Nonlinear Elimination Research Articles

Model-based Investigation of Inadequate Efficacy of Tesnatilimab, an Anti- Natural Killer Group 2 Member D (NKG2D) Monoclonal Antibody, in Moderately to Severely Active Crohn's Disease.

Tesnatilimab is a human immunoglobulin G4 isotype monoclonal antibody that blocks the natural killer group 2 member D (NKG2D) receptor and prevent the downstream signaling of proinflammatory cytokines and cytotoxic mediators. Subcutaneous tesnatilimab was investigated in a phase 2 randomized, double-blind, placebo-controlled trial in patients with moderately to severely active Crohn's disease (CD). While the proof-of-concept Part I of the study demonstrated significant treatment effects, Part II (dose-ranging) revealed unexpected lack of dose-response and a modest degree of clinical benefit for treatment groups. To inform further drug development, population pharmacokinetic (PopPK) modeling and exposure-response (E-R) analyses were planned and performed. A one-compartment PopPK model with first-order absorption and parallel linear and non-linear elimination pathways was established for tesnatilimab in CD patients. No clinically significant covariates were identified and overall consistent PK was observed between Part I and Part II patients. Receptor occupancy data suggested full occupancy of the peripheral blood NKG2D receptors and target engagement at all tested dose levels. Pooled Part I and Part II data showed a positive efficacy E-R relationship, however, this was driven by data from Part I. Part II only analysis did not show an apparent efficacy E-R relationship. No important covariates were identified in efficacy E-R analyses, overall and in various subpopulations. No apparent E-R relationships were observed for the investigated safety endpoints. The PopPK and E-R analysis indicated that the inadequate efficacy of tesnatilimab in CD was unlikely due to insufficient drug exposure and target engagement. This article is protected by copyright. All rights reserved.

A Monte Carlo Thermal Radiative Transfer Solver with Nonlinear Elimination

In this paper, we present a new Monte Carlo method for solving the thermal radiative transfer (TRT) equations via the method of nonlinear elimination (NLEM). This method is inspired by the previous application of NLEM to thermal radiation diffusion. Our approach, called diffusion accelerated Implicit Monte Carlo (DAIMC), is a hybrid technique which combines a Monte Carlo method for solving a purely-absorbing transport equation and a diffusion solution that accounts for effective scattering, or absorption–reemission. The method aims to improve the implicitness of the traditional implicit Monte Carlo (IMC) method. We derive DAIMC generally for 3D Cartesian geometries, but in this paper, we present results and analysis in 1D slab geometry. These preliminary results indicate that DAIMC implementations may provide more accurate and robust TRT solutions than IMC in certain test problems.

Voriconazole exposure is influenced by inflammation: A population pharmacokinetic model.

Voriconazole is an antifungal drug used for the treatment of invasive fungal infections. Due to highly variable drug exposure, therapeutic drug monitoring (TDM) has been recommended. TDM may be helpful to predict exposure accurately, but covariates, such as severe inflammation, that influence the metabolism of voriconazole have not been included in the population pharmacokinetic (popPK) models suitable for routine TDM. To investigate whether the effect of inflammation, reflected by C-reactive protein (CRP), could improve a popPK model that can be applied in clinical care. Data from two previous studies were included in the popPK modelling. PopPK modelling was performed using Edsim++. Different popPK models were compared using Akaike Information Criterion and goodness-of-fit plots. In total, 1060 voriconazole serum concentrations from 54 patients were included in this study. The final model was a one-compartment model with non-linear elimination. Only CRP was a significant covariate, and was included in the final model and found to affect the maximum rate of enzyme activity (Vmax). For the final popPK model, the mean volume of distribution was 145 L [coefficient of variation percentage (CV%)=61%], mean Michaelis-Menten constant was 5.7 mg/L (CV%=119%), mean Vmax was 86.4 mg/h (CV%=99%) and mean bioavailability was 0.83 (CV%=143%). Internal validation using bootstrapping resulted in median values close to the population parameter estimates. This one-compartment model with non-linear elimination and CRP as a covariate described the pharmacokinetics of voriconazole adequately.

Research on Suppression of Fuses of Potential Transformer Fuse

In this paper, through the analysis of an electromagnetic Potential Transformer (PT) fuse fault in the distribution network, it is found that the cause of this type of fault is the low-frequency oscillation and inrush current of the voltage transformer caused by the disturbance, and its occurrence mechanism is studied and explained. After analyzing the advantages and disadvantages of the common PT fuse-blowing fault control measures, this paper proposes a treatment plan for the PT neutral point to suppress the fuse blowing through a nonlinear flow-sensitive harmonic elimination device. The harmonic device has a remarkable suppression effect on the PT fuse blown fault.

Population pharmacokinetics and exposure-response analyses of daratumumab plus pomalidomide/dexamethasone in relapsed or refractory multiple myeloma.

A population pharmacokinetic (PPK) model was developed to characterize pharmacokinetics (PK) of subcutaneous or intravenous daratumumab administration in a new indication (i.e., combination with pomalidomide and dexamethasone [D-Pd] in patients with relapsed or refractory multiple myeloma [RRMM]). Analyses were conducted to explore exposure-response (E-R) relationships for efficacy and select treatment-emergent adverse events (TEAEs). The PPK analysis included pooled data from the D-Pd cohorts of the phase 3 APOLLO and phase 1b EQUULEUS studies. Covariates were evaluated in the PPK model. Model-predicted exposures to daratumumab were compared between covariate subgroups of interest and used to investigate relationships between daratumumab exposure and efficacy and safety in APOLLO. The PPK analysis included 1146 daratumumab PK samples from 239 patients (APOLLO, n = 140; EQUULEUS, n = 99). Observed concentration-time data of daratumumab were well described by a two-compartment PPK model with first-order absorption and parallel linear and nonlinear elimination pathways. Treatment with D-Pd provided similar daratumumab PK characteristics versus historical daratumumab monotherapy. The E-R dataset contained data from 290 APOLLO patients (D-Pd, n = 140; Pd, n = 150). The PK-efficacy relationship of daratumumab supported improved progression-free survival for patients in the D-Pd group vs. the Pd group. Additionally, TEAEs did not increase with increasing PK exposure in the D-Pd group. The PPK and E-R analyses support the daratumumab subcutaneous 1800 mg dosing regimen in combination with Pd for treatment of patients with RRMM. No dose adjustment is recommended in this indication for any of the investigated factors, none of which had clinically relevant effects on daratumumab PK.

622. Population Pharmacokinetic Analysis and Probability of Target Attainment Simulations of Pivmecillinam for the Treatment of Uncomplicated Urinary Tract Infection

Abstract Background A population pharmacokinetic model was developed to characterize mecillinam (MEC) pharmacokinetics (PK) and urine exposure after intravenous (IV) administration of MEC or after oral (PO) administration of its prodrug pivmecillinam (PIV) in healthy subjects and patients with renal impairment (RI) or infections. MEC is a β-lactam antibiotic with a targeted spectrum of activity against Enterobacterales. The model was used to investigate various PIV treatment regimens and covariate scenarios on plasma exposure and urine excretion, and to perform probability of target attainment (PTA) simulations in support of dose justification for the treatment of uncomplicated urinary tract infection (uUTI). Methods The analysis was based on MEC PK data obtained in plasma, serum, and urine in 15 clinical studies. The dataset included a total of 3964 plasma or serum concentrations and 989 urine samples obtained in 228 subjects. Those 228 subjects consisted of 172 healthy volunteers, 23 patients with infections (uUTI, Gram-negative infection, typhoid, or paratyphoid fever), and 33 patients with various degrees of renal impairment (RI). Subjects were treated with single or multiple doses of MEC (IV, 200-1410 mg) or PIV (PO, 137-500 mg). Results MEC PK profiles in plasma and urine were well characterized by a 2-compartment distribution model with first-order renal elimination and nonlinear non-renal elimination. Oral absorption of PIV was best described using a single (Erlang) transit compartment. The PK model included parameter-covariate relationships for WT on all clearance and volume parameters (with fixed allometric exponents of 0.75 and 1), a nonlinear dose effect on bioavailability, formulation effects on Ka, food effects on both Ka and F1, and effects of renal function on both CL and Km. PTA simulations for the proposed dosing regimen of 200 mg TID predicts up to 70% fT>MIC for the CLSI susceptibility breakpoint of 8 mg/L in 90% of the population for a voiding frequency of 45 min. Conclusion MEC PK was well characterized by a 2-compartment distribution model with first-order renal and nonlinear non-renal elimination. The oral PIV absorption was best described using a single transit compartment. PTA simulations were supportive of a 200 mg TID dosing. Disclosures Anne Laurence Santerre Henriksen, PhD, Shionogi: Contractor|UTILITY therapeutics Ltd: Advisor/Consultant Maxime Lagraauw, PhD, qPharmetra: Employee Marita Prohn, n/a, qPharmetra: Employee Lars Lindbom, PhD, qPharmetra: Employee.

593. Population Pharmacokinetic Model Development for Epetraborole and Mycobacterium avium Complex (MAC) Lung Disease Patients Using Data from Phase 1 and 2 Studies

593. Population Pharmacokinetic Model Development for Epetraborole and <i>Mycobacterium avium</i> Complex (MAC) Lung Disease Patients Using Data from Phase 1 and 2 Studies

Population pharmacokinetic modeling of daridorexant, a novel dual orexin receptor antagonist.

The analysis aimed at identifying subject-specific characteristics (covariates) influencing exposure to daridorexant and quantification of covariate effects to determine clinical relevance. Data from 13 phase I, two phase II, and two phase III studies were pooled to develop a population pharmacokinetic model describing daridorexant concentration over time. Covariate effects were quantified based on model predictions. A two-compartment model with dose-dependent bioavailability, absorption lag time, linear absorption, and nonlinear elimination described the data best. Statistically significant covariates were food status on absorption (lag time and rate constant), time of drug administration (morning, bedtime) on absorption rate constant, lean body weight on central volume of distribution and elimination, fat mass on peripheral volume of distribution and intercompartmental drug transfer, and age and alkaline phosphatase on elimination. Age, lean body weight, fat mass, and alkaline phosphatase influence exposure (area under the curve, time of maximum concentration after dose administration, maximum plasma concentration, and next-morning concentration) to a limited extent, that is, less than 20% difference from a typical subject. Morning administration is not relevant for daridorexant use by insomnia patients. The food effect with simultaneous intake of a high-fat, high-calorie food is an extreme-case scenario unlikely to occur in clinical practice. Body composition, alkaline phosphatase, and age showed clinically negligible effects on exposure to daridorexant. Lean body weight and fat mass described the pharmacokinetics of daridorexant better than other body size descriptors (body weight, height, body mass index), suggesting a convenient physiological alternative to reduce the number of covariates in population pharmacokinetic models. The results indicate that differences between subjects do not require dose adjustments.

Population pharmacokinetics analysis of camidanlumab tesirine in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma.

The objective of this analysis was to develop a population pharmacokinetic (PPK) model to characterize camidanlumab tesirine (Cami) pharmacokinetics based on the phase 1 study in relapsed/refractory lymphoma (NCT02432235). An initial PPK model was developed based on a two-compartment model with parallel linear and nonlinear elimination pathways. Pharmacokinetic parameters were evaluated for correlation with potential demographic covariates; significant covariates were retained in the final model. In the final PPK model, baseline weight effects were included on clearance (CL), intercompartmental clearance (Q), and the volumes of distribution in the central (V1) and peripheral (V2) compartments. The baseline soluble CD25 (sCD25) effect was included on CL and maximum velocity of saturable clearance (Vmax); sex effect was included on CL and V1; and ethnicity effect was included on deconjugation clearance (CLdec). For a typical patient, CL and CLdec were 0.516 and 0.21L/day, respectively (tAb elimination half-life: 18.72days); V1 and V2 were 4.41 and 2.67 L, respectively; Vmax was 0.49mg/day; the Michaelis-Menten constant (Km) was 0.409µg/mL; and the first-order rate for decrease of Vmax (KDES) was 0.0197/day. Cami exposure was higher for patients with low baseline sCD25, higher body weight, and females. The final model described the observed data well, estimates of PK parameters were obtained, and covariates with significant effects on Cami exposure were identified. Altogether, this final PPK model provides a robust basis for analysis of Cami exposure-response relationships and further supports identification of the optimal Cami dosing schedule for patients with relapsed/refractory lymphoma.

Nonlinear elimination of pharmaceutical substances in multi-compartment and non-compartment pharmaco-kinetic models

Currently, about 90% of drug kinetics studies published in specialized veterinary journals are based on classical compartmental models. This contrasts with the situation in medical pharmacology, where non-compartmental analysis and alternative novel approaches are increasingly being used. These approaches are becoming increasingly important not only for characterizing drug distribution and concentration versus potency in therapeutic applications, but also for regulating the safety levels of chemicals in industrial settings and in animal products.A compartment is considered open if it interacts with the environment, or closed if it does not interact. In pharmacokinetics, most models in use have at least one open compartment with first-order elimination.The selection and analysis of scientific publications was carried out according to the recommendations of H. Snyder for writing review articles.In English and Russian, in various bibliographic databases (Elibrary, Pubmed, Scopus(Elsevier), Web of Science (Clarivate)) thematic publications were searched by keywords with further highlighting the most cited ones. Articles published earlier than 2015 were used only if they contained information critical to the disclosure of the topic that was not found in later publications.This publication summarizes the various approaches that are currently being used to analyze kinetic data and will stimulate interest in applying some of these new approaches to studying drug distribution in different animal species. Undoubtedly, without the use of alternative and/or new models, it would be difficult to improve our experimental approaches and understand the complex pharmacological differences between animal species.

Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed-Effects Analysis.

Phosphoramide mustard (PM) is the final cytotoxic metabolite formed from the parent compound cyclophosphamide through a complex metabolic pathway, primarily through hepatic metabolism. Little is known about the effect of renal elimination on the disposition of PM. We evaluated the effect of renal function on PM exposure after single doses of cyclophosphamide in 85 patients undergoing allogeneic hematopoietic cell transplantation using nonlinear mixed-effects modeling. Mixed linear and nonlinear elimination pathways were required to adequately describe the disposition of PM. Creatinine clearance (CrCL) was incorporated as a covariate associated with first-order elimination, representing renal clearance (ClR ) of PM. For a 70-kg patient, ClR was 14.9 L/h, Volume of distribution was 525 L, maximum rate was 81.2 mg/h, and the concentration to achieve 50% of maximum rate was 0.51 mg/L. We conducted simulations to explore the impact of CrCL as a measure of renal function and observed that when CrCL decreases from 120 to 40 mL/min, PM area under the plasma concentration-time curve (AUC) from time 0 to 8 hours and AUC increases by 9.2% and 80.9% on average after a single dose, respectively. Our data suggest that renal function has limited influence on PM exposure during the first 8 hours after dosing but has a large impact on the total exposure. Dose adjustment of cyclophosphamide may not be necessary in hematopoietic cell transplant recipients with moderate to severe kidney dysfunction to attain targeted exposures based on AUC from time 0 to 8 hours. However, dose reduction may be necessary if demonstrated at some future time that total AUC is a better surrogate for safety or toxicity.

Nonlinear Elimination of Pharmaceutical Substances in Single Compartment Pharmacokinetic Models

Pharmacokinetic modeling is a mathematical representation of the behavior of a pharmaceutical substance in the presence or anatomical and topographical area, created to describe pharmacological or refined kinetic characteristics. Pharmacokinetics is the science of basic processes observed over time and approaching the action of clinical manifestations. These nutritional patterns model biological processes, refer to the kinetic behavior of a drug after it has been introduced into the body, leading to a better understanding of its natural effects. Mathematical modeling is currently preferred, used in the study of research and biochemical systems. The spectrum of its use is from non-compartmental to large-scale multichamber models. In the case of compartmental models ("block model", "compartment model"), mass balance equations are used to represent each compartment. The number of compartments in the models depends on the rate of drug distribution over different topographic areas of the body. Most studies use one- or two-chamber models. When a substance is excreted from the body, its concentration in the systemic circulation and in all tissues decreases at the same rate due to the rapid distribution of distribution. This article is spent on the components of a one-component pharmacokinetic model specifically designed for various drug elimination models. The single-compartment open model is a simple way to describe the distribution and excretion of drug compounds from the body. This model assumes that drugs can enter or leave the body (an "open" model), and the whole body appears as a whole.

A multi-level nonlinear elimination-based JFNK method for multi-scale multi-physics coupling problem in pebble-bed HTR

In the pebble-bed high-temperature gas-cooled reactor, various physical phenomena occur at different spatial scales and are coupled together tightly in a nonlinear manner. More specifically, the local temperature profiles inside the fuel sphere and TRISO particle, which are essential in reactor design and safety analysis, are coupled with the global physical fields, such as the pebble bed temperature, helium temperature, as well as the fission heat source. Therefore, the multi-physics calculation combined with multi-scale model should be employed to describe the reactor behavior. The computational efficiency is the critical issue for the numerical solution of such global and local coupled systems. Jacobian-free Newton Krylov (JFNK) algorithm is an excellent candidate for multi-physics coupling issues due to its high convergence rate and superior computational performance, but it doesn’t consider the physical features at different scales. In this work, a multi-level nonlinear elimination is proposed within the JFNK framework to deal with the multi-scale coupled system in high-temperature gas-cooled reactor. The numerous local multi-scale temperature variables, including the fuel sphere and TRISO particle temperatures, are eliminated efficiently based on the Schur complement factorization due to its well sparse matrix structure. As a result, the number of unknowns is significantly reduced and the computational performance is improved. A steady-state pebble-bed HTR model is used in this work, and the numerical results show that multi-level nonlinear elimination-based JFNK method has high computational efficiency and numerical robustness, whose performance is 4 ∼ 6 times higher than that of the original JFNK algorithm.

Globalization of Nonlinear FETI-DP Domain Decomposition Methods Using an SQP Approach

The globalization of Nonlinear FETI-DP (Dual Primal Finite Element Tearing and Interconnecting) methods is considered using a Sequential Quadratic Programming (SQP) approach. Nonlinear FETI-DP methods are parallel iterative solution methods for nonlinear finite element problems, based on divide and conquer, using Lagrange multipliers. In these methods, nonlinear elimination is an important ingredient to increase the convergence radius of Newton’s method. We prove standard globalization results for SQP-based globalization of Nonlinear FETI-DP, first for the case that the elimination set is empty. We then show how to combine nonlinear elimination and SQP-based globalization. The globalization preserves the block structure of the FETI-DP operator, which is the basis of the computational parallelism.Supporting numerical experiments using homogenous and heterogeneous model problems from nonlinear structural mechanics are provided. In the numerical experiments, we consider four standard choices of different elimination sets and different problem setups including stiff or almost incompressible inclusions in every subdomain. The numerical experiments illustrate that a good elimination set is important. However, the use of the SQP-based globalization approach presented here can improve the convergence of Nonlinear FETI-DP methods further, especially, if combined with a good choice of the elimination set.

Active linearized PGC demodulation with fusion of PGC-Arctan and PGC-DCM schemes for nonlinear error elimination in SPM interferometer.

To eliminate the nonlinear error of phase generated carrier (PGC) demodulation in sinusoidal phase modulating interferometer (SPMI), an active linearized PGC demodulation with fusion of differential-and-cross-multiplying (PGC-DCM) and the arctangent (PGC-Arctan) schemes is proposed. In this method, the periodic integer multiple of π (π-integer phases) of PGC-Arctan without nonlinear error and the corresponding PGC-DCM results recorded at the same time are fused to obtain a calibration coefficient for PGC-DCM demodulation. Combining the accurate π-integer phases of PGC-Arctan and the calibrated fractional phase in the range of π of PGC-DCM, a linearized PGC demodulation result can be achieved, effectively eliminating the nonlinear error caused by drifts of phase demodulation depth (m) and carrier phase delay (θ). The distinct advantage of the proposed method is that it actively and linearly calibrates the fractional result of PGC-DCM without needing to measure or compensate m and θ. Simulation and displacement measurement experiments with different m and inherent arbitrary θ are performed to validate the proposed method. The experimental results show that nonlinear error of the proposed method can be reduced to about 0.1 nm with real-time linearization.

Nonlinear Error Correction for Color Phase-Shifting Profilometry with Histogram Equalization

Because color patterns with multiple channels can carry more information than gray patterns with only one channel, color phase-shifting profilometry (CPSP) has been widely used for high-speed, three-dimensional (3D) shape measurement. However, the accuracy of CPSP suffers from nonlinear errors caused by color crosstalk. This paper presents an effective nonlinear error correction method for CPSP based on histogram equalization. The two main steps of the proposed method are eliminating nonlinear errors with histogram equalization and optimizing the results using a spline fitting algorithm. Compared with other compensation methods, the proposed approach does not require any precalibration information or additional patterns, which are very time-consuming. The simulations and experiments indicate that the proposed method has a promising performance for nonlinear error elimination.

Nonlinear Population Pharmacokinetics of Anifrolumab in Healthy Volunteers and Patients With Systemic Lupus Erythematosus.

We characterized the population pharmacokinetics of anifrolumab, a type I interferon receptor–blocking antibody. Pharmacokinetic data were analyzed from the anifrolumab (intravenous [IV], every 4 weeks) arms from 5 clinical trials in patients with systemic lupus erythematosus (SLE) (n = 664) and healthy volunteers (n = 6). Population pharmacokinetic modeling was performed using a 2‐compartment model with parallel linear and nonlinear elimination pathways. The impact of covariates (demographics, interferon gene signature [IFNGS, high/low], disease characteristics, renal/hepatic function, SLE medications, and antidrug antibodies) on pharmacokinetics was evaluated. Time‐varying clearance (CL) was characterized using an empirical sigmoidal time‐dependent function. Anifrolumab exposure increased more than dose‐proportionally from 100 to 1000 mg IV every 4 weeks. Based on population pharmacokinetics modeling, the baseline median linear CL was 0.193 L/day in IFNGS‐high patients and 0.153 L/day in IFNGS‐low/healthy volunteers. After a year, median anifrolumab linear CL decreased by 8.4% from baseline. Body weight and IFNGS were significant pharmacokinetic covariates, whereas age, sex, race, disease activity, SLE medications, and presence of antidrug antibodies had no significant effect on anifrolumab pharmacokinetics. Anifrolumab at a concentration of 300 mg IV every 4 weeks was predicted to be below the lower limit of quantitation in 95% of patients ≈10 weeks after a single dose and ≈16 weeks after stopping dosing at steady state. To conclude, anifrolumab exhibited nonlinear pharmacokinetics and time‐varying linear CL; doses ≥300 mg IV every 4 weeks provided sustained anifrolumab concentrations. This study provides further evidence to support the use of anifrolumab 300 mg IV every 4 weeks in patients with moderate to severe SLE.

Impact of Pharmacokinetic and Pharmacodynamic Properties of Monoclonal Antibodies in the Management of Psoriasis.

The treatment of psoriasis has been revolutionized by the emergence of biological therapies. Monoclonal antibodies (mAb) generally have complex pharmacokinetic (PK) properties with nonlinear distribution and elimination. In recent years, several population pharmacokinetic/pharmacodynamic (PK/PD) models capable of describing different types of mAb have been published. This study aims to summarize the findings of a literature search about population PK/PD modeling and therapeutic drug monitoring (TDM) of mAb in psoriasis. A total of 22 articles corresponding to population PK/PD models of tumor necrosis factor (TNF)-α inhibitors (adalimumab and golimumab), interleukin (IL)-23 inhibitors (guselkumab, tildrakizumab, and risankizumab), IL-23/IL-12 inhibitor (ustekinumab), and IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab) were collected. A summary of the clinical trials conducted so far in psoriasis was included, together with the current structural population PK and PD models. The most significant and clinical covariates were body weight (BW) and the presence of immunogenicity on clearance (CL). The lack of consensus on PK/PD relationships has prevented establishing an adequate dosage and, therefore, accentuates the need for TDM in psoriasis.

Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective.

Eculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient. We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) [classical pathway (CP) activity levels] of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modelling was performed with non-linear mixed-effects modelling. The final model was used to develop improved dosing strategies. A PK model with parallel linear and non-linear elimination rates best described the data with the parameter estimates clearance 0.163 L/day, volume of distribution 6.42 L, maximal rate 29.6 mg/day and concentration for 50% of maximum rate 37.9 mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0 mg/L and Hillcoefficient5.42. A weight-based loading dose, followed by PK-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity<10%),compared with 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in ∼33% of the population by means of individualized dosing. With a fixed-dose 4-week dosing interval to allow for holidays, treatment costs will increase by 7.1% and we predict 91% of the patients will reach the efficacy target. A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.

Population pharmacokinetics of tanezumab following intravenous or subcutaneous administration to patients with osteoarthritis or chronic low back pain.

Describe population pharmacokinetics of intravenous (IV) and subcutaneous (SC) tanezumab across Phase 2b/3 studies of osteoarthritis and chronic low back pain. Data from 10 studies of IV or SC tanezumab (2.5-20 mg every 8 wk for up to 56 wk) were included in a multistep analysis. In Step 1, a 2-compartment model with linear and nonlinear elimination (based on prior analysis of pre-2015 IV osteoarthritis studies) was expanded to include other pre-2015 studies. In Step 2, post-2015 SC studies were combined into the model. Steps 3 and 4 evaluated impact of baseline nerve growth factor (NGF) and treatment-emergent anti-drug antibodies (TE ADA). SC bioavailability was estimated at 62-76%. The key disposition parameters CL, Vc , Vp and KM were estimated to be 0.133 L d-1 , 2.6 L, 1.77 L and 31.2 μg L-1 , respectively. Plasma tanezumab concentration was predicted to reach Cmax at 8.9-11.2 days following single and multiple SC administration in typical patients within the dose range of SC Phase 3 studies (2.5-10 mg every 8 wk). Exposure of a typical patient was similar between IV and SC for the second part of the dosing interval (wk 4-8). Covariates selected on the absorption parameters were weight, age, sex and injection site. Baseline NGF had minimal effect on maximum elimination capacity and TE ADA status was associated with slightly higher tanezumab clearance (6-7%). Our model adequately described plasma tanezumab concentration vs. time following IV or SC administration. Weight was the most influential covariate with respect to absorption of tanezumab in comparison to patient population (osteoarthritis and chronic low back pain) or other demographics. There was no clinically relevant effect of baseline NGF or TE ADA on tanezumab PK.