scholarly journals Terminal half‐life of FVIII and FIX according to age, blood group and concentrate type: data from the WAPPS database

2021 ◽  
Author(s):  
Olav Versloot ◽  
Emma Iserman ◽  
Pierre Chelle ◽  
Federico Germini ◽  
Andrea N. Edginton ◽  
...  
Keyword(s):  
Blood Group ◽  
Half Life ◽  
Terminal Half Life ◽  
Type Data

scholarly journals Terminal Half-Life of Factor VIII/IX According to Age and Blood Group Based on 8550 Assessments

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Olav Versloot ◽  
Emma Iserman ◽  
Pierre Chelle ◽  
Federico Germini ◽  
Tushara Mathew ◽  
...  
Keyword(s):  
Factor Viii ◽  
Blood Group ◽  
Half Life ◽  
Research Funding ◽  
Linear Models ◽  
Real Life ◽  
Population Pharmacokinetic ◽  
Haemophilia A ◽  
Terminal Half Life ◽  
History Of

Introduction: Extended half-life concentrates were recently introduced and limited data have shown extended terminal half-life (THL). However, real-life data on pharmacokinetics in large cohorts of patients with haemophilia (PWH) and information on the effects of age, body composition and blood group (THL) are lacking. Aim: to assess THL for standard half-life (SHL) and extended half-life (EHL) concentrates according to age and blood group. Methods: Data on THL, age and blood group were extracted from the WAPPS (Web-Accessible Population Pharmacokinetics Service; www.wapps-hemo.org) database. WAPPS provides an on-line service of individual pharmacokinetic (PK) calculations for clinicians, based on concentrate-specific population pharmacokinetic models. Informed consent was waived by the ethical committee. THL according to age and blood group was assessed by multivariable linear modelling. Results: Infusion data (n=8550) was collected from 4832 (2222 children, 2610 adults) patients with severe haemophilia (89% haemophilia A; 34% treated with EHL concentrates, 9.7% with history of inhibitors, median age: 20 (range: 1 month - 85 years)). Details on infusions, calculated THL and results from regression models are shown in Table 1. For factor VIII, median THL was longer in EHL at 15.1 hours (interquartile range (IQR): 12.0-19.0) vs. 11.1 hours (8.8-14.2) in SHL-FVIII. Linear models identified age, type of concentrate and blood group as independent predictors of THL in FVIII. THL increased with age by 1 hour/10 years, and THL was 2.2 hours longer in patients with blood group non-O, independent of concentrate type. For FIX, median THL was considerably longer in EHL at median 106.9 (81.1-134.2) vs. 36.5 (31.2-42.6) hours in SHL. Age was only a significant predictor of THL in children using EHL-FIX concentrates: THL increased by 2,5 hours/year until adulthood for EHL concentrates (e.g.: from 77 hrs at age 4 to 112 hrs at age 18), whereas THL was stable across all ages for SHL-FIX. THL was stable across blood groups for all FIX concentrates. In PWH with a positive inhibitor history, THL was decreased by 1,3 hours for FVIII and 22 hours for FIX. Discussion: This study was the largest study describing THL according to concentrate type and patient characteristics so far. At group level, a significant extension of THL was confirmed for both FVIII-EHL and FIX-EHL. THL was associated with age and blood group for all FVIII concentrates. In contrast, THL for FIX concentrates, was only associated with age in children using EHL-FIX. THL was significantly reduced in patients with a history of inhibitors. The results support the need for individual assessment of THL, especially for patients with haemophilia A and children treated with EHL-FIX. This was a group-based study. Within the age of personalized medicine, individualized PK assessments seem more appropriate. Our next project will be to analyse the effects of switching from SHL to EHL in individual patients. Disclosures Versloot: Bayer: Research Funding. Germini:Bayer: Research Funding; Roche: Research Funding; Takeda: Research Funding; NovoNordisk: Research Funding. Iorio:CSL: Research Funding; BioMarin: Research Funding; Bayer: Research Funding; Uniqure: Research Funding; Takeda: Research Funding; Spark: Research Funding; Sanofi: Research Funding; Roche: Research Funding; Pfizer: Research Funding; Octapharma: Research Funding; NovoNordisk: Research Funding; Grifols: Research Funding; Freeline: Research Funding. Fischer:Bayer, Biogen, Pfizer, Baxter/Shire, and Novo Nordisk: Research Funding; Bayer, Baxter, Biogen, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, and Sobi: Consultancy; Bayer, Baxter/Shire, SOBI/Biogen, CSL Behring, Octapharma, Pfizer, NovoNordisk: Research Funding.

Common Genetic Variants in ABO and CLEC4M Modulate the Pharmacokinetics of Recombinant FVIII in Severe Hemophilia A Patients

2020 ◽  
Vol 120 (10) ◽  
pp. 1395-1406 ◽  
Author(s):  
Iris Garcia-Martínez ◽  
Nina Borràs ◽  
Marta Martorell ◽  
Rafael Parra ◽  
Carme Altisent ◽  
...  
Keyword(s):  
Blood Group ◽  
Half Life ◽  
Robust Regression ◽  
Hemophilia A ◽  
Illumina Miseq ◽  
Activity Levels ◽  
Severe Hemophilia ◽  
Single Nucleotide Variants ◽  
Common Genetic Variants ◽  
Recombinant Fviii

AbstractThe 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.

Phase I Dose-Finding Study of Weekly Single-Agent Patupilone in Patients With Advanced Solid Tumors

2005 ◽  
Vol 23 (36) ◽  
pp. 9120-9129 ◽  
Author(s):  
Eric H. Rubin ◽  
John Rothermel ◽  
Fisseha Tesfaye ◽  
Tianling Chen ◽  
Martine Hubert ◽  
...  
Keyword(s):  
Partial Response ◽  
Solid Tumors ◽  
Half Life ◽  
Drug Exposure ◽  
Dose Range ◽  
Single Agent ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Blood Concentrations ◽  
Terminal Half Life

Purpose To evaluate the safety and maximum-tolerated dose (MTD) of weekly patupilone, a natural epothilone B, in patients with advanced solid tumors. Patients and Methods Patients were treated with patupilone (0.3 to 3.6 mg/m2) for 6 weeks on/3 weeks off or 3 weeks on/1 week off. Dose-limiting toxicities (DLTs), MTD, and pharmacokinetics were determined for each schedule of administration. Results Ninety-one patients were enrolled. The most common tumor types included ovarian, breast, and colon cancers. Doses of patupilone less than 2.5 mg/m2 using either the 6 weeks on/3 weeks off or the 3 weeks on/1 week off schedule were tolerated well. At higher doses, DLTs were observed using both dosing schedules, with diarrhea the most common DLT. The MTD for both treatment schedules was 2.5 mg/m2. After a short infusion, patupilone blood concentrations declined in a multiphasic manner with a terminal half-life of 4 days. Drug clearance was nonrenal and was not related to body-surface area. Over the dose range evaluated, systemic drug exposure was approximately dose proportional. Three patients achieved a partial response, and 31 patients had stable disease. Two patients experiencing a partial response had received prior taxane therapy. Conclusion Patupilone is well tolerated when administered at a dose of 2.5 mg/m2, using either a 6 weeks on/3 weeks off or a 3 weeks on/1 week off schedule. In contrast with murine studies, patupilone has a relatively prolonged terminal half-life in humans. The partial responses in patients previously treated with taxanes is consistent with promising preclinical results.

scholarly journals hCGbeta core fragment is a metabolite of hCG: evidence from infusion of recombinant hCG

2000 ◽  
Vol 164 (3) ◽  
pp. 299-305 ◽  
Author(s):  
RJ Norman ◽  
MM Buchholz ◽  
AA Somogyi ◽  
F Amato
Keyword(s):  
Renal Clearance ◽  
Clearance Rate ◽  
Half Life ◽  
Urine Samples ◽  
Molar Ratio ◽  
Gel Chromatography ◽  
Core Fragment ◽  
Terminal Half Life ◽  
Intact Molecule ◽  
The Mean

The availability of recombinant human chorionic gonadotrophin (r-hCG) has allowed us to measure its metabolic and renal clearance rates and to study the origin of the beta core fragment of hCG (hCGbetacf). Serum and urine samples were collected from six subjects, after an intravenous injection of 2 mg (equivalent to 44 000 IU Urinary hCG) r-hCG, and assayed for hCG and the beta subunit (hCGbeta). Urine from four of the subjects was also subjected to gel chromatography and assayed for hCGbetacf and hCG. r-hCG, administered as an intravenous dose, was distributed, initially in a volume of 3.4+/-0.7 l (mean+/-s.d.) and then in 6.5+/-1.15 l at steady-state. The disappearance of r-hCG from serum was bi-exponential, with an initial half-life of 4.5+/-0.7 h and a terminal half-life of 29.0+/-4.6 h. The mean residence time was 28. 6+/- 3.6 h and the total systemic clearance rate of r-hCG was 226+/-18 ml/h. The renal clearance rate was 28.75+/-6.2 ml/h (mean+/-s.d). hCGbetacf was detected in all urine samples collected at 6 h intervals. Over the 138 h period of urine collection, 12.9% (range 10.1-17.3% ) of r-hCG injected was recovered as the intact molecule and 1.7% (range 0.8-2.9%) was recovered as the hCGbetacf, in 4 subjects. The molar ratio of hCGbetacf to hCG in urine increased from 3.1+/-1.7%, on day 1, to 76+/-34.3% (mean+/-s.e.m.) on day 5, after r-hCG infusion, suggesting that hCGbetacf is a metabolic product of the infused r-hCG.

scholarly journals Genetic determinants of VWF clearance and FVIII binding modify FVIII pharmacokinetics in pediatric hemophilia A patients

Blood ◽  
2019 ◽  
Vol 134 (11) ◽  
pp. 880-891 ◽  
Author(s):  
Laura L. Swystun ◽  
Kenichi Ogiwara ◽  
Orla Rawley ◽  
Christine Brown ◽  
Ilinca Georgescu ◽  
...  
Keyword(s):  
Blood Group ◽  
Von Willebrand Factor ◽  
Half Life ◽  
Hemophilia A ◽  
Blood Type ◽  
Abo Blood Group ◽  
Genetic Determinants ◽  
Group Status ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Factor VIII (FVIII) pharmacokinetic (PK) properties show high interpatient variability in hemophilia A patients. Although previous studies have determined that age, body mass index, von Willebrand factor antigen (VWF:Ag) levels, and ABO blood group status can influence FVIII PK, they do not account for all observed variability. In this study, we aim to describe the genetic determinants that modify the FVIII PK profile in a population of 43 pediatric hemophilia A patients. We observed that VWF:Ag and VWF propeptide (VWFpp)/VWF:Ag, but not VWFpp, were associated with FVIII half-life. VWFpp/VWF:Ag negatively correlated with FVIII half-life in patients with non-O blood type, but no correlation was observed for type O patients, suggesting that von Willebrand factor (VWF) half-life, as modified by the ABO blood group, is a strong regulator of FVIII PK. The FVIII-binding activity of VWF positively correlated with FVIII half-life, and the rare or low-frequency nonsynonymous VWF variants p.(Arg826Lys) and p.(Arg852Glu) were identified in patients with reduced VWF:FVIIIB but not VWF:Ag. Common variants at the VWF, CLEC4M, and STAB2 loci, which have been previously associated with plasma levels of VWF and FVIII, were associated with the FVIII PK profile. Together, these studies characterize the mechanistic basis by which VWF clearance and ABO glycosylation modify FVIII PK in a pediatric population. Moreover, this study is the first to identify non-VWF and non-ABO variants that modify FVIII PK in pediatric hemophilia A patients.

Human biokinetics of injected bismuth-207

2001 ◽  
Vol 20 (12) ◽  
pp. 601-609 ◽  
Author(s):  
D Newton ◽  
R J Talbot ◽  
N D Priest
Keyword(s):  
Half Life ◽  
Male Volunteer ◽  
Healthy Male Volunteer ◽  
Metabolic Model ◽  
The Body ◽  
Whole Body ◽  
Radiological Protection ◽  
Bismuth Compounds ◽  
Terminal Half Life ◽  
Radioactivity Measurements

A healthy male volunteer received an intravenous injection of 207Bi as citrate. Levels of the tracer in blood and in excretion samples, and its retention and distribution within the body, were investigated by appropriate radioactivity measurements. Levels in blood fell very rapidly, with only 1% of the injection remaining at 7 h and only ca. 0.1% at 18 days. There was rapid initial excretion, with 55% lost during the first 47 h, principally in urine; however, longer-term losses were much slower and 0.6% remained in the body at 924 days, when the contemporary rate of loss implied a half-life of 1.9 years. Integration of the retention pattern suggested that steady exposure to bismuth compounds could lead ultimately to a body content of 24 times the daily systemic uptake. The largest organ deposit was in the liver, which after 3 days contained ca. 60% of the contemporary whole body content, consistent with reports of hepatotoxicity. These findings differ markedly from the metabolic model for bismuth proposed by the International Commission on Radiological Protection, which envisages a terminal half-life in the body of only 5 days and kidney as the site of highest deposition.

scholarly journals Levers to Improve Antibiotic Treatment of Lambs via Drinking Water in Sheep Fattening Houses: The Example of the Sulfadimethoxine/Trimethoprim Combination

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 561
Author(s):  
Aude A. Ferran ◽  
Marlène Z. Lacroix ◽  
Alain Bousquet-Mélou ◽  
Ivain Duhil ◽  
Béatrice B. Roques
Keyword(s):  
Drinking Water ◽  
Oral Bioavailability ◽  
Half Life ◽  
Plasma Concentrations ◽  
Oral Route ◽  
Disease Spread ◽  
Bacterial Diseases ◽  
Terminal Half Life ◽  
High Interindividual Variability ◽  
The Individual

To limit the spread of bacterial diseases in sheep fattening houses, antibiotics are often administered collectively. Collective treatments can be delivered by drinking water but data on the drug’s solubility in water or on plasma exposure of the animals are lacking. We first assessed the solubility of products containing sulfadimethoxine (SDM), associated or not with trimethoprim (TMP), in different waters. We then compared in lambs the SDM and TMP pharmacokinetic profiles after individual intravenous (IV) and oral administrations of SDM-TMP in experimental settings (n = 8) and after a collective treatment by drinking water with SDM-TMP or SDM alone in a sheep fattening house (n = 100 for each treatment). The individual water consumption during the collective treatments was also monitored to characterize the ingestion variability. We showed that TMP had a short terminal half-life and very low oral bioavailability, demonstrating that it would be unable to potentiate SDM by oral route. Conversely, SDM had a long terminal half-life of 18 h and excellent oral bioavailability. However, delivery by drinking water resulted in a very high interindividual variability of SDM plasma concentrations, meaning that although disease spread could be controlled at the group level, some individuals would inevitably be under- or over-exposed to the antibiotic.

Pharmacokinetics, Pharmacodynamics and Tolerability of a Potent, Non-peptidic, GP IIb/IIIa Receptor Antagonist following Multiple Oral Administrations of a Prodrug Form

1998 ◽  
Vol 79 (01) ◽  
pp. 169-176 ◽  
Author(s):  
Nishit Modi ◽  
Sherron Bullens ◽  
Cheryl Pater ◽  
Michael Lipari ◽  
Kirk Robarge ◽  
...  
Keyword(s):  
Half Life ◽  
Rhesus Monkeys ◽  
Ex Vivo ◽  
Active Form ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
A Value ◽  
Terminal Half Life ◽  
The Right

SummaryRo 44-3888 is a potent and selective antagonist of GP IIb/IIIa. Following IV administration to rhesus monkeys, the (mean ± SD.) clear ance, volume of distribution and terminal half-life of Ro 44-3888 were 4.4 ± 1.8 ml/min/kg, 0.8 ± 0.4 l/kg and 2.5 ± 0.8 h respectively. Oral administration of Ro 48-3657 (1 mg/kg), a doubly protected prodrug form, produced peak concentrations of Ro 44-3888 (152 ± 51 ng/ml), 4.2 ± 2.2 h after dosing. Terminal half-life and estimated bioavailabil ity were 5.1 ± 1.6 h and 33 ± 6% respectively. No effect on blood pressure, heart rate or platelet counts were seen. Adenosine diphosohate (ADP) induced platelet aggregation (PA) and cutaneous bleeding times (CBT) were determined prior to and after the last of 8 daily oral administrations of Ro 48-3657 (0.25 or 0.5 mg/kg) to eight rhesus monkeys. Peak and trough plasma concentrations were proportional to dose and steady state was achieved after the second administration. Inhibition of PA and prolongation of CBT were concentration dependent. The ex vivo IC50 (82 nM) for ADP-mediated PA correlated with a value (58 nM) determined in vitro. The CBT response curve was displaced to the right of the PA curve. CBT was prolonged to ≥25 min when levels of Ro 44-3888 exceeded 190 nM and PA was >90% inhibited. Therefore, in rhesus monkeys, Ro 48-3657 is reproducibly absorbed and converted to its active form, is well tolerated, and has a concentration-dependent effect on PA and CBT. These properties make Ro 48-3657 an attractive candidate for evaluation in patients at high risk for arterial thrombosis.

scholarly journals Pharmacokinetics and Immunological Effects of Romidepsin in Rhesus Macaques

2020 ◽  
Vol 11 ◽  
Author(s):  
Adam J. Kleinman ◽  
Cuiling Xu ◽  
Mackenzie L. Cottrell ◽  
Ranjit Sivanandham ◽  
Egidio Brocca-Cofano ◽  
...  
Keyword(s):  
Half Life ◽  
Cytotoxic T Lymphocyte ◽  
Rhesus Macaques ◽  
Plasma Concentrations ◽  
Reversal Agents ◽  
Lymphocyte Surface Markers ◽  
Terminal Half Life ◽  
Immunological Effects ◽  
Kidney Liver ◽  
Transient Plasma

HIV/SIV persistence in latent reservoirs requires lifelong antiretroviral treatment and calls for effective cure strategies. Romidepsin (RMD), a histone deacetylase inhibitor, was reported to reactivate HIV/SIV from reservoirs in virus-suppressed individuals. We characterized in detail the pharmacokinetics and safety profile of RMD in three SIV-naïve rhesus macaques which received two rounds of treatment. In plasma, RMD mean terminal half-life was 15.3 h. In comparison, RMD mean terminal half-life was much longer in tissues: 110 h in the lymph nodes (LNs) and 28 h in gastrointestinal tract. RMD administration was accompanied by transient liver and systemic toxicity. Isoflurane anesthesia induced near-immediate transient lymphopenia, which was further exacerbated and extended with the extensive immune modifications by RMD. The effect of RMD on circulating immune cells was complex: (i) slight increase in lymphocyte death rates; (ii) transient, robust increase in neutrophils; (iii) massive downregulation of lymphocyte surface markers; (iv) important migration of CD3+ T cells to the gut and LNs; and (v) hindrance to CD8+ T cell functionality, yet without reaching significance. Our results show that, in contrast to transient plasma concentrations, RMD has a long-term presence in tissues, with multiple immunomodulatory effects and minimal to moderate kidney, liver, and lymphocyte toxicities. As such, we concluded that RMD can be used for “shock and kill” approaches, preferentially in combination with other latency reversal agents or cytotoxic T lymphocyte boosting strategies with consideration taken for adverse effects.

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