Population Pharmacokinetic Analysis of Emapalumab, a Fully Human, Anti-Interferon Gamma Monoclonal Antibody, in Children with Primary Hemophagocytic Lymphohistiocytosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-20
Author(s):  
Christian Laveille ◽  
Philippe Jacqmin ◽  
Kathy de Graaf ◽  
Cristina de Min
Keyword(s):  
Monoclonal Antibody ◽  
Body Weight ◽  
Interferon Gamma ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Haematopoietic Stem Cell ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Good Precision ◽  
Population Pk ◽  
Volumes Of Distribution

Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by pathologic immune activation and hyperinflammation. It typically manifests during infancy and is invariably fatal if untreated. Interferon gamma (IFNy) is considered a key contributor to the hyperinflammation of HLH. Thus, neutralization of IFNy could help control the disease until haematopoietic stem cell transplantation, the only curative treatment. Emapalumab, a fully human, anti-IFNy monoclonal antibody, binds to and neutralizes IFNy. Emapalumab is the first and only approved (FDA) treatment for primary HLH. It is indicated for the treatment of adult and pediatric patients with HLH with refractory, recurrent, or progressive disease, or intolerance to conventional HLH therapy. Objective: To develop a population pharmacokinetic (PK) model to describe the PK profile of emapalumab. Methods: PK data were obtained from patients with primary HLH administered emapalumab intravenously during an open-label, single-group, phase 2/3 clinical trial (NCT01818492) and as part of a compassionate use program. A population PK analysis was performed using nonlinear mixed effects modeling (NONMEM® version 7.3.0). Predictive performance of the model was assessed using a visual predictive check. Results: The PK of emapalumab was adequately described by a two-compartment model. All model parameters were estimated with good precision. Central and peripheral volumes of distribution were 0.059 and 0.079 L/kg, respectively. Exploratory graphical analysis showed that (i) IFNy production varied significantly between and within patients as a function of time; (ii) the higher the IFNy production, the faster the elimination of emapalumab due to target-mediated drug disposition; and (iii) the higher the IFNy production, the higher the dose of emapalumab required to reach the neutralizing concentration of IFNy (evidenced by a higher target-mediated clearance of emapalumab). Of the parameters examined, only body weight and total IFNy (free and bound) levels were found to significantly influence the PK of emapalumab. The allometric exponents of body weight for the volume of distribution and clearance were 1 (fixed) and 0.886 (95% confidence interval 0.68, 1.09), respectively. These values support the bodyweight-based dosing of emapalumab (i.e. mg/kg). At values of total IFNy from 103 to 106 pg/mL, the total clearance (linear + target mediated) of emapalumab ranged from 0.0012 to 0.0140 L/h for a bodyweight of 5 kg, with corresponding terminal half-lives from 17.5 to 2.3 days. This wide variance in clearances and half-lives partly explains the emapalumab dose adaptations that are required for treating primary HLH patients. Conclusion: The population PK model reliably predicted serum concentrations of emapalumab in patients with primary HLH. The central and peripheral volumes of distribution were low, clearance was slow, and the terminal half-life long. The expected dynamic of the biology of IFNy was confirmed and included in the population PK model. Simulations using this model supported the proposed dosing scheme of emapalumab in patients with primary HLH. Disclosures Laveille: Sobi: Consultancy. Jacqmin:Sobi: Consultancy. de Min:Sobi: Consultancy.

Population Pharmacokinetics of Siplizumab (MEDI-507), a Humanized Anti-CD2 Monoclonal Antibody, in Cancer Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2670-2670
Author(s):  
Chunlin Chen ◽  
John E Janik ◽  
Karen Kaucic ◽  
Lorin Roskos ◽  
Bahija Jallal ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Body Weight ◽  
Serum Concentration ◽  
Dose Escalation ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Serum Concentrations ◽  
Concentration Data ◽  
Non Linear ◽  
Volumes Of Distribution

Abstract Abstract 2670 Poster Board II-646 Introduction: Siplizumab, a humanized IgG1k class monoclonal antibody that targets CD2 expressing T-and NK-cells, was evaluated in phase I dose-escalation trials in patients with CD2-positive lymphoproliferative disorder. The objective of this study was to develop a population pharmacokinetic (PK) model for siplizumab and identify covariates that could explain the variability in siplizumab pharmacokinetic parameters. Methods: A Phase 1, open label, dose-escalation study was conducted in 29 patients (14 males/15 females, age range 34–79 years) who received 0.2–4.8 mg/kg of siplizumab as 1-3 consecutive daily doses every 14 days for a total of 1-8 cycles. Siplizumab serum concentration data was analyzed using a nonlinear mixed effects modeling approach with software (NONMEM). Based on exploratory analysis, 1-and 2-compartment non-linear models were evaluated. Demographic covariates including body weight, age, sex and race (Caucasian/Black/Asian) were screened using Generalized Additive Model (GAM) analysis. Covariates selected during the GAM analysis were further tested for significance in NONMEM using the forward inclusion and backward elimination approach. Results: Siplizumab concentrations were obtained from all 29 patients in the study yielding a total of 619 serum concentration observations. Pronounced non-linearity in siplizumab serum concentrations was observed after the initial and later dosing cycles, with serum concentrations declining faster at lower dose levels. The data was best described by a two-compartment pharmacokinetic model with zero-order input with parallel linear and non-linear elimination pathways. Goodness of fit plots and model diagnostics indicated good agreement between observed and model predicted serum concentration values. The population estimates for linear clearance was 0.168 L/day with inter-subject variability (ISV) of 50%, and inter-compartmental clearance was 2.83 L/day. Nonlinear elimination parameters, Vmax and Km were 10.32 mcg/day (56% ISV) and 51.8 mcg/L, respectively. Sex of the patients was identified as a significant covariate impacting volumes of distribution. Male patients had higher central and peripheral volumes of distribution of 2.8 L and 3.0 L, respectively, compared to1.38 L and 2.4 L in females [32% vs 50% ISV]. Conclusion: The serum concentration-time profile of siplizumab was adequately described by a two-compartment non-linear PK model. Population parameters were precisely estimated and correspond well to reported PK behaviour of monocolonal antibodies with significant target mediated elimination. The lower volume distribution in females is most likely due to lower body weight compared to males in this study. The population PK model combined with pharmacodynamic data could serve as a tool to guide selection of optimal dose regimens for siplizumab. Disclosures: No relevant conflicts of interest to declare.

Population Pharmacokinetic Model of ADVATE in Pediatric and Adult Patients with Hemophilia A.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3492-3492
Author(s):  
Myungshin Oh ◽  
Sven Björkman ◽  
Phillip Schroth ◽  
Sandor Fritsch ◽  
Peter Collins ◽  
...  
Keyword(s):  
Body Weight ◽  
Hemophilia A ◽  
Individual Variability ◽  
Patient Specific ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Data Sets ◽  
Residual Variability ◽  
Population Pk ◽  
Variability Model

Abstract Abstract 3492 Poster Board III-429 Introduction The objective of this analysis was to characterize the population pharmacokinetic (PK) model of ADVATE® (Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method) in hemophilia A patients. This included estimation of typical population pharmacokinetic parameters and inter-individual and residual variability and identification of covariates that are significant predictors of variability in a pooled population of children and adults. Patients and Methods Plasma FVIII activity PK data were collected for 3 ADVATE® clinical trials in previously treated patients: 184 full PK data sets for 100 adults/adolescents, aged 10 to 65 years, and from 52 reduced sample PK data sets for 52 children, aged 1 to 6 years. Population PK analysis was conducted using non-linear mixed effects modeling with the first-order integral approximation method in SAS® software (NLMIXED procedure). A two-compartment model was used as the base model and the influence of age and weight were explored. Results Two-compartment PK models with additive plus proportional residual variability model and exponential inter-individual variability model adequately described the data. Clearance (CL) is significantly correlated with age and body weight and central volume of distribution (V1) is also related with body weight. The estimated population PK parameters were (mean parameter, (inter-individual variability %)): CL (2.92 mL/kg·h, 22%), V1 (0.46 dL/kg, 5.2%), peripheral volume V2 (0.09 dL/kg) and inter-compartmental clearance Q (2.07 mL/ kg·h). Conclusions A population PK model that describes the combined PK data from adults and pediatric studies has been constructed. A significant portion of inter-individual variability in both volume and clearance can be explained by subject weight. An additional smaller effect of age on clearance but not volume was observed. A population PK model for Factor VIII could provide the clinician with advantages in designing a patient specific treatment regimen. It could provide more relevant guidance in individual patient pharmacokinetics than just incremental recovery without the burden of a full PK assessment of the patient. Disclosures: Oh: Baxter: Employment. Off Label Use: Prophylaxis is not indicated in the US. Björkman:Baxter: Consultancy; Octapharma: Consultancy. Schroth:Baxter: Employment. Fritsch:Baxter: Employment. Collins:Bayer: Consultancy; Novo Nordisk: Consultancy; Baxter: Consultancy. Fischer:Bayer: Consultancy; Wyeth: Consultancy; Baxter: Consultancy. Blanchette:Bayer: Consultancy; Baxter: Consultancy. Casey:Baxter: Employment. Spotts:Baxter: Employment. Ewenstein:Baxter: Employment.

scholarly journals Paediatric population pharmacokinetic and pharmacodynamic modelling of ambrisentan in pulmonary arterial hypertension and comparison with adult data

2021 ◽  
Author(s):  
Malek Okour ◽  
Mita Thapar ◽  
Colm Farrell ◽  
Mary Ann Lukas ◽  
Maurice Beghetti ◽  
...  
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Adult Population ◽  
Systemic Exposure ◽  
Paediatric Population ◽  
Walking Distance ◽  
Population Pharmacokinetic ◽  
Paediatric Patients ◽  
Population Pk ◽  
Pulmonary Arterial

Aims: To develop a population pharmacokinetic (PK) model of ambrisentan in paediatric patients aged 8 to <18 years with pulmonary arterial hypertension (PAH), compare paediatric ambrisentan systemic exposure to historical adult data, and assess PK–PD relationships. Methods: A previously developed adult population PK model provided an initial step for modelling the 211 PK observations from 39 paediatric patients with PAH in the randomised Phase IIb study AMB112529 (NCT01332331). Subsequently, a population PK model was developed using only paediatric PK data. Steady-state systemic exposure metrics were estimated for the paediatric population and compared with historical adult data (adult patients with PAH and healthy volunteers). Exploratory exposure–response analysis assessed ambrisentan systemic exposure versus change from baseline in 6-minute walking distance in paediatric patients; findings were compared with adult data. An exploratory analysis of ambrisentan exposure versus incidence of ambrisentan-related adverse events in paediatric patients was also performed. Results: The final paediatric population PK model was a two-compartment model which includes the effect of body weight (allometric scaling), first-order absorption and elimination, and absorption lag time. Similar steady-state ambrisentan exposure was confirmed in paediatric patients and historical adult data when differences in body weight were accounted for. There was no apparent correlation in the paediatric or adult population between ambrisentan exposure and change in 6-minute walking distance, or between ambrisentan exposure and incidence of ambrisentan-related adverse events in paediatric patients. Conclusions: Similar ambrisentan exposure and PK–PD profiles were observed in paediatric and adult populations with PAH.

scholarly journals P61 Population pharmacokinetics of vancomycin in chinese ICU neonates: initial dosage recommendations

2019 ◽  
Vol 104 (6) ◽  
pp. e42.2-e42
Author(s):  
Z Li ◽  
Z Jiao
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Pharmacokinetic Model ◽  
Preterm Neonates ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Current Guideline ◽  
Mixed Effect ◽  
Pediatric Cancer Patients

The main goal of our study was to characterize the population pharmacokinetics of vancomycin in critically ill Chinese neonates to develop a pharmacokinetic model and investigate factors that have significant influences on the pharmacokinetics of vancomycin in this population.1 2 The study population consisted of 80neonates in the neonatal intensive care unit (ICU)from which 165 trough and peak concentrations of vancomycin were obtained.Nonlinear mixed effect modeling was used to develop a population pharmacokinetic model for vancomycin.4 The stability and predictive ability of the final model were evaluated based on diagnostic plots, normalized prediction distribution errorsandthe bootstrap method.Serum creatinine (Scr) and body weight were significant covariates on the clearance of vancomycin.5 6 The average clearance was 0.309L/h for a neonate with Scr of 23.3mmol/L and body weight of 2.9 kg. No obvious ethnic differences in the clearance of vancomycin were found relative to the earlier studies of Caucasian neonates. Moreover, the established model indicated that in patients with a greater renal clearance status, especially Scr < 15mmol/L,current guideline recommendationswould likely not achieve therapeuticarea under the concentration-time curve over24 h/minimum inhibitoryconcentration (AUC24h/MIC) ≥ 400.3 The exceptions to this areBritish National Formulary (2016–2017), Blue Book (2016) and Neofax (2017). Recommended dose regimensfor neonates with differentScrlevelsandpostmenstrual ageswere estimatedbased on Monte Carlo simulations andthe established model.These findings will be valuable for developing individualized dosage regimens in the neonatal ICU setting.ReferencesAbdel HO, Al OS, Nazer LH., Mubarak S, Le, J. Vancomycin pharmacokinetics and predicted dosage requirements in pediatric cancer patients. Journal of Oncology Pharmacy Practice 2015;22(3):448–453doi: 10.1177/1078155215591386Anderson, B. J., Allegaert, K., Jn, V. D. A., Cossey, V., &amp;Holford, N. H. ( 2007). Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. British Journal of Clinical Pharmacolog;63(1):75–84. doi: 10.1111/j.1365-2125.2006.02725.xAllegaert K, Anderson BJ, Jn, VDA, Vanhaesebrouck, S., & De, Z. F. ( 2007). Renal drug clearance in preterm neonates: relation to prenatal growth. Therapeutic Drug Monitoring, 29(3), 284–291. doi: 10.1097/FTD.0b013e31806db3f5Byon, W., Smith, M. K., Chan, P., Tortorici, M. A., Riley, S., & Dai, H., et al. ( 2013). Establishing best practices and guidance in population modeling: an experience with an internal population pharmacokinetic analysis guidance. CptPharmacometrics & Systems Pharmacology,2(7), e51. doi: 10.1016/j.cmpb.2010.04.018Capparelli, E. V., Lane, F. R., Romanowski, G. L., Pharm, M. F., Murray, W., & Sousa, P., et al. ( 2001). The influences of renal function and maturation on vancomycin elimination in newborns and infants. Journal of Clinical Pharmacology, 41(9), 927–934.Centers for Disease Control and Prevention. ( 2009). WHO Child Growth Standards. http://www.who.int/childgrowth/en. [EB/OL] 2017-09-12Disclosure(s)Nothing to disclose

scholarly journals A Population Pharmacokinetic Model for Vancomycin in Pediatric Patients and Its Predictive Value in a Naive Population

2000 ◽  
Vol 44 (2) ◽  
pp. 278-282 ◽  
Author(s):  
Patrice Lamarre ◽  
Denis Lebel ◽  
Murray P. Ducharme
Keyword(s):  
Pediatric Patients ◽  
Pediatric Population ◽  
Predictive Ability ◽  
Volume Of Distribution ◽  
Population Characteristics ◽  
Rank Test ◽  
Population Pharmacokinetic ◽  
Good Precision ◽  
Weighted Residuals ◽  
Population Pk

ABSTRACT The objectives of this study were to (i) construct a population pharmacokinetic (PK) model able to describe vancomycin (VAN) concentrations in serum in pediatric patients, (ii) determine VAN PK parameters in this population, and (iii) validate the predictive ability of this model in a naive pediatric population. Data used in this study were obtained from 78 pediatric patients (under 18 years old). PK analyses were performed using compartmental methods. The most appropriate model was chosen based on the evaluation of pertinent graphics and calculation of the Akaike information criterion test. The population PK analysis was performed using an iterative two-stage method. A two-compartment PK model using age, sex, weight, and serum creatinine as covariates was determined to be the most appropriate one to describe serum VAN concentrations. The quality of fit was very good, and the distribution of weighted residuals was found to be homoscedastic (Wilcoxon signed rank test). Fitted population PK parameters (mean ± standard deviation) were as follows: central clearance (0.1 ± 0.05 liter/h/kg), central volume of distribution (0.27 ± 0.07 liter/kg), peripheral volume of distribution (0.16 ± 0.07 liter/kg), and distributional clearance (0.16 ± 0.07 liter/kg). The predictive ability of the developed model (including the above-mentioned covariates) was evaluated in a naive population of 19 pediatric patients. The predictability was very good. Precision (±95% confidence interval [CI]) (peak, 4.1 [±1.4], and trough, 2.2 [±0.7]) and bias (±95% CI) (peak, −0.58 [±2.2], and trough, 0.63 [±1.1] mg/liter) were significantly (P < 0.05) superior to those obtained using a conventional method (precision [±95% CI]: peak, 8.03 [±2.46], and trough, 2.7 [±0.74]; bias: peak, −7.1 [±2.9], and trough, −1.35 [±1.2] mg/liter). We propose the use of this population PK model to optimize VAN clinical therapies in our institution and others with similar patient population characteristics.

scholarly journals Developmental Pharmacokinetics of Lamivudine in 580 Pediatric Patients Ranging from Neonates to Adolescents

2011 ◽  
Vol 55 (7) ◽  
pp. 3498-3504 ◽  
Author(s):  
Naïm Bouazza ◽  
Déborah Hirt ◽  
Stéphane Blanche ◽  
Pierre Frange ◽  
Elisabeth Rey ◽  
...  
Keyword(s):  
Body Weight ◽  
Expectation Maximization Algorithm ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Apparent Clearance ◽  
Routine Basis ◽  
Time Courses ◽  
Elimination Clearance

ABSTRACTLamivudine concentration-time courses were described for a very large range of ages to study the effects of body weight and maturation on lamivudine pharmacokinetics and to check the consistency of dosing recommendations. Lamivudine concentrations were monitored on a routine basis to produce concentrations similar to the known values in adults. Concentrations were measured in 580 children from 2 days to 18 years old. A total of 2,106 plasma lamivudine concentrations were measured, and a population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization algorithm implemented in MONOLIX 3.1 software. A two-compartment model adequately described the data. After standardization for a mean standard body weight by using an allometric model, age also had a significant effect on clearance maturation. Typical population estimates (percent interindividual variability) standardized for 70 kg of the apparent clearance, including central and peripheral volumes of distribution, intercompartmental clearance, and absorption rate constant, were 31 liters·h−1(32%), 76.4 liters (77%), 129 liters, 5.83 liters·h−1, and 0.432 h−1, respectively. According to the model, elimination clearance (liters/h/70 kg) increases gradually during the first years of life. Theoretical doses needed to reach the range of 24 h of exposure observed in adults were calculated: to be closer to adult exposure, children should receive 4 mg/kg/day from birth to 8 weeks of age, 5 mg/kg/day from 8 to 16 weeks of age, 6 mg/kg from 16 to 25 weeks of age, 8 mg/kg/day from 25 weeks of age to 14 kg of body weight, 150 mg/day from 14 to 25 kg of body weight, 225 mg/day from 25 to 35 kg of body weight, and 300 mg/day thereafter.

scholarly journals Population Pharmacokinetic Analysis of Colistin in Burn Patients

2013 ◽  
Vol 57 (5) ◽  
pp. 2141-2146 ◽  
Author(s):  
Jongtae Lee ◽  
Seunghoon Han ◽  
Sangil Jeon ◽  
Taegon Hong ◽  
Wonkeun Song ◽  
...  
Keyword(s):  
Total Body Surface Area ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Burn Patients ◽  
Time Curve ◽  
Mixed Effect ◽  
Final Model ◽  
Content Type ◽  
Population Pk

ABSTRACTColistin is increasingly used as a salvage therapy for nosocomial infections caused by multidrug-resistant Gram-negative bacteria such asPseudomonas aeruginosaandAcinetobacter baumannii. However, the available pharmacokinetic (PK) data for colistin are limited to guide dosing. The aim of this study was to develop a population PK model of colistin and to identify the optimal dosage regimens for burn patients. Fifty patients with burns ranging from 4% to 85% of total body surface area who had been treated with colistimethate sodium (CMS) were studied. CMS, which is hydrolyzedin vivoto an active metabolite, was intravenously administered every 12 h. Blood samples were collected at 0, 1, 2, 4, 6, and 8 h after more than five infusions to measure the colistin concentration using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. The population PK model was developed using nonlinear mixed effect modeling (NONMEM, v. 6.2). A one-compartment linear PK model for colistin best described the data. The covariates included in the final model were creatinine clearance for the relative fraction of CMS converted into colistin and the presence of edema for the turnover rate constant of CMS converted into colistin. A steady-state 24-h area under the concentration-time curve was simulated from 1,000 virtual patients receiving 150 mg colistin base activity every 12 h using the final model. Relative to previous studies with critically ill patients, the elimination half-life of colistin (6.6 h) was much shorter, and continuous renal replacement therapy was not a significant covariate for any PK parameters.

scholarly journals A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Marlou L. P. S. van Iersel ◽  
Stefaan Rossenu ◽  
Rik de Greef ◽  
Hetty Waskin
Keyword(s):  
Body Weight ◽  
High Risk ◽  
Pharmacokinetic Model ◽  
Tablet Formulation ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Clinical Factors ◽  
Oral Tablet ◽  
First Order ◽  
The Impact

ABSTRACT A delayed-release solid tablet formulation that releases posaconazole in the small intestine was developed to maximize systemic absorption. This study aimed to characterize the pharmacokinetics of the posaconazole solid tablet formulation in adult subjects and to investigate the potential impact of demographic and clinical factors on posaconazole exposure through a population pharmacokinetic approach. Nonlinear mixed-effects modeling was performed using data from several studies conducted in healthy volunteers and patients. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final pharmacokinetic model was used to simulate posaconazole exposure in patients at high risk for invasive fungal diseases treated with the proposed posaconazole dose of 300 mg twice daily on day 1, followed by 300 mg daily for 27 days. A one-compartment pharmacokinetic model with sequential zero-order and first-order absorption and a first-order disposition from the central compartment adequately described the pharmacokinetic profile of the posaconazole solid tablet formulation. Significant covariates included disease state (acute myeloid leukemia/myelodysplasia versus allogeneic hematopoietic stem cell transplantation), body weight, and formulation on bioavailability; food status on first-order absorption rate; and dosing regimen (a single dose versus multiple doses) on clearance. Except for body weight, the impact of these covariates on posaconazole exposure was considered clinically irrelevant. This population pharmacokinetic analysis confirmed that the proposed dose of the posaconazole solid tablet formulation provides adequate target therapeutic exposure (>0.5 mg/liter) to a broad range of patients at high risk for invasive fungal disease.

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