Pharmacokinetics of factor VIII and factor IX

Morfini, Massimo

doi:10.1046/j.1365-2516.9.s1.8.x

Cited by 39 publications

(53 citation statements)

References 34 publications

(54 reference statements)

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“…25 An on-demand treatment regimen in conjunction with FFPs and fresh whole blood as the primary treatment modalities endorse a high mortality rate in settings of severe HB. 26 Another explanation might be the fact that 69.5% of the cases with HB reported by the low-income countries lack classification into a severity class. 9 Appropriate categorization of this nonclassified group might change the current picture.…”

Section: Discussionmentioning

confidence: 99%

Mutation Spectrum and Genotype–Phenotype Analyses in a Pakistani Cohort With Hemophilia B

Khan

Naz

Ahmed

et al. 2017

Clin Appl Thromb Hemost

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This study aimed to (1) identify F9 genetic alterations in patients with hemophilia B (HB) of Pakistani origin and (2) determine the genotype-phenotype relationships in these patients. Diagnosed cases of HB were identified through registries at designated tertiary health-care centers across the country. Consenting patients were enrolled into the study. The factor IX (FIX) coagulation activity (FIX:C) and key clinical features were recorded. Direct sequencing of F9 was carried out in all patients. All the variants identified were analyzed for functional consequences employing in silico analysis tools. Accession numbers from National Center of Biotechnology Information ClinVar database were retrieved for the novel variants. Genotype-FIX:C relationships were determined followed by FIX:C clinical phenotype assessment. A total of 52 patients with HB from 36 unrelated families were identified, which mainly comprised patients with moderate HB (n ¼ 35; 67.3%). Among these, 35 patients from 22 unrelated families could be contacted and enrolled into the study. Missense variants were the most frequent (58.8%), followed by nonsense variants (17.6%). A missense, a short insertion, and a nonsense novel variants in exon 2, 6, and 7, respectively, were also identified. The disease manifested FIX:C heterogeneity in relation to the corresponding mutation in a significant number of cases. Clinical phenotype heterogeneity was also observed in relation to FIX:C-based severity assessment. We concluded that the registered FIX-deficient population of Pakistan mainly comprises moderate HB. F9 mutation spectrum in Pakistani patients with HB is heterogeneous. The HB population of Pakistan manifests a significant amount of genotype-FIX:C and FIX:C-clinical phenotype heterogeneities.

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Section: Discussionmentioning

confidence: 99%

Mutation Spectrum and Genotype–Phenotype Analyses in a Pakistani Cohort With Hemophilia B

Khan

Naz

Ahmed

et al. 2017

Clin Appl Thromb Hemost

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“…The WT and VIR covariates accounted for 34% and 66% of the unexplained variation across patients for CL and V, respectively. However, a portion of unexplained variability still remains, so monitoring may still be necessary, depending on the treatment and the patient's state [8,11].…”

Section: Discussionmentioning

confidence: 99%

“…Once the (usually numerous) samples are collected and assayed, noncompartmental analysis (NCA) is easy to perform and amenable to automation. However, the NCA has less utility as a predictive tool, and its use compared with the advantages offered by compartmental PK is criticized [9][10][11]. Several studies have addressed the compartmental PK properties of factor VIII [12].…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of recombinant factor VIII:C (ReFacto®) in adult HIV-negative and HIV-positive haemophilia patients

Karafoulidou¹,

Súárez

Anastasopoulou³

et al. 2009

Eur J Clin Pharmacol

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Purpose The aim of this study was to explore possible differences in the pharmacokinetics (PK) of recombinant factor VIII:C (ReFacto® -ReFacto ) in HIV+ vs. HIVpatients and also differences in the chromogenic substrate bioassay (CHS) and one-stage clotting (OSC) methods. Methods Twenty-eight haemophilia A adults (20 HIV-and eight HIV+) were assayed with both the CHS and OSC methods. An average of two and six samples were collected per patient for HIV-/+, respectively, after one, and occasionally two more, prophylactic doses (mean 2,003 IU; range 1,000-4,300 IU). The observations were analysed with the mixed-effects (population) compartmental PK modelling package NONMEM (nonlinear mixed-effects modelling) and the FOCE (first-order conditional estimation) method. Base modelling was performed independently for the CHS and OSC bioassays for comparison, and covariate models and simulation tests were done only for the commonly used OSC bioassay. The final covariate model was validated using the bootstrap method. Monte Carlo simulations were used to estimate the expected probability of exceeding 20%, 40% or 60% of normal factor VIII:C in plasma after a single dose, corresponding to required levels for preventing mild, moderate and lifethreatening haemorrhages. Results One-compartment base-model population PK parameters were [mean parameter (interpatient variability %)] for CHS: clearance (CL)=2.56 dl h −1 (33.2%); volume of distribution (V)=34.8 dl (12.8%); and for OSC: CL= 3.83 dl h −1 (47.8%), V=53.7 dl (22.4%). The volumes differed significantly between the CHS and OSC methods (p<0.0001), and variabilities were higher for OSC. Nevertheless, the empirical half-lives (t 1/2 =l n (2) × V/CL) were similar for CHS and OSC, [(mean ± standard deviation (SD)], 9.5 ± 3 h and 10.2 ± 4 h, respectively. In covariate modelling with the OSC-derived model, HIV status (VIR) was a significant categorical predictor (p<0.005) for V.The final covariate models with OSC were for CL=3.93 + 0.09 × (WT-75) and for V=48.6 × (1 + 0.36 × VIR) + 0.55 × (WT-75); therefore, V for the typical HIV+ patient was 36% higher than for the HIV-patient. Conclusions Both HIV-and HIV+ patients showed 100% success with the 20% threshold at doses >20 IU/kg. HIVpatients receiving >50 IU/kg had a 100% expected chance of success for all thresholds. HIV+ patients for moderate or life-threatening haemorrhage treatment need 10 IU/kg more than the HIV-patient equivalent to have the same probability of success.

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“…FVIII:C half-lives of 5 h or longer were observed in 31 out of the 47 evaluable patients, suggesting that their FVIII is removed from circulation similarly to normal subjects, and to patients diagnosed with type 1 VWD but with no identified VWF mutation [23]. The half-life of autologous FVIII is typically shorter than that of allogeneic FVIII provided through replacement therapy, which is usually around 10-15 h in the absence of an inhibitor [22]. This discrepancy is perhaps explained by the presence of normal FVIII in concentrates, whereas FVIII released by desmopressin in mild hemophilia A patients is often variably qualitatively abnormal.…”

Section: Pattern Of Response To Desmopressin and Phenotypic Determinantsmentioning

confidence: 99%

Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A

Castaman

Mancuso

Giacomelli

et al. 2009

Journal of Thrombosis and Haemostasis

101

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Summary. Background: The relationship of the biologic response to desmopressin with the F8 mutation and physiological characteristics has been poorly investigated in patients with mild hemophilia A. Objectives: We prospectively assessed the molecular and phenotypic determinants of the biologic response to desmopressin in a cohort of 50 patients with mild hemophilia A. Methods: Up to 24 h after desmopressin, blood samples were serially obtained and factor (F)VIII and von Willebrand factor (VWF) measured. The promoter region, all exons and exonintron boundaries of the F8 gene were screened using denaturing high-performance liquid chromatography (DHPLC). Direct sequencing was done when DHPLC screening was normal. Genomic DNA was also sequenced for exons 18-21, 24 and 27 of VWF. Results: Mean basal FVIII:C was 19 ± 9 IU dL )1 (range 6-37) and the median postdesmopressin peak increase was 2.5-fold (range 1.1-7.1). Eleven patients with a cross-reacting material positive (CRM + ) phenotype had similar basal levels and relative increases of FVIII:C to the remaining patients with low FVIII:Ag. Using multivariate regression, FVIII:C half-life was positively related to basal and peak VWF:Ag levels (P = 0.008) and patient age (P = 0.004). Eleven patients had evidence of reduced FVIII survival. While 27 different gene mutations were identified in 41 patients, nine patients had no detectable mutation. These patients had significantly smaller peaks and smaller relative increase of postdesmopressin FVIII:C (median FVIII:C 26 IU dL )1 vs. IU dL )1; P < 0.001; fold 1.8 ± 0.6 vs. 2.9 ± 0.8; P = 0.002). Conclusions: In this cohort of patients with mild hemophilia A, a poor biologic response to desmopressin was frequently associated with the absence of detectable F8 mutations.

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Pharmacokinetics of factor VIII and factor IX

Cited by 39 publications

References 34 publications

Mutation Spectrum and Genotype–Phenotype Analyses in a Pakistani Cohort With Hemophilia B

Mutation Spectrum and Genotype–Phenotype Analyses in a Pakistani Cohort With Hemophilia B

Population pharmacokinetics of recombinant factor VIII:C (ReFacto®) in adult HIV-negative and HIV-positive haemophilia patients

Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A

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