Cross-evaluation of Pharmacokinetic-Guided Dosing Tools for Factor VIII

2018 ◽  
Vol 118 (03) ◽  
pp. 514-525 ◽  
Author(s):  
T. Preijers ◽  
I. van Moort ◽  
K. Fijnvandraat ◽  
F. Leebeek ◽  
M. Cnossen ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Trough Level ◽  
Patient Characteristics ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Haemophilia A ◽  
Blood Samples ◽  
Fviii Activity ◽  
Recombinant Fviii

Background Patients with severe and moderate haemophilia A are treated prophylactically with factor VIII (FVIII) concentrate. Individualization of prophylaxis can be achieved by pharmacokinetic (PK)-guided dosing. Aim In this study, the performance of three PK tools (myPKFiT, Web-Accessible Population Pharmacokinetic Service-Hemophilia [WAPPS] and NONMEM) is compared. Methods In 39 patients, with severe or moderate haemophilia A, blood samples were collected 4, 24 and 48 hours after administration of 50 IU kg−1 of recombinant FVIII (Advate [n = 30] or Kogenate [n = 9]). FVIII dose, FVIII activity and patient characteristics were entered into the three PK tools. Obtained PK parameters and dosing advises were compared. Results myPKFiT provided PK parameters for 24 of 30 patients receiving Advate, whereas WAPPS and NONMEM provided estimates for all patients. Half-life was different among the three methods: medians were 12.6 hours (n = 24), 11.2 hours (n = 30) and 13.0 hours (n = 30) for myPKFiT, WAPPS and NONMEM (p < 0.001), respectively. To maintain a FVIII trough level of 0.01 IU mL−1 after 48 hours, doses for myPKFiT and NONMEM were 15.1 and 11.0 IU kg−1 (p < 0.01, n = 11) and for WAPPS and NONMEM were 9.0 and 8.0 IU kg−1 (p < 0.01, n = 23), respectively. In nine patients receiving Kogenate, WAPPS and NONMEM produced different PK-parameter estimates; half-life was 15.0 and 12.3 hours and time to 0.05 IU mL−1 was 69.2 and 60.8 hours, respectively (p < 0.01, n = 9). However, recommended doses to obtain these levels were not different. Conclusion The three evaluated PK tools produced different PK parameters and doses for recombinant FVIII. Haematologists should be aware that recommended doses may be influenced by the choice of PK tool.

scholarly journals Population Pharmacokinetic Modeling and Simulation of Recombinant Single-Chain Factor VIII (r VIII-SingleChain) in Patients with Hemophilia a

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2814-2814
Author(s):  
Ying Zhang ◽  
Tharin Limsakun ◽  
Debra M. Bensen-Kennedy ◽  
Alex Veldman ◽  
Zhenling Yao
Keyword(s):  
Body Weight ◽  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Fviii Activity ◽  
Dosing Regimens ◽  
Trough Levels ◽  
Plasma Activity

Abstract Introduction: Hemophilia A is a rare but serious X-linked recessive bleeding disorder that affects males and is characterized by a deficiency in the plasma protein known as coagulation Factor VIII. rVIII-SingleChain is a proprietary, lyophilized formulation of clotting factor VIII (FVIII) produced by recombinant technology. As part of the clinical development of rVIII-SingleChain, a population pharmacokinetic (PK) analysis was undertaken, utilizing data from Study CSL627_1001 in subjects with hemophilia A, with the objectives of (a) characterizing the PK of rVIII-SingleChain at a population level, (b) assessing the ability of various patient characteristics (e.g., von Willebrand factor, VWF) to describe variability in the PK parameters, and (c) enable population-based simulations of rVIII-SingleChain dosing regimens that may provide improved prophylaxis coverage compared with octocog alfa (Advate®). Methods: Twenty-seven male subjects (aged 19-60 years) enrolled in Study CSL627_1001 (Part 1) received a single 50 IU/kg IV infusion of Advate®, followed by a single 50 IU/kg IV infusion of rVIII-SingleChain, with a minimum 4-day washout period. Plasma PK samples (for the determination of FVIII activity) were collected over 72 hours for both Advate® and rVIII-SingleChain (at pre-specified time points) and were measured by a validated chromogenic assay. Population PK models were developed separately for rVIII-SingleChain and Advate®, using the NONMEM 7 with FOCEI method. Various covariates, including VWF, body weight, and effect of age on clearance (CL) and volume of distribution were tested. Bootstrap and visual predictive check (VPC) were used for model evaluation. Simulations of different dosing regimens were performed to evaluate the FVIII activity plasma exposure profiles that may provide improved prophylaxis coverage. Results: A two-compartmental model with first-order elimination was developed to describe FVIII plasma activity data for both rVIII-SingleChain and Advate®. VWF was found to be a significant covariate influence on FVIII plasma activity CL, whilst body weight influenced both CL and volume of distribution in the central compartment. Population parameter estimates indicated a lower CL (2.02 vs 2.49 dL/h) and longer half-life (13.1 vs 9.3 h) for rVIII-SingleChain compared with Advate®. The results of bootstrap and VPC implied that the model was stable, and the parameters were estimated with good precision. PK simulations indicated that rVIII-SingleChain, at the same doses and frequencies, resulted in higher FVIII plasma activities throughout the dosing period, as reflected in higher area-under-the-curve (AUC). The dosing regimens for the simulations were designed based on the dosing recommendations of the Advate® label and rVIII-SingleChain phase III study. The results showed that rVIII-SingleChain provided a higher percentage of subjects with trough levels of at least 1% FVIII plasma activity, compared with Advate® at the same dosing regimen. Every 3 days dosing at 40-50 IU/kg rVIII-SingleChain was predicted to achieve similar prophylaxis protection compared with Advate® every 2 days (i.e., about 90% of subjects with trough levels of at least 1% FVIII plasma activity). In addition, 73-90% of subjects were predicted to achieve trough levels of at least 1% FVIII plasma activity with twice weekly dosing (4- and 3-day schedule) at 50 IU/kg rVIII-SingleChain, compared with 65-80% of subjects dosed with Advate® using the same regimen. Conclusion: The population model shows that rVIII-SingleChain has a longer half-life, lower CL and higher AUC compared with Advate®. Simulations demonstrated that rVIII-SingleChain resulted in higher trough concentrations when compared with Advate®, indicating the possibility of greater prophylaxis coverage. Disclosures Zhang: CSL Behring: Employment. Limsakun:CSL Behring: Employment. Bensen-Kennedy:CSL Behring: Employment. Veldman:CSL Behring GmbH: Employment. Yao:CSL Behring: Employment.

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.

Continuous infusion of extended half-life factor VIII (efmoroctocog alpha) for surgery in severe haemophilia A

Haemophilia ◽  
2018 ◽  
Vol 24 (4) ◽  
pp. e280-e283
Author(s):  
I. C. L. Kremer Hovinga ◽  
R. E. G. Schutgens ◽  
P. R. van der Valk ◽  
L. F. D. van Vulpen ◽  
E. P. Mauser-Bunschoten ◽  
...  
Keyword(s):  
Factor Viii ◽  
Continuous Infusion ◽  
Half Life ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Life Factor

Acetaminophen Developmental Pharmacokinetics in Premature Neonates and Infants

2002 ◽  
Vol 96 (6) ◽  
pp. 1336-1345 ◽  
Author(s):  
Brian J. Anderson ◽  
Richard A. van Lingen ◽  
Tom G. Hansen ◽  
Yuan-Chi Lin ◽  
Nicholas H. G. Holford
Keyword(s):  
Half Life ◽  
Lag Time ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Nonlinear Mixed Effects Models ◽  
Premature Neonates ◽  
First Order ◽  
Neonates And Infants

Background The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens. Methods A population pharmacokinetic analysis of acetaminophen time-concentration profiles in 283 children (124 aged &lt; or = 6 months) reported in six studies was undertaken using nonlinear mixed-effects models. Neonates and infants were given either single or multiple doses of four different formulations: oral elixir, rectal solution, or triglyceride or capsular suppository. The median postnatal age of children younger than 6 months was 1 day (range, birth to 6 months), median postconception age was 40 weeks (range, 28-64 weeks), and median weight was 3.1 kg (range, 1.2-9.0 kg). Results Population pharmacokinetic parameter estimates and their variability (percent) for a one-compartment model with first-order input, lag time, and first-order elimination were as follows: volume of distribution, 66.6 l (20%); clearance, 12.5 l/h (44%); standardized to a 70-kg person using allometric "1/4 power" models. The volume of distribution decreased exponentially with a maturation half-life of 11.5 weeks from 109.7 l/70 kg at 28 weeks after conception to 72.9 l/70 kg by 60 weeks. Clearance increased from 28 weeks after conception (0.74 l x h(-1) x 70 kg(-1)) with a maturation half-life of 11.3 weeks to reach 10.8 l x h(-1) x 70 kg(-1) by 60 weeks. The absorption half-life for the oral elixir preparation was 0.21 h (120%) with a lag time of 0.42 h (70%), but absorption was further delayed (2 h) in premature neonates in the first few days of life. Absorption half-life parameters for the triglyceride base and capsule suppositories were 0.80 h (100%) and 1.4 h (57%), respectively. The absorption half-life for the rectal solution was 0.33 h. Absorption lag time was negligible by the rectal route for all three formulations. The bioavailability of the capsule suppository relative to elixir decreased with age from 0.92 (22%) at 28 weeks after conception to 0.86 at 2 yr of age, whereas the triglyceride base decreased from 0.86 (35%) at 28 weeks postconception to 0.5 at 2 yr of age. The relative bioavailability of the rectal solution was 0.66. Conclusions A mean steady state target concentration greater than 10 mg/l at trough can be achieved by an oral dose of 25 mg x kg(-1) x d(-1) in premature neonates at 30 weeks' postconception, 45 mg x kg(-1) x d(-1) at 34 weeks' gestation, 60 mg x kg(-1) x d(-1) at term, and 90 mg x kg(-1) x d(-1) at 6 months of age. The relative rectal bioavailability is formulation dependent and decreases with age. Similar concentrations can be achieved with maintenance rectal doses of 25 (capsule suppository) or 30 (triglyceride suppository) mg. kg-1. d-1 in premature neonates at 30 weeks' gestation, increasing to 90 (capsule suppository) or 120 (triglyceride suppository) mg x kg(-1) x d(-1) at 6 months. These regimens may cause hepatotoxicity in some individuals if used for longer than 2-3 days.

scholarly journals Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 380 ◽  
Author(s):  
Quentin Allard ◽  
Zoubir Djerada ◽  
Claire Pouplard ◽  
Yohann Repessé ◽  
Dominique Desprez ◽  
...  
Keyword(s):  
Half Life ◽  
Random Effect ◽  
Real Life ◽  
Compartment Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Severe Haemophilia ◽  
Fviii Activity ◽  
Data Files

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

scholarly journals Characterization of Interaction of Factor VIII with Engineered Variants of a Single-Chain Variable Antibody Fragment

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1170-1170
Author(s):  
Svetlana A Shestopal ◽  
Leonid A Parunov ◽  
Mikhail V Ovanesov ◽  
Timothy K Lee ◽  
Andrey G Sarafanov
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Conflicts Of Interest ◽  
Antibody Fragment ◽  
Density Lipoprotein ◽  
Size Exclusion ◽  
Single Chain ◽  
Study Objective ◽  
Thrombin Cleavage ◽  
Fviii Activity

Abstract Introduction Replacement therapy for Hemophilia A requires frequent infusions of Factor VIII (FVIII) due to its relatively short half-life of ~12 h in plasma. Previous attempts to extend this half-life by genetic and chemical modification of FVIII met the barrier of ~20 h, which is a half-life of von Willebrand factor (VWF), a carrier of FVIII in plasma. A single-chain variable antibody fragment (scFv) KM33 was shown to inhibit FVIII activity, and interactions with VWF and the low-density lipoprotein receptor-related protein 1 (LRP), the major clearance receptor of FVIII (Bovenschen et al, 2005, Blood, 106:906-12). A study indicated that scFv KM33 may prolong the half-life of FVIII in mice to the level exceeding that of VWF half-life (Mertens et al, US Patent 2008, 20080219983A1). This would make scFv KM33 a promising tool for new designs of the longer-acting FVIII products. Study objective We aimed to generate a scFv KM33 variant that can delay FVIII clearance but can be removed from FVIII during its activation by thrombin. Such antibody fragment may extend the half-life of FVIII above that of VWF. Experimental design We generated three scFv KM33 variants with different linkers connecting the subunits VL and VH of the antibody fragment. The linkers contained variants of thrombin cleavage sites identical to those on FVIII. The proteins were expressed using a baculovirus system, purified by Ni-affinity and size exclusion chromatography (SEC), and tested for their properties. Results The engineered scFv variants, along with the unmodified KM33, were tested for binding to FVIII by surface plasmon resonance (SPR). All scFv versions demonstrated similar affinity for FVIII (~1 nM). In addition, a selected variant of scFv inhibited FVIII binding to LRP. These showed that the modifications of scFv did not affect its binding to FVIII. Thrombin treatment of the engineered scFv variants resulted in dissociation of their VL and VH domains, verified by SEC. However, the respective rates of thrombin cleavage were slower than that of FVIII. The preparation of a thrombin-cleaved scFv still inhibited the interaction of FVIII with LRP by SPR, similarly to that observed for the unmodified KM33. All variants of scFv inhibited FVIII activity in a thrombin generation assay suggesting that their moiety remained in complex with FVIII upon its activation. Conclusions The rate of thrombin cleavage of sites within FVIII is higher than that of the identical sites within the scFv. This suggests that additional determinants of FVIII (e. g. sulfated tyrosines adjacent to the sites) contribute to the higher rate of cleavage. The cleavage of the linker between the VL and VH subunits of scFv KM33 results in dissociation of the subunits and breakdown of the antibody fragment. This mechanism is likely applicable to any scFv, and may be useful in a broad range of applications involving such ligands. Both subunits of thrombin-cleaved scFv KM33, most likely, re-assemble on FVIII and form a tertiary complex FVIII/VL/VH. In turn, thrombin cleavage of the scFv, complexed with FVIII, does not result in its dissociation from FVIII. These indicate that in such design, an scFv should have lower affinity for FVIII to ensure its release from the complex. Disclosures No relevant conflicts of interest to declare.

scholarly journals Thrombelastography (TEG) and Thrombin Generation Assay (TGA) in Severe Hemophilia Following Factor Replacement Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4666-4666 ◽  
Author(s):  
Tania T. Sarker ◽  
Donald Brophy ◽  
Meera B. Chitlur
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Thrombin Generation ◽  
Factor Activity ◽  
Treatment Frequency ◽  
Thrombin Generation Assay ◽  
Fviii Activity ◽  
The Mean ◽  
Life Factor ◽  
Time Point

Abstract Background: Monitoring therapy in hemophilia is a major challenge. Measurement of factor levels is time consuming and not available in time to make clinical decisions. With the introduction of extended half-life factor products, determination of treatment frequency becomes important. Global hemostatic assays such as Thrombelastography (TEG) and Thrombin Generation Assay (TGA) may improve monitoring. Focused toward individualizing therapy, these assays may help determine treatment frequency based not just on Factor VIII PK (pharmacokinetic), but also on total hemostatic potential. Objective: To determine the correlation between TGA and TEG parameters, and Factor activity and half-life (t1/2). Design/Methods: With IRB approval and participant consent baseline FVIII activity was obtained at enrollment, 15minutes, 1, 4, 8, 24 and 48 hours post factor replacement in patients who had not received replacement factor for a minimum of 72 hours and were not bleeding. FVIII:C, TEG, and TGA at each time point were measured. Non-compartmental PK analysis was performed on each individual patient profile to measure Factor VIII terminal half-life (t 1/2), mean normalized factor clearance rate and volume of distribution at steady-state (Vdss). Pearson correlation statistical analyses on other variables were performed using JMP ¨ Pro version 12.0.1 (SAS Institute, Cary, NC, USA) Results: 27 patients with hemophilia have enrolled, with a median age of 14 years (range: 2-24 years). 9 patients were eliminated from analysis because of a diagnosis of inhibitors (n=1), factor activity >1% (n=4), inadequate sample collection (n=2), patient on episodic factor replacement (n=1), and inaccurate TGA time point (n=1). The mean Factor level prior to factor administration, after elimination of the subjects (n=18) was 0.4%. As expected, our results indicate a rise in ETP and Factor activity following factor replacement, peaking at 15 minutes post infusion. The mean normalized factor clearance rate was 3.3 ± 1.2ml/h/kg. The Vdss was 2.3 ± 1 L and Factor VIII t½ was 11.5 ± 3 hours. There were strong correlations between ETP and FVIII:C (R2=0.65; p<0.0001), Peak and FVIII:C (R2=0.6; p<0.0001), R Time and Factor VIII:C (R2=0.71; p<0.0001), Peak and R Time (R2=0.59; p<0.0001), ETP and R Time (R2=0.51; p<0.0001) as shown in table 1. Table 1. Correlation data on Factor VIII:C with TGA & TEG Parameters; and TGA parameters with TEG R time R2 P-value TGA Parameters (Peak & ETP) ETP and Factor VIII:C 0.65 p<0.0001 Peak and Factor VIII:C 0.60 p<0.0001 TEG Parameter (R Time) R Time and Factor VIII:C 0.71 p<0.0001 TEG and TGA Parameters Peak and R Time 0.59 p<0.0001 ETP and R Time 0.51 p<0.0001 Conclusions: Global hemostatic assays are less expensive than traditional PK testing and are available at the time of care decisions. Results of global coagulation assays (TEG and TGA) correlated closely with FVIII activities. Global assays may predict breakthrough bleeding independent of factor levels, representing an improvement in monitoring over traditional PK. With the emergence of the bioengineered extended half-life factor products, there is a renewed interest in pharmacokinetic analysis and individualization of therapy. Assays like TEG provide the opportunity to receive feed back in real time that corresponds to FVIII activity, and enable us to make treatment decisions rapidly for each individual patient. Since these assays measure more than just the factor activity, the parameters such as ETP on TGA may be more prognostic of bleeding tendency, as has been shown previously. Pharmacokinetic and pharmacodynamics analysis of this data is ongoing. Our small sample size precludes us from making global predictions. Larger multi center trials would assist in confirming these findings. Disclosures No relevant conflicts of interest to declare.

scholarly journals Investigating myotoxicity following Australian red-bellied black snake (Pseudechis porphyriacus) envenomation

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0256653
Author(s):  
Suchaya Sanhajariya ◽  
Stephen B. Duffull ◽  
Geoffrey K. Isbister
Keyword(s):  
Half Life ◽  
Time Course ◽  
Model Development ◽  
Clinical Manifestations ◽  
Patient Characteristics ◽  
Time Profile ◽  
Population Pharmacokinetic ◽  
Pkpd Model ◽  
Parameter Values ◽  
The Relationship

Background Myotoxicity is one of the common clinical manifestations of red-bellied black snake (Pseudechis porphyriacus) envenomation characterised by elevated creatine kinase (CK) concentrations of greater than 1000 U/L. This study aimed to investigate the occurrence of myotoxicity in patients following envenomation. Methods/Principal findings Patient characteristics and serial blood samples (timed venom concentrations and CK concentrations, pre- and post- antivenom) from 114 patients (median age 41, 2-90y; 80 male) were extracted from the Australian Snakebite Project database. Patients were categorised into three groups based on peak CK concentrations [no myotoxicity (<1000 U/L), mild (1000–10,000 U/L) and severe (>10,000 U/L)]. The odds of (mild or severe) myotoxicity was lower in patients that received early antivenom (within 6 hours post-bite) compared to those that received late or no antivenom (odd ratio was 0.186; 95% confidence interval, 0.052–0.664). A population pharmacokinetic-pharmacodynamic (PKPD) model was developed to describe the relationship between the time course of venom (a mixture of toxins) and effect (elevated CK). In addition, a kinetic-pharmacodynamic (KPD) model was developed to describe the relationship between time course of a theoretical toxin and effect. Model development and parameter estimation was performed using NONMEM v7.3. No single set of parameter values from either the PKPD or KPD models were found that could accurately describe the time course of different levels of severity of myotoxicity. The predicted theoretical toxin half-life from the KPD model was 11 ± 3.9 hours compared to the half-life of venom of 5.3 ± 0.36 hours. This indicates that the putative causative toxin’s concentration-time profile does not parallel that of venom. Conclusion Early antivenom administration reduces the incidence of myotoxicity. The venom concentration profile does not appear to be the driver for myotoxicity following envenomation. Additional factors that affect the sensitivity of the patient to snake venom/toxins must be explored to understand the relationship with myotoxicity.

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