ABSTRACT
The pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKFiT device was used to estimate individual PK parameters, and SNVs and clinically reportable F8 variants were simultaneously analyzed in an Illumina MiSeq instrument, using the microfluidics-based Fluidigm Access Array system. The contribution of SNVs to FVIII half-life and clearance was addressed by robust regression modeling, taking into account other modulators. In line with previous studies, we provide robust evidence that age, body weight, and blood group, as well as SNVs in ABO and CLEC4M, participate in the variability of FVIII PK in HA patients. Main results: each copy of the rs7853989 (ABO) allele increases FVIII half-life by 1.4 hours (p = 0.0131) and decreases clearance by 0.5 mL/h/kg (p = 5.57E-03), whereas each additional rs868875 (CLEC4M) allele reduces FVIII half-life by 1.1 hours (p = 2.90E-05) and increases clearance by 0.3 mL/h/kg (p = 1.01E-03). These results contribute to advancing efforts to improve FVIII replacement therapies by adjusting to each patient's PK profile based on pharmacogenomic data. This personalized medicine will decrease the burden of treatment and maximize the benefits obtained.
Subject(s)
ABO Blood-Group System/genetics , Cell Adhesion Molecules/genetics , Factor VIII/pharmacokinetics , Galactosyltransferases/genetics , Hemophilia A/drug therapy , Lectins, C-Type/genetics , Receptors, Cell Surface/genetics , Adolescent , Adult , Child , Factor VIII/genetics , Factor VIII/therapeutic use , Hemophilia A/genetics , Humans , Pharmacogenomic Testing , Polymorphism, Single Nucleotide , Recombinant Proteins/genetics , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/therapeutic use , Young AdultABSTRACT
El objetivo de este estudio fue evaluar las concentraciones plasmáticas de efavirenz y nevirapina en pacientes hemofílicos infectados por el virus de la inmunodeficiencia humana (VIH), controlados en dos hospitales de Barcelona. Las concentraciones del fármaco se determinaron por cromatografía líquida de alta resolución junto con la carga viral del VIH y el recuento de linfocitos CD4 a intervalos de 4 meses. Se incluyeron 19 pacientes tratados con efavirenz y 8 con nevirapina y se realizaron un total de 68 determinaciones de efavirenz y 31 de nevirapina. El tiempo medio de seguimiento fue de 12 meses. En los pacientes con supresión viral la concentración mediana de efavirenz fue 2,95 ìg/ml (intervalo: 1,54-5,26 ìg/ml) y en los pacientes con carga viral detectable 1,86 ìg/ml (0,82-4,88 ìg/ml) (p = 0,32). En el caso de la nevirapina las concentraciones fueron 4,41 ìg/ml (3,50-6,72 ìg/ml) y 3,12 ìg/ml (2,44-3,80 ìg/ml), respectivamente (p = 0,18) (AU)
The aim of this study was to evaluate efavirenz and nevirapine plasma levels in HIV-infected hemophilic patients seen in two hospitals in Barcelona. Plasma levels of these drugs were determined by high-performance liquid chromatography (HPLC) at four-month intervals, together with viral load and CD4 cell count. Nineteen patients treated with efavirenz and 8 with nevirapine were included, and 68 efavirenz and 31 nevirapine determinations were performed. Mean study time was 12 months. Median efavirenz plasma concentration was 2.95 ìg/ml (interval: 1.54-5.26 ìg/ml) in patients with favorable virological response and 1.86 ìg/ml (0.82-4.88 ìg/ml) in patients with detectable viral load (p = 0.32). Nevirapine plasma concentrations were 4.41 ìg/ml (3.50-6.72 ìg/ml) and 3.12 ìg/ml (2.44-3.80 ìg/ml) respectively (p = 0.18) (AU)
Subject(s)
Adult , Humans , Anti-Retroviral Agents/adverse effects , Anti-Retroviral Agents/therapeutic use , HIV Infections/complications , HIV Infections/etiology , Hemophilia A/complications , Hemophilia A/immunology , Viral Load/methods , Viral Load , Hemophilia A/metabolism , Liver Diseases/physiopathologyABSTRACT
The aim of this study was to evaluate efavirenz and nevirapine plasma levels in HIV-infected hemophilic patients seen in two hospitals in Barcelona. Plasma levels of these drugs were determined by high-performance liquid chromatography (HPLC) at four-month intervals, together with viral load and CD4 cell count. Nineteen patients treated with efavirenz and 8 with nevirapine were included, and 68 efavirenz and 31 nevirapine determinations were performed. Mean study time was 12 months. Median efavirenz plasma concentration was 2.95 .g/ml (interval: 1.54-5.26 .g/ml) in patients with favorable virological response and 1.86 .g/ml (0.82-4.88 .g/ml) in patients with detectable viral load (p = 0.32). Nevirapine plasma concentrations were 4.41 .g/ml (3.50-6.72 .g/ml) and 3.12 .g/ml (2.44-3.80 .g/ml) respectively (p = 0.18).
Subject(s)
Anti-HIV Agents/blood , HIV Infections/blood , Hemophilia A/blood , Nevirapine/blood , Oxazines/blood , Reverse Transcriptase Inhibitors/blood , Adult , Alkynes , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , Antimetabolites/administration & dosage , Antimetabolites/therapeutic use , Antiretroviral Therapy, Highly Active , Benzoxazines , Cyclopropanes , Female , HIV Infections/complications , HIV Infections/drug therapy , Hemophilia A/complications , Humans , Male , Middle Aged , Nevirapine/administration & dosage , Nevirapine/therapeutic use , Oxazines/administration & dosage , Oxazines/therapeutic use , RNA, Viral/blood , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/therapeutic use , Spain , Treatment Outcome , Viral LoadABSTRACT
BACKGROUND AND OBJECTIVES: The modulation of disease severity in hemophilia A (HA) patients may be related to the co-inheritance of mutations in genes with a known thrombotic effect such as factor V Leiden (FVL) and prothrombin. In the Spanish population, the prothrombin 20210A (PT20210A) allele is the most prevalent genetic risk factor for venous thromboembolism. DESIGN AND METHODS: We investigated the presence of both mutations in a cohort of 265 hemophiliac patients divided into two groups: I) 140 unrelated patients with moderate and mild HA and II) 125 unrelated patients with severe HA (83 carrying an inversion of intron 22). RESULTS: In group I, 4 patients had the FVL (2.8% vs. 2.98% controls) and 5 had the PT20210A (3.6% vs. 6.46% controls). In group II, two patients with inversion had the FVL (1.6%) and PT20210A was found in 10 patients (8%), five of them with inversion of intron 22 without inhibitors. One of these patients had the FVL and PT20210A mutations concomitantly. In the subgroup of patients with inversion who were carriers of the PT20210A, three parameters i.e. spontaneous bleeding (p=0.008), factor VIII utilization (p=0.016) and number of hemophilic arthropathies (p<0.0005) were significantly lower than in a subgroup of 11 age-matched non-PT20210A severe HA patients with inversion and without inhibitors. INTERPRETATION AND CONCLUSIONS: These results indicate that the inheritance of PT20210A could be a protective factor that mitigates the clinical severity of HA.
