Development of a quantitative semi-mechanistic model of Alzheimer's disease based on the amyloid/tau/neurodegeneration framework (the Q-ATN model).

INTRODUCTION: A quantitative model of Alzheimer's disease (AD) based on the amyloid/tau/neurodegeneration biomarker framework (Q-ATN model) was developed to sequentially link amyloid positron emission tomography (PET), tau PET, medial temporal cortical thickness, and clinical outcome (Clinical Dementia Rating - Sum of Boxes; CDR-SB). METHODS: Published data and biologically plausible mechanisms were used to construct, calibrate, and validate the model. Clinical trial simulations were performed for different anti-amyloid antibodies, including a 5-year simulation of subcutaneous gantenerumab treatment. RESULTS: The simulated time-course of biomarkers and CDR-SB was consistent with natural history studies and described the effects of several anti-amyloid antibodies observed in trials with positive and negative (or non-significant) outcomes. The 5-year simulation predicts that the beneficial effects of continued anti-amyloid treatment should increase markedly over time. DISCUSSION: The Q-ATN model offers a novel approach for linking amyloid PET to CDR-SB, and provides theoretical support for the potential clinical benefit of anti-amyloid therapy. HIGHLIGHTS: A semi-mechanistic model was developed to link amyloid/tau/neurodegeneration biomarkers to clinical outcome (Q-ATN model). The Q-ATN model describes the disease progression seen in natural history studies. Model simulations agree well with mean data from the aducanumab EMERGE study. A 5-year simulation of gantenerumab predicts greater benefit with longer treatment.

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.

In silico exploration of amyloid-related imaging abnormalities in the gantenerumab open-label extension trials using a semi-mechanistic model.

Introduction: Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) are commonly observed with anti-amyloid therapies in Alzheimer's disease. We developed a semi-mechanistic, in silico model to understand the time course of ARIA-E and its dose dependency. Methods: Dynamic and statistical analyses of data from 112 individuals that experienced ARIA-E in the open-label extension of SCarlet RoAD (a study of gantenerumab in participants with prodromal Alzheimer's disease) and Marguerite RoAD (as study of Gantenerumab in participants with mild Alzheimer's disease) studies were used for model building. Gantenerumab pharmacokinetics, local amyloid removal, disturbance and repair of the vascular wall, and ARIA-E magnitude were represented in the novel vascular wall disturbance (VWD) model of ARIA-E. Results: The modeled individual-level profiles provided a good representation of the observed pharmacokinetics and time course of ARIA-E magnitude. ARIA-E dynamics were shown to depend on the interplay between drug-mediated amyloid removal and intrinsic vascular repair processes. Discussion: Upon further refinement and validation, the VWD model could inform strategies for dosing and ARIA monitoring in individuals with an ARIA-E history.

Estimation of Attainment of Steady-State Conditions for Compounds With a Long Half-Life.

Half-life is a standard result reported with analysis of pharmacokinetic data. Different definitions such as noncompartmental half-life, terminal half-life, effective half-life, and context-sensitive half-life can yield substantially different estimates of the quantity "half-life." Time to attainment of steady-state conditions is generally derived from (terminal) half-life and therefore sensitive toward the definition of half-life. Thus, estimates of the time to attain steady state must be provided with a precise definition of steady state and the method used for estimation, particularly for drugs with long (terminal) half-life. For clinical purposes, terminal half-life can have limited relevance if drug concentrations in the terminal elimination phase are low. A general rule for which half-life to use is infeasible. While limited accumulation can be negligible if a plateau in pharmacokinetics/pharmacodynamics is reached or with a wide therapeutic window (ie, exposure range), small additional drug accumulation can be highly relevant for drugs with a narrow therapeutic window. Beyond the average, estimation of individual time to attainment of steady state can add highly relevant information about the variability between subjects. Simulations from population models and the use of different definitions of steady state provide an assessment of robustness of the results. The relevance of accurate estimation of time to attainment of steady state is illustrated with cenerimod, an sphingosine-1-phosphate 1 receptor modulator with long half-life currently in clinical development for which estimates of time to steady state ranged from 35 to 110 days with different calculations.

Modelling pharmacokinetics and pharmacodynamics of the selective S1P1 receptor modulator cenerimod in healthy subjects and systemic lupus erythematosus patients.

AIMS: Assessment of time to attain steady state as well as drug accumulation following long-term treatment with the selective sphingosine-1-phosphate 1 receptor modulator cenerimod and prediction of the incidence of low total lymphocyte (LY) counts. Differences in pharmacokinetics and pharmacodynamics based on demographic characteristics and between healthy subjects and systemic lupus erythematosus (SLE) patients were to be identified. METHODS: Data from 4 Phase I studies and 1 Phase II study were pooled to develop a population pharmacokinetic/pharmacodynamic model describing cenerimod concentration and its effect on LY count. Simulations addressed the objectives. RESULTS: Simulations of 365 days of treatment indicated a time to steady state of 49 days and changes in exposure of 15% beyond 35 days. For a dose of 2 mg, the predicted incidences of LY counts below 0.5 and 0.2 × 109 cells/L were 18.2 and 0.6% for healthy subjects and 25.9 and 1.0% for SLE patients, respectively. Incidence increased with higher dose and lower baseline LY counts. For body weights of 50 and 100 kg compared to 75 kg, exposure was predicted to change by +37% and -20%, respectively. CONCLUSION: Long-term cenerimod administration is not expected to result in exposure and LY count reduction substantially different from results of completed studies. Low LY counts are predicted to occur more frequently in SLE patients compared to healthy subjects. Dose individualization based on the model is not considered necessary. Model-based simulations enable benefit-risk evaluations, supporting planning of late-phase clinical studies and scientific exchange with health authorities.

Pharmacokinetics, pharmacodynamics, tolerability and prediction of clinically effective dose of ACT-774312: A novel CRTH2 antagonist.

ACT-774312 is an antagonist of the chemoattractant receptor-homologous molecule expressed on T helper (Th) 2 cells (CRTH2), in development for the treatment of nasal polyposis or other allergic and type-2 inflammatory diseases. Placebo, single doses of 1-1000 mg, or multiple doses of 30-500 mg either once or twice daily for 4 days of ACT-774312 were administered orally to healthy subjects. The single- and multiple-dose pharmacokinetics (PK) of ACT-774312 were dose proportional and characterized by a time to attainment of maximum plasma concentrations between 1 and 3 hours and a terminal elimination half-life of about 12 hours In the presence of food, tmax was delayed by 1 hour and exposure to ACT-774312 slightly decreased. Full blockade (>90% of the maximum effect, Emax ) of CRTH2 as measured in a whole blood internalization assay was observed after 50 mg ACT-774312 twice daily and lasted for at least 9 hours The relationship between ACT-774312 concentration and CRTH2 blockade was described by a Emax model. The estimated twice-daily dose of ACT-774312 at which full blockade of CRTH2 is achieved at trough in at least 80% of subjects was estimated at 109 mg. Administration of ACT-774312 was safe and well tolerated at all doses. For none of the recorded adverse events, a relationship to dose was discerned, and there were no clinically relevant findings on the measured ECG, clinical laboratory and vital signs variables. The observed PK, pharmacodynamics and safety profile warrant further development of ACT-774312.

Modeling Tolerance Development for the Effect on Heart Rate of the Selective S1P1 Receptor Modulator Ponesimod.

Ponesimod is a selective sphingosine-1-phosphate-1 (S1P1 ) receptor modulator currently under investigation for the treatment of multiple sclerosis. S1P receptor modulators reduce heart rate following treatment initiation. This effect disappears with repeated dosing, enabling development of innovative uptitration regimens to optimize patient safety. There are currently no published pharmacokinetic/pharmacodynamic models describing the heart rate reduction of S1P receptor modulators in humans. The model developed here provides quantification of this effect for ponesimod. A direct-effect Imax model with estimated maximum reduction of 45%, tolerance development, and circadian variation best described this effect. The pooled data from nine clinical studies enabled characterization of interindividual variability. The model was used to simulate different treatment regimens to compare the effect of high initial doses vs. gradual uptitration with respect to the occurrence of bradycardia. The results indicate a better safety profile when using gradual uptitration. The model allows studying dosing regimens not clinically tested in silico.

Biomarker-guided clinical development of the first-in-class anti-inflammatory FPR2/ALX agonist ACT-389949.

AIMS: The main objectives of these two phase I studies were to investigate safety and tolerability as well as the pharmacokinetic/pharmacodynamic profile of the novel potent and selective formyl peptide receptor type 2 (FPR2)/Lipoxin A4 receptor (ALX) agonist ACT-389949. A challenge model was used to assess the drug's anti-inflammatory potential, with the aim of selecting a dosing regimen for future patient studies. METHODS: Two double-blind, randomized phase I studies investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT-389949 at different doses and dosing regimens. Drug exposure was correlated with target engagement markers such as receptor internalization and cytokine measurements. The effect of FPR2/ALX agonism on neutrophil migration was studied in a lipopolysaccharide (LPS) inhalation model. RESULTS: ACT-389949 was well tolerated. Maximum concentrations were reached around 2 h after dosing, with a mean terminal half-life of 29.3 h [95% confidence interval (CI) 25.5, 33.7]. After multiple-dose administration, exposure increased by 111% (95% CI 89, 136), indicating drug accumulation. Administration of ACT-389949 resulted in a dose-dependent, long-lasting internalization of FPR2/ALX into leukocytes. Pro- and anti-inflammatory cytokines were dose-dependently but transiently upregulated only after the first dose. No pharmacological effect on neutrophil count was observed in the LPS challenge test performed at steady state. CONCLUSIONS: FPR2/ALX agonism with ACT-389949 was shown to be safe and well tolerated in healthy subjects. Receptor internalization and downstream mediators pointed towards a desensitization of the system, which may explain the lack of effect on neutrophil recruitment in the LPS challenge model.

Impact of Demographics, Organ Impairment, Disease, Formulation, and Food on the Pharmacokinetics of the Selective S1P1 Receptor Modulator Ponesimod Based on 13 Clinical Studies.

BACKGROUND: Ponesimod is a selective, orally active sphingosine-1-phosphate receptor 1 modulator currently undergoing clinical evaluation for the treatment of multiple sclerosis (MS) in phase III clinical trials. Ponesimod dose-dependently reduces peripheral blood lymphocyte counts by blocking the egress of lymphocytes from lymphoid organs. METHODS: A population pharmacokinetic (PK) analysis was performed based on pooled data from 13 clinical studies. Interindividual variability (IIV) and the impact of key demographic variables and other covariates on ponesimod exposure were assessed quantitatively. RESULTS: A two-compartment model with sequential zero/first-order absorption, including lag time, intercompartmental drug flow, and first-order clearance, adequately described the PK of ponesimod. Body weight, race, MS, psoriasis, hepatic impairment, drug formulation, and food were identified to significantly affect the concentration-time profile. The inclusion of these covariates into the model explained approximately 25 % of the IIV in the PK of ponesimod. Model predictions indicated that the impact of the identified covariates on ponesimod steady-state exposure is within 20 % of exposure, and thus within the margins of the IIV, with the exception of hepatic impairment. Changes up to threefold were predicted for severe cases of liver dysfunction. CONCLUSION: The rich data set enabled building a comprehensive population PK model that accurately predicts the concentration-time data of ponesimod. Covariates other than hepatic impairment were considered not clinically relevant and thus do not require dose adjustment. A potential dose adaptation can be conducted based on the final model.

Modeling the Effect of the Selective S1P1 Receptor Modulator Ponesimod on Subsets of Blood Lymphocytes.

PURPOSE: This analysis aimed at describing the effect of the selective sphingosine-1-phosphate receptor 1 modulator ponesimod on lymphocyte subsets in peripheral blood. As the involvement of different lymphocyte subsets varies among different autoimmune diseases, characterizing the effect of ponesimod on these may be beneficial in better understanding treatment effects. METHODS: Three phase 1 clinical studies in healthy human subjects were pooled. Non-linear mixed-effects modeling techniques were used to study the effect of ponesimod on lymphocyte subsets such as B cells, T helper cells, T cytotoxic cells, and natural killer cells in a qualitative and quantitative manner. RESULTS: Indirect-response Imax models including circadian variation best described the effect of ponesimod on lymphocyte subsets. B cells and T helper cells were shown to be more affected compared to T cytotoxic cells with respect to the maximum possible reduction (100% for B and T helper cells, 95% for T cytotoxic cells) and the concentration required to reach half the maximum effect. Inter-individual variability was found to be larger for T cytotoxic compared to T helper, and B cells. CONCLUSION: These first models for ponesimod on the level of lymphocyte subsets offer a valuable tool for the analysis and interpretation of results from ponesimod trials in autoimmune diseases.

Population pharmacokinetics of ponesimod and its primary metabolites in healthy and organ-impaired subjects.

Ponesimod, a selective, orally active S1P1 receptor modulator, reduces total blood lymphocyte counts by blocking the egress of lymphocytes from lymphoid organs. It is currently in clinical development for the treatment of relapsing-remitting multiple sclerosis. Ponesimod has two primary metabolites, M12 and M13, that circulate in human plasma. The work presented in this paper predicts and quantifies the accumulation of ponesimod and both metabolites in healthy and organ-impaired subjects. Based on clinical data including studies in renally and hepatically impaired subjects, a population pharmacokinetic (PK) model was developed to characterize the PK of ponesimod and its primary metabolites and to qualify and quantify the influence of organ impairment on the concentration-time profiles of these compounds. As hepatic and renal function are critical for the elimination of the majority of drugs, being able to quantify their influence is important for the treatment in these populations. The PK of ponesimod and its metabolites were characterized by 2 compartments for each of the analytes, inter-connected via a liver compartment that serves as a physiologically meaningful approach to model first-pass metabolism. Absorption and elimination were described by first-order processes whereas metabolism was found to be saturable at supratherapeutic doses. Body weight and hepatic impairment were identified as significant covariates. Whereas the effect of body weight is small and within the margins of between-subject variability, hepatic impairment markedly affects the PK of ponesimod and its metabolites with up to 9-fold higher steady-state exposure in subjects with severe hepatic impairment.