Volume Of Peripheral Compartment Research Articles

Population pharmacokinetic modeling of ilaprazole in healthy subjects and patients with duodenal ulcer in China.

Aims: This study aimed to develop a population pharmacokinetic (PopPK) model of ilaprazole in healthy subjects and patients with duodenal ulcer in Chinese and investigate the effect of potential covariates on pharmacokinetic (PK) parameters. Methods: Pharmacokinetic data from 4 phase I clinical trials and 1 phase IIa clinical trial of ilaprazole were included in PopPK analysis. Phoenix NLME 8.3 was used to establish a PopPK model and quantify the effects of covariate, such as demographic data, biochemical indicators and disease state on the PK parameters of ilaprazole. The final model was evaluated by goodness-of-fit plots, bootstrap analysis, and visual predictive check. Results: A two-compartment model with first-order elimination successfully described the pharmacokinetic properties of ilaprazole. In the final PopPK model, body weight and sex were identified as statistically significant covariates for volume of peripheral compartment (Vp) and clearance of central compartment (CL), respectively, and disease status was also screened as a significant covariate affecting both CL and Vp. The validation results demonstrated the good predictability of the model, which was accurate and reliable. Conclusion: This is the first population pharmacokinetics study of ilaprazole in the Chinese, and the PopPK model developed in this study is expected to be helpful in providing relevant PK parameters and covariates information for further studies of ilaprazole.

Population pharmacokinetic modeling of multiple-dose intravenous fosfomycin in critically ill patients during continuous venovenous hemodialysis

The aim of this study was to investigate the pharmacokinetics of multiple-dose intravenous (i.v.) fosfomycin in critically ill patients during continuous venovenous hemodialysis (CVVHD). Non-compartmental analysis and population pharmacokinetic modeling were used to simulate different dosing regimens. We evaluated 15 critically ill patients with renal insufficiency and CVVHD undergoing anti-infective treatment with fosfomycin in our ICU. Five grams of fosfomycin were administered for 120 min every 6 h. Plasma concentrations were determined with and without CVVHD. Pharmacokinetic analysis and simulations were performed using non-linear mixed effects modelling (NONMEM). A two-compartment model with renal and dialysis clearance was most accurate in describing the pharmacokinetics of i.v. fosfomycin during CVVHD. Population parameter estimates were 18.20 L and 20.80 L for the central and peripheral compartment volumes, and 0.26 L/h and 5.08 L/h for renal and intercompartmental clearance, respectively. Urinary creatinine clearance (CLCR) represented a considerable component of renal clearance. Central compartment volume increased over time after the first dose. For patients with CLCR > 50 (90) mL/min and CVVHD, dosage should be increased to ≥ 15 (16) grams of i.v. fosfomycin across three (four) daily doses. Individual CLCR must be considered when dosing i.v. fosfomycin in critically ill patients during CVVHD.

Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia.

Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). A two-compartment model was built using 483 data points from 45 patients (0.33-17.83years of age) treated with MTX (0.25-5g/m2) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as [Formula: see text]. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size.

Population pharmacokinetic analysis and dosing regimen optimization of teicoplanin in critically ill patients with sepsis.

Objectives: Teicoplanin has been extensively used in the treatment for infections caused by gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). However, current teicoplanin treatment is challenging due to relatively low and variable concentrations under standard dosage regimens. This study aimed to investigate the population pharmacokinetics (PPK) characteristics of teicoplanin in adult sepsis patients and provide recommendations for optimal teicoplanin dosing regimens. Methods: A total of 249 serum concentration samples from 59 septic patients were prospectively collected in the intensive care unit (ICU). Teicoplanin concentrations were detected, and patients' clinical data were recorded. PPK analysis was performed using a non-linear, mixed-effect modeling approach. Monte Carlo simulations were performed to evaluate currently recommended dosing and other dosage regimens. The optimal dosing regimens were defined and compared by different pharmacokinetic/pharmacodynamic parameters, including trough concentration (Cmin), the ratio of 24-h area under the concentration-time curve to the minimum inhibitory concentration (AUC0-24/MIC), as well as the probability of target attainment (PTA) and the cumulative fraction of response (CFR) against MRSA. Results: A two-compartment model adequately described the data. The final model parameter estimates for clearance, central compartment volume of distribution, intercompartmental clearance and peripheral compartment volume were 1.03L/h, 20.1 L, 3.12L/h and 101L, respectively. Glomerular filtration rate (GFR) was the only covariate that significantly affected teicoplanin clearance. Model-based simulations revealed that 3 or 5 loading doses of 12/15mg/kg every 12h followed by a maintenance dose of 12/15mg/kg every 24h-72h for patients with different renal functions were required to achieve a target Cmin of 15mg/L and a target AUC0-24/MIC of 610. For MRSA infections, PTAs and CFRs were not satisfactory for simulated regimens. Prolonging the dosing interval may be easier to achieve the target AUC0-24/MIC than reducing the unit dose for renal insufficient patients. Conclusion: A PPK model for teicoplanin in adult septic patients was successfully developed. Model-based simulations revealed that current standard doses may result in undertherapeutic Cmin and AUC, and a single dose of at least 12mg/kg may be needed. AUC0-24/MIC should be preferred as the PK/PD indicator of teicoplanin, if AUC estimation is unavailable, in addition to routine detection of teicoplanin Cmin on Day 4, follow-up therapeutic drug monitoring at steady-state is recommended.

Population pharmacokinetic model for once-daily intravenous busulfan in pediatric subjects describing time-associated clearance.

This study aimed to characterize the population pharmacokinetics (PK) of busulfan focusing on how busulfan clearance (CL) changes over time during once‐daily administration and assess different methods for measuring busulfan exposure and the ability to achieve target cumulative exposure under different dosing adjustment scenarios in pediatric stem cell transplantation recipients. Daily serial blood sampling was performed and concentration‐time data were analyzed using a nonlinear mixed‐effects approach. The developed PK model was used to assess achievement of target exposure under six dose‐adjustment scenarios based on simulations performed in RStudio (RxODE package)®. A total of 2491 busulfan plasma concentration–time measurements were collected from 95 patients characterizing 379 dosing days. A two‐compartment model with time‐associated CL best described the data with a typical CL of 14.5 L/h for an adult male with 62 kg normal fat mass (NFM; equivalent to 70 kg total body weight), typical volume of distribution central compartment (V1) of 40.6 L/59 kg NFM (equivalent to 70 kg total body weight), and typical volume of distribution peripheral compartment of 3.57 L/62 kg NFM. Model interindividual variability in CL and V1 was 14.7% and 34.9%, respectively, and interoccasional variability in CL was 6.6%. Patient size described by NFM, a maturation component, and time since start of treatment significantly influenced CL. Simulations demonstrated that using model‐based exposure estimates with each dose, and either a proportional dose‐adjustment calculation or model‐based calculated individual CL estimates to support dose adjustments, increased proportion of subjects attaining cumulative exposure within 5% of target compared with using noncompartmental analysis (100% vs. 0%). A time‐associated reduction in CL during once‐daily busulfan treatment was described.

Population pharmacokinetic analysis of dexmedetomidine in children using real-world data from electronic health records and remnant specimens.

Our objectives were to perform a population pharmacokinetic analysis of dexmedetomidine in children using remnant specimens and electronic health records (EHRs) and explore the impact of patient's characteristics and pharmacogenetics on dexmedetomidine clearance. Dexmedetomidine dosing and patient data were gathered from EHRs and combined with opportunistically sampled remnant specimens. Population pharmacokinetic models were developed using nonlinear mixed-effects modelling. Stage 1 developed a model without genotype variables; Stage 2 added pharmacogenetic effects. Our final study population included 354 post-cardiac surgery patients aged 0-22 years (median 16 mo). The data were best described with a 2-compartment model with allometric scaling for weight and Hill maturation function for age. Population parameter estimates and 95% confidence intervals were 27.3L/h (24.0-31.1L/h) for total clearance, 161 L (139-187 L) for central compartment volume of distribution, 26.0L/h (22.5-30.0L/h) for intercompartmental clearance and 7903 L (5617-11 119 L) for peripheral compartment volume of distribution. The estimate for postmenstrual age when 50% of adult clearance is achieved was 42.0weeks (41.5-42.5weeks) and the Hill coefficient estimate was 7.04 (6.99-7.08). Genotype was not statistically or clinically significant. Our study demonstrates the use of real-world EHR data and remnant specimens to perform a population pharmacokinetic analysis and investigate covariate effects in a large paediatric population. Weight and age were important predictors of clearance. We did not find evidence for pharmacogenetic effects of UGT1A4 or UGT2B10 genotype or CYP2A6 risk score.

Real-Time Analytical Solutions as Series Formulas and Heaviside off/on Switch Functions for Multiple Intermittent Intravenous Infusions in One- and Two-Compartment Models

Pharmacokinetic compartment models are the only models that can extract pharmacokinetic parameters from data collected in clinical studies but their estimates lack accuracy, explanations and physiological significance. The objective of this work was to develop particular solutions to drug concentration and AUC in the form of mathematical series and Heaviside functions for repetitive intermittent infusions in the one- and two-compartment models, as a function of dose number and total time using differential calculus. It was demonstrated that the central and peripheral compartment volumes determined from regression analysis of the aminoglycoside antibiotic Sisomicin concentration in plasma represent the actual physiological body fluid volumes accessible by the drug. The drug peak time and peak concentration in the peripheral compartment were also calculated as a function of dose number. It is also shown that the time of intercompartmental momentary distribution equilibrium can be used to determine the drug’s apparent volume of distribution within any dosing interval in multi-compartment models. These estimates were used to carry out simulations of plasma drug concentration with time in the one-compartment model. In conclusion, the two-compartment open mammillary pharmacokinetic model was fully explained for the aminoglycoside antibiotic sisomicin through the new concept of the apparent volume of distribution.

Identification of factors affecting meropenem pharmacokinetics in critically ill patients: Impact of inflammation on clearance

IntroductionThe purpose of this study was to explore factors influencing meropenem pharmacokinetics (PKs) in critically ill patients by developing a population PK model and to determine the optimal dosing strategy. MethodsThis prospective observational study involved 12 critically ill patients admitted to the intensive care unit and treated with meropenem 1 g infused over 1 h every 8 h. Blood samples were collected on days 1, 2, and 5 immediately prior to dosing, and at 1, 2, 4, and 6 h after the start of infusion. Population PK parameters were estimated using nonlinear mixed-effects model software. ResultsMeropenem PK was adequately described using a two-compartment model. Typical values of total and inter-compartmental clearance were 9.30 L/h and 9.70 L/h, respectively, and the central and peripheral compartment volumes of distribution were 12.61 L and 7.80 L, respectively. C-reactive protein (CRP) was identified as significant covariate affecting total meropenem clearance. The probability of target attainment (PTA) predicted by Monte Carlo simulations varied according to the patients’ CRP. The PTA of 100% time above the minimum inhibitory concentration ≤2 mg/L for bacteria was achieved after a dose of 1 and 2 g infused over 4 h every 8 h in patients with CRP of 30 and 5 mg/dL, respectively. ConclusionThe findings of this study suggest that CRP might be helpful in managing meropenem dosing in critically ill patients. Higher doses and extended infusion may be required to achieve optimal pharmacodynamic targets.

1087. Imipenem-Cilastatin-Relebactam (I/R) Pharmacokinetics (PK) in Critically Ill Patients with Augmented Renal Clearance (ARC)

BackgroundImipenem (IMI) and relebactam (REL) are predominantly excreted via glomerular filtration. ARC is a common syndrome in critically ill patients with sepsis, whereby increased renal blood flow may result in enhanced solute clearance; therefore, sub-therapeutic antibiotic concentrations are of concern. Herein, we describe the PK of I/R in critically-ill patients with confirmed ARC. MethodsInfected patients in the intensive care unit with ARC (CrCl ≥130 mL/min) received a single dose of I/R 1.25g as a 30min infusion. Blood samples were collected over 6 hours (hr) for IMI and REL concentration determination by a validated LC/MS/MS assay. Protein binding was assessed at 0.5hr by ultrafiltration (UF). An 8hr urine creatinine (UCr) collection was performed to confirm ARC. IMI and REL plasma concentrations were fitted to compartmental models in WinNonlin. Simulated concentration vs time profiles were used to assess attainment of pharmacodynamic (PD) targets for IMI (30%fT >MIC) and REL (fAUC:MIC 18) at the susceptibility breakpoint of 2 mg/L. ResultsFive patients (60% female) completed the study. Mean (SD) age, weight, and APACHE II were 43 (14) years, 90 (15) kg, and 16 (6), respectively. All patients had confirmed ARC with CrCl of 160.6 ± 47.0 mL/min (range: 135-244mL/min) based on UCr. Both IMI and REL concentrations fitted a 2-compartment better than 1-compartment model. IMI PK was: clearance, 17.9 ± 8.7 L/hr; volume of central compartment, 15.6 ± 11.2 L; volume of peripheral compartment, 10.6 ± 5.4 L; and intercompartmental clearance, 16.6 ± 14.5 L/hr. REL PK parameters were 11.9 ± 7.5 L/hr, 17.0 ± 11.3 L, 13.5 ± 9.9 L, and 13.4 ± 11.1 L/hr, respectively. Half-life was 1.5 ± 0.5 for IMI and 2.8 ± 2.2 hr for REL. Protein binding for IMI ranged from 0-10%, while REL was 0-14%. IMI fT >MIC ranged from 40-90%, and REL fAUC:MIC ranged from 22.6-59.0. ConclusionThese are the first data to describe IMI and REL PK in critically-ill infected patients with ARC. Despite plasma clearance values greater than those reported in healthy volunteers and patients in clinical trials, I/R 1.25g as a 30 minute infusion provided optimal exposure in all patients for isolates with MICs ≤2 mg/L. Disclosures David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)BioMérieux (Consultant, Research Grant or Support, Speaker’s Bureau)Contrafect (Scientific Research Study Investigator)GSK (Consultant)Merck (Research Grant or Support)Paratek (Speaker’s Bureau)Roche Diagnostics (Research Grant or Support)Shionogi (Research Grant or Support)Summit (Scientific Research Study Investigator)

Does Prolonged Infusion Time Really Improve the Efficacy of Meropenem Therapy? A Prospective Study in Critically Ill Patients.

IntroductionMeropenem is a carbapenem antibiotic, which has demonstrated excellent antimicrobial activity against gram-negative clinical isolates. It is also commonly used in critically ill patients. This study aimed to determine the pharmacokinetics/pharmacodynamics of meropenem in critically ill patients and whether prolonged injection duration is really beneficial to meropenem therapy.MethodsWe included 209 samples in 64 patients in this prospective study. PPK analysis and Monte Carlo dosing simulations were developed using Phoenix.ResultsA two-compartment model described the data adequately. Clearance (CL), volume (V), clearance of peripheral compartment (CL2), and volume of peripheral compartment (V2) were 6.15 l/h, 2.83 l/h, 17.40 l, and 17.48 l, respectively. Creatinine clearance and uric acid were significant covariates. Patients with creatinine clearance ≤ 60 ml/min and uric acid > 400 μmol/l could achieve the target > 90% under the minimum inhibitory concentration (MIC) of 8 mg/l, even with the administration dose of 500 mg/8 h with a 2-h infusion. Prolonging the infusion time significantly improved the therapeutic effect when MIC < 4. However, for the pharmacodynamic (PD) effects of 100% fT > MIC and 100% fT > 4 MIC, no significant statistical difference was observed in critically ill patients.ConclusionsCritically ill patients with lower creatinine clearance and higher uric acid levels tended to need a lower dosage of meropenem. Prolonged infusion time was not always beneficial for those who needed a higher therapeutic target (100% fT > MIC, 100% fT > 4 MIC) or with MIC > 4 mg/l. Increasing dose or alternative therapeutic strategies may be required for critically ill patients with drug-resistant or severe infections. The study is of great significance to guide the rational use of meropenem in critically ill patients.Trial RegistrationThe trial was registered in the China Clinical Trial (ChiCTR1900020672). Registered on 12 January 2019.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00551-2.

Population pharmacokinetics of vedolizumab in Asian and non-Asian patients with ulcerative colitis and Crohn's disease.

Background/AimsVedolizumab is indicated for moderately-to-severely active ulcerative colitis (UC) and Crohn’s disease (CD). Because multiple factors may result in different pharmacokinetics and clinical efficacies, understanding determinants of vedolizumab clearance may enhance dose and treatment strategies. The aim was to characterize vedolizumab pharmacokinetics in Asian and non-Asian UC and CD patients.MethodsPopulation pharmacokinetic analysis for repeated measures, using data from 5 studies, was conducted using nonlinear mixed-effects modeling. A Bayesian estimation approach in NONMEM 7.3 was utilized to leverage the predominantly sparse data available for this analysis with results from a prior population pharmacokinetic analysis of vedolizumab.ResultsVedolizumab pharmacokinetics were described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half life of vedolizumab was 24.7 days for anti-vedolizumab antibody (AVA)-negative patients and 18.1 days for AVA-positive patients; linear clearance (CLL) was 0.165 L/day for AVA-negative patients and 0.246 L/day for AVA-positive patients; central (Vc) and peripheral compartment volumes of distribution were 3.16 L and 1.84 L, respectively. Interindividual variabilities (percent coefficient of variation) were 30.8% for CLL and 19% for Vc; interoccasion variability on CLL was 20.3%; residual variance was 17.8%. For albumin, body weight and AVA, only extreme values were identified as potentially clinically important predictors of CLL. The effect of race (Asian/non-Asian) and diagnosis (UC/CD) on CLL was negligible and likely not of clinical importance.ConclusionsPharmacokinetic parameters were similar in Asian and non-Asian patients with moderately-to-severely active UC and CD. This analysis supports use of vedolizumab flat-fixed dosing in these patients. (Clinicaltrials.gov Identifiers: NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2). CCT 101; NCT02039505 and CCT-001; NCT02038920)

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?

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.

Population Pharmacokinetic Analysis of Meropenem in Critically Ill Patients With Acute Kidney Injury Treated With Continuous Hemodiafiltration.

The aim of this study was to conduct a population pharmacokinetic (PK) analysis of meropenem and to explore the optimal dosing strategy for meropenem in critically ill patients with acute kidney injury receiving treatment with continuous hemodiafiltration (CHDF). Blood samples were obtained on days 1, 2, and 5 after the start of meropenem administration, immediately before dosing, and at 1, 2, 6, and 8 hours after dosing. Population PK model analysis was performed and concentration-time profiles were simulated using the Nonlinear Mixed Effects Model software. Twenty-one patients receiving CHDF in our intensive care unit were enrolled and 350 serum concentration-time data points were obtained. The PKs of meropenem were best described using a 2-compartment model. Typical total and intercompartmental clearance values were 4.22 L/h and 7.84 L/h, respectively, whereas the central and peripheral compartment volumes of distribution were 14.82 L and 11.75 L, respectively. Estimated glomerular filtration rate was identified as a significant covariate of meropenem total clearance. In simulations of patients with renal failure receiving CHDF, the dose was affected by estimated glomerular filtration rate; a dose of 0.5 g every 8 hours or 1 g every 12 hours showed the probability of target attainment of achieving 100% time above the minimum inhibitory concentration for bacteria with a minimum inhibitory concentration ≤2 mg/L. A population PK model was developed for meropenem in critically ill patients with acute kidney injury receiving CHDF. Our results indicated that a meropenem dosage of 0.5 g every 8 hours or 1 g every 12 hours was suitable in this population and for susceptible bacteria.

Population pharmacokinetics of immunoglobulin intravenous preparation in very low birth weight neonates

BackgroundImmunoglobulin products are widely used across multiple therapeutic areas such as immunodeficiency syndromes, infection and autoimmune diseases. The pharmacokinetics (PK) of immunoglobulins are well characterized in adults, but very little is known about the PK of immunoglobulins in neonates and infants (<2 years of age). ObjectiveThe objectives of the present study were: (1) characterize the PK of immunoglobulin intravenous preparation using model-independent (non-compartmental analysis), and (2) develop and evaluate a population PK model with extensive blood samples (8 blood samples) and sparse blood samples (2–3 blood samples). MethodImmunoglobulin G (IgG) concentration versus time data from very low birth weight neonates (n = 20) following intravenous administration were analyzed using nonlinear mixed effect modeling and non-compartmental approaches. Population pharmacokinetic models were developed from extensive and sparse sampling schemes. Models were evaluated based on the difference in objective function, goodness-of-fit plots and simulation based visual predictive check analysis. ResultsA non-compartmental analysis of IgG from neonates (bodyweight range 0.78–1.38 kg) indicated an average clearance of 3.0 ± 2.1 mL/day and volume of distribution at steady state 68 ± 25 mL. The population pharmacokinetic model from extensive sampling adequately described concentration- time data with mean clearance (2.7 mL/day), volume of central compartment (8.7 mL) and peripheral compartment (60 mL). The clearance and volume of distribution estimates using sparse sampling model (1 pre-and 2 post-dose blood samples) were comparable with extensive sampling. ConclusionOur study provides important bridging data in scaling PK and dosing of immunoglobulins across a wide age range.

Population pharmacokinetic analysis of weekly and biweekly IgPro20 (Hizentra®) dosing in patients with primary immunodeficiency

BackgroundIgPro20 (Hizentra®), a 20% subcutaneous immunoglobulin G (IgG), is an effective treatment for patients with primary immunodeficiencies with impaired IgG production. Flexible dosing regimens of IgPro20 have been supported by pharmacokinetic (PK) modeling and simulation. This study further describes the PK characteristics of serum IgG concentrations after weekly and biweekly administration of IgPro20 and compares predicted and actual serum IgG data using a previously-developed population PK (popPK) model. MethodsA popPK model was developed by combining data from a previously-published model with data from a Phase 4 study (IgPro20_4005). An external validation of the original model using dosing, demographics, and historic endogenous serum IgG concentrations from patients enrolled in study IgPro20_4005 was performed. This dataset was then simulated 300 times and predicted serum IgG PK characteristics compared with the observed data. ResultsA total of 173 patients (156 unique patients from original model and 17 patients from study IgPro20_4005) provided 4078 observations of serum IgG concentrations. The popPK estimates obtained demonstrated a clearance (% inter-individual variability) of 0.138 L/day (35%), volume of central compartment of 3.95 L (78.6%), inter-compartmental clearance of 0.260 L/day (56%), and volume of peripheral compartment of 4.44 L. Validation results indicated that observed serum IgG concentration vs time data fell within the 90% prediction intervals for median, 25th, and 75th percentiles of the simulated IgG concentration time courses. ConclusionsThe present analysis validated the ability of the previously published popPK model to predict serum IgG concentration time profiles after biweekly subcutaneous IgPro20 administration.

First China Approved Rituximab Biosimilar HLX01: Pharmacokinetics, Safety and Efficacy Comparison to Reference Rituximab in the Phase 3 Diffuse Large B-Cell Lymphoma Study

Background In February 2019, the National Medicinal Products Administration (NMPA) approved the first China-manufactured rituximab (RTX) biosimilar, HLX01, for the treatment of non-Hodgkin's lymphoma in accordance to the development of biosimilar guidelines with stepwise approach demonstrating bioequivalence. HLX01 was also developed as a novel drug for rheumatoid arthritis (RA) since the indication has not been approved in China. Studying pharmacokinetics (PK) in healthy volunteers as the most sensitive population is not ethically acceptable due to the safety concerns associated with rituximab. The NMPA approval was based on a comprehensive data package of extensive analytical characterization, non-clinical studies, clinical trials and the population PK (PopPK) model. Here, we report the Phase 3 confirmatory study aimed to establish equivalence in safety and efficacy of HLX01 and RTX in patients with diffuse large B-cell lymphoma (DLBCL) and the PopPK model derived from the PK data of HLX01 and RTX in RA compared the PK data in DLBCL and the Caucasian RTX data in RA. Methods In this multicenter, randomized, double-blind, parallel active-controlled, Phase 3 study (NCT02787239), treatment-naïve adults aged 18-80 years with histologically confirmed CD20+ DLBCL were treated with cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) and randomly assigned at 1:1 ratio to co-administer with HLX01 (H-CHOP) or RTX (R-CHOP) every 21 days cycle treatment. The primary efficacy endpoint was the best overall response rate (ORR) for HLX01 and RTX over 6-cycle therapy. The therapeutic equivalence was concluded if 95% confidence interval (CI) of the difference in best ORRs between the two treatments fell within the pre-specified range of ±12%. Additional endpoints included long-term efficacy outcomes, safety and immunogenicity profiles and sparse PK samplings for peak and trough levels comparison. The PopPK model was developed from the randomized, double-blind PK study (NCT03355872) of HLX01 and RTX in 196 patients with moderately to severely active RA (serum sample=4289) using non-linear mixed-effect modeling (NONMEM®) and the first-order estimation with interaction (FOCEI) method. The PK and PK-pharmacodynamic relationship being characterized with various covariates were tested on forward addition (p&lt;0·01) / backward elimination (p&lt;0·001). After the final model being examined with Bayesian bootstrapping, visual predictive check (VPC) and 1000 simulations from the observed covariates, external validations were tested using the Phase 3 PK data in 110 patients with DLBCL and comparing the Chinese data with other races by simulations from several published PK data in Caucasian RA patients. Results The best ORRs [95% CI] within 6 cycles therapy were 94·1% [89·77%, 97·04%] in H-CHOP and 92·8% [88·19%, 96·00%] in R-CHOP with the ORR difference (1·4% [−3·59%, 6·32%], p=0·608) fell in the pre-specified equivalent margin. Long-term efficacy and safety profiles, including the incidence of treatment-emergent adverse events (p=1·000) and serious adverse events (p=0·752), were similar in two treatment groups (Table 1). The best model fit for the PopPK was a two-compartment model with first-order elimination. The estimated clearance (CL), central volume (Vc), peripheral-compartment volume and clearance-of-distribution from the central-to-peripheral-compartment were 27·32%, 16·56%, 21·61%, and 40·79%, respectively. The correlation between CL and Vc was 0.02239. The observed concentrations and simulations for the corresponding model predicted all subjects in the dataset with no significant difference in area under the curve from zero to infinity between two clinical studies of HLX01 and RTX. The PK results were also similar to the existing model in Caucasian. Conclusion HLX01 demonstrated equivalent safety and efficacy to the reference RTX with no clinically meaningful differences in CD20+ DLBCL. The PopPK model successfully proved the PK similarity between HLX01 and RTX in patients with RA or DLBCL with no racial differences. Based on the totality of evidence with the results from this Phase 3 study and PopPK modeling, China NMPA approved HLX01 as the first China RTX biosimilar with the potential to provide alternative treatment option for patients. To the best of our knowledge, we are the first reporting the establishment of biosimilarity with RTX in DLBCL patient population. Disclosures Zhao: Certara Strategic Consulting China: Employment. Hong:Shanghai Henlius Biotech, Inc.: Employment. Ma:Shanghai Henlius Biotech, Inc.: Employment. Cheng:Shanghai Henlius Biotech, Inc.: Employment. Ting:Shanghai Henlius Biotech, Inc.: Employment. Li:Shanghai Henlius Biotech, Inc.: Employment. Jiang:Shanghai Henlius Biotech, Inc.: Employment. Liu:Shanghai Henlius Biotech, Inc.: Employment. Liu:Shanghai Henlius Biotech, Inc.: Employment. Zhang:Shanghai Henlius Biotech, Inc.: Employment. Chai:Shanghai Henlius Biotech, Inc.: Employment. Yao:Shanghai Henlius Biotech, Inc.: Employment. Luk:Shanghai Henlius Biotech, Inc.: Employment.

266O - A population pharmacokinetic model: Assessment of pharmacokinetic similarity of HLX01 and rituximab in diffuse large B-cell lymphoma

BackgroundHLX01, the first China (CN)-manufactured rituximab (RTX) biosimilar, was approved by the National Medicinal Products Administration (NMPA) for the treatment of non-Hodgkin's lymphoma on 22-February-2019, and was concurrently developed as a novel drug for rheumatoid arthritis (RA) since the indication has not been approved in CN. Here, we describe the development of a population pharmacokinetic (PopPK) model derived from the PK data of HLX01 and rituximab in patients with RA, and external validation in patients with CD20+ diffuse large B-cell lymphoma (DLBCL). MethodsA PopPK model of HLX01 and the European-sourced RTX (EU-RTX) from HLX01-RA01 study in 196 RA pts (serum sample number=4289) was developed using non-linear mixed-effect modelling (NONMEM®) with the first-order estimation with interaction (FOCEI) method. PK and PK-pharmacodynamic (PK-PD) relationship were characterised with various covariates (i.e., demographics, pathophysiologic/disease conditions and medical history, etc) which were examined by using forward addition (p < 0.01) / backward elimination (p < 0.001). The model was then examined using Bayesian bootstrapping and visual predictive check (VPC) followed by 1000 simulations were tested using the observed covariates. The final model was validated using PK samples of HLX01 and CN-RTX from HLX01-NHL03 study in ∼110 patients with CD20+ DLBCL and bridged the Chinese data to other races by simulation of Caucasian RA data from publication. ResultsA two-compartment model with first-order elimination provided the best model fit. The estimated clearance (CL), central volume (Vc), peripheral compartment volume (Vp) and clearance-of-distribution from the central to the peripheral compartment (Q) were 27.32%, 16.56%, 21.61%, and 40.79%, respectively. The correlation between CL and Vc was 0.02239. The observed concentrations and simulations-based 95% confidence interval for the corresponding model successfully predicted all subjects in the dataset, demonstrating PK similarity of HLX01 and RTX in patients with RA and CD20+ DLBCL. No significant difference in area under the curve from zero to infinity (AUC0-inf) was observed in two different sourced RTXs. This model was similar to the existing model in Caucasian population.Table266O Estimated parameter of HLX01 and EU-rituximab from the final PopPK modelTableParameters and CovariatesEstimateChange from Typical (%)Inter-individual Variability (%)CL (L/h)0.01046N/A27.322.5th percentile BCR CL (L/h)0.009063- 13.35N/A97.5th percentile BCR CL (L/h)0.01196+ 14.3N/A2.5th percentile BALB CL (L/h)0.01203+ 14.99N/A97.5th percentile BALB CL (L/h)0.009473- 9.432N/AVc (L)2.701N/A16.56Vp (L)2.708N/A21.61Inter-compartmental clearance, Q (L/h)0.02909N/A40.79Correlation between CL and Vc0.02239Typical values for baseline creatinine clearance (BCR), baseline albumin (BALB), body surface area (BSA)are 125 mL/min, 41.2 g/L, 1.62 m2 respectively. ConclusionsThis PopPK model derived from RA patients adequately predicts HLX01 and CN-RTX in patients with CD20+ DLBCL. HLX01 and EU-/CN-RTXs had similar PK parameters and influential PK covariates. These results provided further evidence for PK similarity between HLX01 and RTXs in patients with RA or DLBCL regardless of ethnicity. Clinical trial identificationHLX01-RA01 Phase 1/2 study (NCT03355872) in moderately-to-severely active rheumatoid arthritis; HLX01-NHL03 Phase 3 study (NCT02787239) in CD20+ diffuse large B-cell lymphoma. Legal entity responsible for the studyShanghai Henlius Biotech, Inc. FundingShanghai Henlius Biotech, Inc. DisclosureY. Shi: Advisory / Consultancy: Shanghai Henlius Biotech, Inc. X. Zhang: Full / Part-time employment: Shanghai Henlius Biotech,Inc. W. Jiang: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S. Liu: Full / Part-time employment: Shanghai Henlius Biotech,Inc. E. Liu: Full / Part-time employment: Shanghai Henlius Biotech,Inc. K. Chai: Full / Part-time employment: Shanghai Henlius Biotech,Inc. A. LUK: Full / Part-time employment: Shanghai Henlius Biotech,Inc. D. Yao: Full / Part-time employment: Shanghai Henlius Biotech,Inc. All other authors have declared no conflicts of interest.

1080P - A new population model validated pharmacokinetic similarity of HLX01 and rituximab in B-cell lymphoma

BackgroundHLX01, the first-ever China (CN)-manufactured rituximab (RTX) biosimilar, was approved by National Medicinal Products Administration (NMPA) for the treatment of diffuse large B-cell lymphoma (DLBCL) on 22 February 2019, and was concurrently developed as a novel drug to treat rheumatoid arthritis (RA) in CN since the indication has not been approved. The objective of this study was to develop a reliable population pharmacokinetic (PopPK) model of rituximab in patients with RA, the most appropriate patient population for PK evaluation, and validate HLX01 and CN-RTX PK data in patients with DLBCL. MethodsA PK model for HLX01 and the EU-RTX from a randomised, double-blind phase 1/2 study (NCT03355872) in 196 RA patients (serum sample n=4289) was developed using non-linear mixed-effect modeling (NONMEM®) with the first-order conditional estimation with interaction (FOCEI) method. PK and PK-pharmacodynamic relationship were characterised with various covariates (ie. demographics, pathphysiologic/disease conditions etc) which were examined by using forward addition (p<0.01) / backward elimination (p<0.001). The final model was evaluated using Bayesian bootstrap and visual predictive check (VPC). A total of 1000 simulations were tested using the observed covariates. The final model was validated using PK samples of HLX01 and CN-RTX from a randomised, double-blind phase 3 registrational study (NCT02787239) in 110 patients with CD20+ DLBCL. ResultsA two-compartment model with first-order elimination provided the best model fit. The estimated clearance (CL), central volume (Vc), peripheral compartment volume (Vp) and clearance of distribution from the central to the peripheral compartment (Q) were 27.32%, 16.56%, 21.61%, and 40.79%, respectively. The correlation between CL and Vcwas 0.02239. The PopPK model of HLX01 and EU-RTX using RA patients adequately predicts the central tendency and variability of the HLX01 and CN-RTX in patients with DLBCL. ConclusionsThis PopPK model derived from RA patients can predict HLX01 and CN-RTX in patients DLBCL. HLX01 and EU-/CN-RTX had similar PK parameters and influential PK covariates. These results provided further evidence for PK similarity between HLX01 and RTXs in patients with RA or DLBCL. Clinical trial identificationTwo trials were listed in this abstract: 1. A Randomised, Double-blind, Phase 1/2 Study to Evaluate the PK, PD, Safety, and Efficacy Between HLX01 and Rituximab in Patients With Moderate to Severe Rheumatoid Arthritis and Inadequate Response to Treatment With DMARDs ClinicalTrials.gov Identifier: NCT03355872 2. Clinical Phase 3 Study to Compare the Efficacy and Safety of Rituximab Biosimilar HLX01 and Rituximab in Combination With CHOP, in Previously Untreated Subjects With CD20+ DLBCL ClinicalTrials.gov Identifier: NCT02787239. Legal entity responsible for the studyShanghai Henlius Biotech, Inc. FundingShanghai Henlius Biotech,Inc. DisclosureY. Shi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Y. Dan: Full / Part-time employment: Shanghai Henlius Biotech,Inc. Y. Hong: Shareholder / Stockholder / Stock options, Full / Part-time employment: Shanghai Henlius Biotech, Inc. J. Guo: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S. Zhao: Advisory / Consultancy: Certara Strategic Consulting China. X. Zeng: Research grant / Funding (institution): Peking Union Medical College Hospital. P. Hu: Research grant / Funding (institution): Peking Union Medical College Hospital. W. Jiang: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: I am an employee of Shanghai Henlius Biotech, Inc. S. Liu: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Shanghai Henlius Biotech,Inc. X. Zhang: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Shanghai Henlius Biotech,Inc. A. Luk: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Shanghai Henlius Biotech,Inc. K. Chai: Full / Part-time employment: Shanghai Henlius Biotech,Inc. E. Liu: Leadership role, Full / Part-time employment: I am an employee of Shanghai Henlius Biotech,Inc.

Saturable elimination of piperacillin in critically ill patients: implications for continuous infusion

The study aimed to evaluate saturation of piperacillin elimination in critically ill adult patients. Seventeen critically ill adult patients received continuous and intermittent infusion of piperacillin/tazobactam. Piperacillin plasma concentrations (n = 217) were analysed using population pharmacokinetic (PopPK) modelling. Post-hoc simulations were performed to evaluate the type I error rate associated with the study. Unseen data were used to validate the final model. The mean error (ME) and root mean square error (RMSE) were calculated as a measure of bias and imprecision, respectively. A PopPK model with parallel linear and non-linear elimination best fitted the data. The median and 95% confidence interval (CI) for the model parameters drug clearance (CL), volume of central compartment (V), volume of peripheral compartment (Vp) and intercompartmental clearance (Q) were 9 (7.69-11) L/h, 6.18 (4.93-11.2) L, 11.17 (7.26-12) L and 15.61 (12.66-23.8) L/h, respectively. The Michaelis-Menten constant (Km) and the maximum elimination rate for Michaelis-Menten elimination (Vmax) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for Km and Vmax were 37.09 mg/L and 353.57 mg/h, respectively. The bias (ME) was -20.8 (95% CI -26.2 to -15.4) mg/L, whilst imprecision (RMSE) was 49.2 (95% CI 41.2-56) mg/L. In conclusion, piperacillin elimination is (partially) saturable. Moreover, the population estimate for Km lies within the therapeutic window and therefore saturation of elimination should be accounted for when defining optimum dosing regimens for piperacillin in critically ill patients.

Pharmacokinetic-Pharmacodynamic Analyses to Provide Rezafungin Prophylaxis Dose Selection for Prevention of Invasive Fungal Infections for Bone Marrow Transplant Patients

Background: Rezafungin is a novel antifungal of the echinocandin class being developed as a single agent for prevention of invasive fungal infections (IFIs) caused by Candida, Aspergillus, and Pneumocystis spp. in patients at high risk of infection. Rezafungin exhibits an exceptionally long half-life (~133 h) which enables the administration of once-weekly dosing regimens. Treatment efficacy in a mouse Pneumocystis model is achieved at a human equivalent dose of <50 mg once-weekly [EHA. 2017. Abstr 9645]. A dose of 400 mg, followed by 200 mg once-weekly achieved >90% target attainment for treatment of Candida [AAC. 2018. 62:e02614-17]. Although lower doses of rezafungin might be useful for prevention of Pneumocystis and Candida infections, prevention of invasive aspergillosis in immunosuppressed populations is often considered more challenging. Pharmacokinetic-pharmacodynamic simulations were performed, at the dosing regimen for treatment of Candida, to evaluate the appropriateness of rezafungin for prophylaxis against A. fumigatus among bone marrow transplant (BMT) patients.Methods: A previously developed rezafungin population pharmacokinetic (PK) model [AAC. 2018. 62:e02603-17] was refined in NONMEM Version 7.2 using intravenous (IV) data from additional Phase 1 and Phase 2 studies. The ability of covariates such as body size, age, sex, albumin, markers of liver and renal function, and infection status to explain a portion of the interindividual variability on select PK parameters was explored using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). The final model was validated by comparing model-based predictions to observed data.Baseline demographic data were available from 100 patients who underwent a BMT at Stanford Medical Center. Using this dataset and the developed population PK model, a Monte Carlo simulation (n=2,000) was conducted to simulate expected rezafungin concentration-time profiles in BMT patients following administration of rezafungin 400 mg IV on Week 1 then 200 mg IV weekly x11. Using a human protein-binding value of 97.4%, free-drug concentration-time profiles were evaluated relative to the maximum observed A. fumigatus minimal effective concentration to inhibit 100% of isolates tested (MEC100) from surveillance data collected in 2016 [ASM Microbe 2018. Abstr Friday-485].Results: The final population PK model was a linear, 4-compartment model with zero order IV input. Albumin was an important predictor of the interindividual variability in rezafungin PK, as significant relationships were found between serum albumin concentration and clearance and volume of peripheral compartment 1. Additional relationships were found between PK parameters and sex, body surface area, presence of cirrhosis, and infection status. The model provided precise and unbiased fits to the observed data (r2=0.993 observed vs individual-predicted concentrations).The demographic dataset utilized for the simulations contained 100 BMT patients, of which 39 were female. Median (range) baseline body surface area and albumin were 1.84 m2 (1.27 - 2.61) and 3.35 g/dL (1.8 - 4.43), respectively. None of the patients had a baseline infection nor did any of the patients have cirrhosis. Following administration of rezafungin 400 mg IV on Week 1 then 200 mg IV weekly x11, free-drug plasma concentration-time profiles for Weeks 1, 2, and 12 relative to the A. fumigatus MEC100 (0.03 mg/L) are displayed in Figure 1. On Weeks 1, 2, and 12, 98.4%, 93.3%, and 91.9% of simulated patients, respectively, had rezafungin free-drug concentrations above the MEC100 value for the entire dosing interval (one week). This result was ≥99.9% for all 12 weeks when based on the MEC90 (0.015 mg/L).Conclusions: These data provide support for a once-weekly rezafungin dosing regimen for prevention of A. fumigatus infections among BMT patients. The effectiveness of current antifungal prophylactic regimens is frequently limited by safety, tolerability, drug interactions, adherence, pill burden and patient factors such as mucositis or background chemotherapeutic regimens. In addition to the excellent safety, tolerability, and lack of drug interactions exhibited by echinocandin agents, the favorable PK profile of rezafungin presents the opportunity to mitigate the typical challenges faced when administering IFI prophylaxis in BMT and other immunocompromised patients. [Display omitted] DisclosuresLakota:Cidara Therapeutics: Research Funding. Flanagan:Cidara Therapeutics: Employment, Equity Ownership. Sandison:Cidara Therapeutics: Employment, Equity Ownership. Brown:Cidara Therapeutics: Consultancy. Rubino:Cidara Therapeutics: Research Funding.