocog alfa and myPKFiT® application is clinically effective also with the use of other FVIII concentrates.

Windyga:Alnylam: Research Funding; Amgen: Speakers Bureau; Bayer: Speakers Bureau; CSL Behring: Speakers Bureau; Novartis: Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Octapharma: Speakers Bureau; Pfizer: Speakers Bureau; Roche: Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Siemens: Speakers Bureau; SOBI: Speakers Bureau; SWIXX BioPharma: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Odnoczko:Novo Nordisk: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Roche: Speakers Bureau; SOBI: Speakers Bureau; Siemens: Speakers Bureau; Werfen: Speakers Bureau; Bioksel: Speakers Bureau. Stefanska-Windyga:Novo Nordisk: Research Funding, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; CSL Behring: Speakers Bureau. Baran:Novo Nordisk: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Siemens: Speakers Bureau. Sikorska:Takeda: Speakers Bureau. Gorska-Kosicka:Novo Nordisk: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Zawilski:Novo Nordisk: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau. Letowska:Takeda: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; CSL Behring: Speakers Bureau; Octapharma: Speakers Bureau; Pfizer: Speakers Bureau.