Longitudinal modeling of efficacy response in patients with lupus nephritis receiving belimumab.

Belimumab was approved for active lupus nephritis (LN) in adults in the European Union and patients ≥ 5 years of age in the USA based on a Phase 3, double-blind, placebo-controlled, 104-week study. The study evaluated the efficacy of belimumab plus background standard therapy in adults with active LN using an intravenous (IV) dose of 10 mg/kg. A longitudinal analysis of Primary Efficacy Renal Response (PERR) and Complete Renal Response (CRR) was performed to assess whether patients with high proteinuria at the start of belimumab treatment would benefit from a higher dose. Responder probability was modeled as a logistic regression with probability a function of time and treatment (belimumab or placebo). Dropout risk at each visit was incorporated into a joint model of efficacy response; only efficacy data prior to dropout events (belimumab discontinuation, treatment failure, or withdrawal) were included. Average belimumab concentration over the first 4 and 12 weeks and baseline proteinuria were considered as continuous covariates. In general, renal response (PERR and CRR) over time was higher in patients receiving belimumab than in those receiving placebo. Baseline proteinuria was considered the most relevant predictor of renal response, with reduced efficacy in patients with increased proteinuria for both belimumab or placebo treatment. For belimumab-treated patients, belimumab exposure was not found to be an important predictor of renal response. In conclusion, the 10 mg/kg IV dose was considered appropriate in all patients and there was no evidence to suggest a higher response would be achieved by increasing the dose.

Longitudinal Model-Based Meta-Analysis of Lung Function Response to Support Phase III Study Design in Chinese Patients With Asthma.

Asthma is a chronic disease of the lungs characterized by airway inflammation, bronchoconstriction, and increased airway responsiveness. Forced expiratory volume in the first second (FEV1) is used as a measure of lung function and to help diagnose and monitor lung diseases, including asthma. An exponential longitudinal model has been previously developed to adequately describe the FEV1 response in asthma patients with placebo. This model was the basis of a longitudinal model-based meta-analysis which was undertaken to describe the trough FEV1 responses ranging up to 1 year from nine clinical studies in a population with asthma (N = 3,896), following placebo, dual combination (fluticasone furoate/vilanterol), and triple combination (fluticasone furoate/umeclidinium/vilanterol) given via inhalation. Numerical, graphical and simulation-based diagnostics showed that a Weibull model adequately characterized the longitudinal trough FEV1 response with time. Automatic covariate selection supported by statistically based regression models identified a range of patient characteristics influencing the model parameters. Race was a significant covariate on baseline but not on the parameters that impact the FEV1 trajectory. Based on the trough FEV1, all active treatments were found to be significantly different when compared with placebo and showed clinically meaningful improvement in FEV1. The model was able to predict the longitudinal FEV1 response in Chinese patients with inadequately controlled asthma and was used to provide additional support with respect to the design for a shorter-duration phase III study to the China National Medical Products Administration (NMPA).

A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid-targeted bromodomain and extra-terminal domain inhibitor.

AIMS: GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995). METHODS: Part A (N = 23) included three dose-escalating periods of 1-40 mg of GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts. RESULTS: In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization. CONCLUSIONS: Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.

Response to Inhibition of Receptor-Interacting Protein Kinase 1 (RIPK1) in Active Plaque Psoriasis: A Randomized Placebo-Controlled Study.

Receptor-interacting protein kinase 1 (RIPK1), a regulator of inflammation and cell death, is a potential therapeutic target in immune-mediated inflammatory diseases (IMIDs). The objective of this phase IIa multicenter, randomized, double-blind, placebo-controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque-type psoriasis. Psoriasis patients (N = 65) were randomized to 60 mg twice daily (b.i.d.) or three times daily (t.i.d.), or placebo for 84 days. Most adverse events (AEs) were mild with no severe drug-related AEs reported. Plaque Lesion Severity Sum improved with b.i.d. treatment compared with placebo; interpretation of t.i.d. treatment results was complicated by a high placebo response. Reductions in epidermal thickness and infiltration by CD3+ T cells in the epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs.

MPBPK-TMDD models for mAbs: alternative models, comparison, and identifiability issues.

The aim of the present study was to evaluate model identifiability when minimal physiologically-based pharmacokinetic (mPBPK) models are integrated with target mediated drug disposition (TMDD) models in the tissue compartment. Three quasi-steady-state (QSS) approximations of TMDD dynamics were explored: on (a) antibody-target complex, (b) free target, and (c) free antibody concentrations in tissue. The effects of the QSS approximations were assessed via simulations, taking as reference the mPBPK-TMDD model with no simplifications. Approximation (a) did not affect model-derived concentrations, while with the inclusion of approximation (b) or (c), target concentration profiles alone, or both drug and target concentration profiles respectively deviated from the reference model profiles. A local sensitivity analysis was performed, highlighting the potential importance of sampling in the terminal pharmacokinetic phase and of collecting target concentration data. The a priori and a posteriori identifiability of the mPBPK-TMDD models were investigated under different experimental scenarios and designs. The reference model and QSS approximation (a) on antibody-target complex were both found to be a priori identifiable in all scenarios, while under the further inclusion of QSS approximation (b) target concentration data were needed for a priori identifiability to be preserved. The property could not be assessed for the model including all three QSS approximations. A posteriori identifiability issues were detected for all models, although improvement was observed when appropriate sampling and dose range were selected. In conclusion, this work provides a theoretical framework for the assessment of key properties of mathematical models before their experimental application. Attention should be paid when applying integrated mPBPK-TMDD models, as identifiability issues do exist, especially when rich study designs are not feasible.

Population Pharmacokinetic Modelling for Estimation of Remifentanil Metabolic-Ratio Using Non-steady-State Concentrations under Rapidly Adaptive Dosing.

PURPOSE: To predict steady-state metabolite-to-drug concentration ratio (metabolic ratio) for analgesic drug remifentanil, using sparse non-steady-state data from patients with normal or impaired renal function during individualised, highly variable and rapidly adaptive intravenous infusion. METHODS: A three-compartment joint parent-metabolite population pharmacokinetic model was developed using concentrations of remifentanil and its metabolite remifentanil acid from two trials. Renal function was included as an important mechanistic covariate. To address the large covariate effect and highly individualised and rapidly adaptive dosing, standardised visual predictive check was conducted on the observations and individualised visual predictive check was conducted on metabolic ratio estimates. The model was used to simulate metabolic ratio distribution in patients with various renal functions. RESULTS: The model, including its covariate structure, adequately described the data. The predictive checks allowed informative model evaluation. The predicted median (10th - 90th percentile) of remifentanil metabolic ratio was 12.5 (2.4-58.2) for patients with normal or mildly impaired renal function, or 54.3 (12.8-218.4) for patients with moderately or severely impaired renal function. CONCLUSIONS: The methodologies applied here allowed robust estimation of steady-state parameters using non-steady-state sparse data under highly variable adaptive dosing.

Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers.

GSK2982772 is a highly selective inhibitor of receptor-interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo-controlled, double-blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1-120 mg) or placebo in a crossover design during each of 4 treatment periods. In Part B, subjects received repeat doses of GSK2982772 (20 mg once daily [QD] to up to 120 mg twice daily [BID]) or placebo for 14 days. Part C was an open-label relative bioavailability study comparing 20-mg tablets vs capsules. Safety, tolerability, pharmacokinetics (PK), RIPK1 target engagement (TE), and pharmacodynamics (PD) were assessed. The most common adverse events (AEs) were contact dermatitis and headache. Most AEs were mild in intensity, and there were no deaths or serious AEs. The PK of GSK2982772 was approximately linear over the dose range studied (up to 120 mg BID). There was no evidence of drug accumulation upon repeat dosing. Greater than 90% RIPK1 TE was achieved over a 24-hour period for the 60-mg and 120-mg BID dosing regimens. Single and repeat doses of GSK2982772 were safe and well tolerated. PK profiles showed dose linearity. The high levels of RIPK1 TE support progression into Phase II clinical trials for further clinical development.

Proof-of-Concept Randomized Trial of the Monoclonal Antibody GSK249320 Versus Placebo in Stroke Patients.

BACKGROUND AND PURPOSE: One class of poststroke restorative therapy focuses on promoting axon outgrowth by blocking myelin-based inhibitory proteins such as myelin-associated glycoprotein. The purpose of the current study was to extend preclinical and clinical findings of GSK249320, a humanized monoclonal antibody to myelin-associated glycoprotein with disabled Fc region, to explore effects on motor outcomes poststroke. METHODS: In this phase IIb double-blind, randomized, placebo-controlled study, patients at 30 centers with ischemic stroke 24 to 72 hours prior and gait deficits were randomized to 2 IV infusions of GSK249320 or placebo. Primary outcome measure was change in gait velocity from baseline to day 90. RESULTS: A total of 134 subjects were randomized between May 2013 and July 2014. The 2 groups were overall well matched at baseline. The study was stopped at the prespecified interim analysis because the treatment difference met the predefined futility criteria cutoff; change in gait velocity to day 90 was 0.55±0.46 (mean±SD) in the GSK249320 group and 0.56±0.50 for placebo. Secondary end points including upper extremity function were concordant. The 2 IV infusions of GSK249320 were well tolerated. No neutralizing antibodies to GSK249320 were detected. CONCLUSIONS: GSK249320, within 72 hours of stroke, demonstrated no improvement on gait velocity compared with placebo. Possible reasons include challenges translating findings into humans and no direct evidence that the therapy reached the biological target. The antibody was well tolerated and showed low immunogenicity, findings potentially useful to future studies aiming to use a monoclonal antibody to modify activity in specific biological pathways to improve recovery from stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01808261.

First administration of the Fc-attenuated anti-ß amyloid antibody GSK933776 to patients with mild Alzheimer's disease: a randomized, placebo-controlled study.

OBJECTIVE: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the Fc-inactivated anti-ß amyloid (Aß) monoclonal antibody (mAb) GSK933776 in patients with mild Alzheimer's disease (AD) or mild cognitive impairment (MCI). METHODS: This was a two-part, single blind, placebo-controlled, first-time-in-human (FTIH) study of single (n = 18) and repeat dose (n = 32) intravenous GSK933776 0.001-6 mg/kg (ClinicalTrials.gov: NCT00459550). Additional safety data from an open-label, uncontrolled, single dose study of intravenous GSK933776 1-6 mg/kg (n = 18) are included (ClinicalTrials.gov: NCT01424436). RESULTS: There were no cases of amyloid-related imaging abnormalities-edema (ARIA-E) or -hemorrhage (ARIA-H) after GSK933776 administration in both studies. Three patients across the two studies developed anti-GSK933776 antibodies. Plasma GSK933776 half-life (t1/2) was 10-15 days after repeat dosing. After each of three administrations of GSK933776, plasma levels of total Aß42 and Aß increased whereas plasma levels of free Aß decreased dose dependently; no changes were observed for placebo. For total Aß42 the peak:trough ratio was ≤2 at doses ≥3 mg/kg; for total Aß the ratio was ≤2 at 6 mg/kg. CSF concentrations of Aß showed increases from baseline to week 12 for Aß X-38 (week 12:baseline ratio: 1.65; 95%CI: 1.38, 1.93) and Aß X-42 (week 12:baseline ratio: 1.18; 95%CI: 1.06, 1.30) for values pooled across doses. CONCLUSION: In this FTIH study the Fc-inactivated anti-Aß mAb GSK933776 engaged its target in plasma and CSF without causing brain ARIA-E/H in patients with mild AD or MCI. TRIAL REGISTRATION: ClinicalTrials.gov NCT00459550.

Modulation of ß-amyloid by a single dose of GSK933776 in patients with mild Alzheimer's disease: a phase I study.

INTRODUCTION: In this study, we evaluated the safety and pharmacodynamic effects of the Fc-inactivated anti-ß-amyloid (anti-Aß) monoclonal antibody GSK933776 in patients with mild Alzheimer's disease and mild cognitive impairment. Aß and tau levels were investigated in cerebrospinal fluid (CSF), and the relationship between Aß levels and Aß modulation in plasma was explored. The feasibility of a continuous sampling method using a lumbar catheter was assessed. METHODS: This trial was a phase I, open-label, uncontrolled, single-dose, exploratory experimental medicine study of intravenous GSK933776 at doses of 1 mg/kg, 3 mg/kg or 6 mg/kg (n = 6/group). The time course of plasma and CSF concentrations of GSK933776 and Aß was assessed. Sample size was based on feasibility, and no formal statistical analyses were performed. RESULTS: Following administration of GSK933776 at doses of 1 mg/kg, 3 mg/kg and 6 mg/kg, there were decreases from baseline in CSF Aß1-42 (from 0 to 12 hours) by 22.8 pg/ml (6.2%), 43.5 pg/ml (9.2%) and 60.5 pg/ml (12.5%), respectively. Plasma concentrations of total Aß18-35 and Aß4228-42 increased immediately after infusion and CSF tau concentration increased slightly, but did not significantly change, following administration of all doses of GSK933776. Pharmacokinetics confirmed the presence of GSK933776 in the CSF, which exhibited a dose-response relationship. One patient underwent minor surgery without sequelae following a ruptured lumbar catheter. CONCLUSION: GSK933776 demonstrated pharmacological activity and target engagement in CSF and plasma, and the continuous sampling method via a catheter successfully assessed the Aß changes following single-dose administration of GSK933776. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01424436. Registered 4 August 2011.

Modeling of human tumor xenografts and dose rationale in oncology.

Xenograft models are commonly used in oncology drug development. Although there are discussions about their ability to generate meaningful data for the translation from animal to humans, it appears that better data quality and better design of the preclinical experiments, together with appropriate data analysis approaches could make these data more informative for clinical development. An approach based on mathematical modeling is necessary to derive experiment-independent parameters which can be linked with clinically relevant endpoints. Moreover, the inclusion of biomarkers as predictors of efficacy is a key step towards a more general mechanism-based strategy.

Safety, pharmacokinetics, and pharmacodynamics of escalating repeat doses of GSK249320 in patients with stroke.

BACKGROUND AND PURPOSE: Restorative therapies have the potential to improve function and reduce disability after stroke with a wide therapeutic window. The current study evaluated GSK249320, a monoclonal antibody that blocks the axon outgrowth inhibition molecule myelin-associated glycoprotein and also protects oligodendrocytes. METHODS: Patients with mild-moderate stroke were randomized to intravenous GSK249320 (1, 5, or 15 mg/kg per infusion, in escalating cohorts of 8-9 subjects) versus placebo (n=17). Infusion 1 was 24 to 72 hours after stroke; infusion 2 was 9 ± 1 days later. The primary objective evaluated safety and tolerability, and the secondary objectives evaluated immunogenicity, pharmacokinetics, biomarkers, neurophysiology, and motor function. RESULTS: Baseline (n=42) characteristics were similar across treatment groups. No safety concerns were found based on adverse events, examination, vital signs, ECG, nerve conduction tests, brain imaging, motor function testing, and laboratory studies. Two of the 25 subjects dosed with GSK249320 developed transient antidrug antibodies after infusion 1. The pharmacokinetics profile was as expected for an IgG1 type monoclonal antibody. Serum levels of the biomarker S100ß did not differ between groups. Global outcome measures were similar across groups. Modality-specific end points could be consistently measured in the first few days after stroke, and one of these, gait velocity, demonstrated a trend toward improvement with GSK249320 compared with placebo. CONCLUSIONS: GSK249320 was generally well tolerated. No major safety issues were identified in this first study of a monoclonal antibody to modulate the neurobiology of brain repair after stroke. Future studies might explore the efficacy of GSK249320 as a restorative therapy for stroke. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00833989.

Modeling Alzheimer's disease progression using the disease system analysis approach.

A novel mechanistic model based on a disease system analysis paradigm was developed to explore the role of homeostatic mechanisms involved in Alzheimer's disease (AD) progression. We used longitudinal AD Assessment Scale-cognitive subscale (ADAS-cog) scores from 926 subjects with AD on stable acetylcholinesterase inhibitor therapy randomized to placebo treatment in two 54-week clinical trials. Alternative mechanistic models were evaluated by assuming that the rate of change of ADAS-cog over time was jointly regulated by a process characterizing the deterioration of ADAS-cog and by a process associated with a compensatory regulatory response. The model based on a time-varying deterioration rate of ADAS-cog performed better than the model based on a time-varying homeostatic control. The covariate analysis indicated that baseline Mini-Mental State Examination score, education, age, and apolipoprotein ɛ4 genotype had a significant effect on the level and shape of the trajectories of the mean model predicted ADAS-cog change from baseline.

A minimal model of tumor growth inhibition.

The preclinical development of antitumor drugs greatly benefits from the availability of models capable of predicting tumor growth as a function of the drug administration schedule. For being of practical use, such models should be simple enough to be identifiable from standard experiments conducted on animals. In the present paper, a stochastic model is derived from a set of minimal assumptions formulated at cellular level. Tumor cells are divided in two groups: proliferating and nonproliferating. The probability that a proliferating cell generates a new cell is a function of the tumor weight. The probability that a proliferating cell becomes nonproliferating is a function of the plasma drug concentration. The time-to-death of a nonproliferating cell is a random variable whose distribution reflects the nondeterministic delay between drug action and cell death. The evolution of the expected value of tumor weight obeys two differential equations (an ordinary and a partial differential one), whereas the variance is negligible. Therefore, the tumor growth dynamics can be well approximated by the deterministic evolution of its expected value. The tumor growth inhibition model, which is a lumped parameter model that in the last few years has been successfully applied to several antitumor drugs, is shown to be a special case of the minimal model presented here.

Validation of two algorithms to evaluate the interface between bone and orthopaedic implants.

The level of fit and fill of the prosthetic stem in the femoral canal is an important parameter when planning a cementless total hip arthroplasty. However, the standard templates used in combination with radiographs are not always effective in the pre-operative evaluation of the level of fitting. For this reason, two algorithms were developed able to provide clinically relevant three-dimensional indicators of the implant fit and fill in the host femur, based on the CT data of each specific patient as collected in vivo. In this study the computational methods were described and validated using digital phantom datasets. Then the algorithms were applied for in vivo datasets and the sensitivity of each indicator was evaluated. The validation showed that the two algorithms are accurate from a computational point of view. Moreover, the in vivo testing demonstrated that the developed methods provide reasonable quantitative indicators of the stem positioning in the femoral CT dataset.

Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth kinetics in xenograft models after administration of anticancer agents.

The available mathematical models describing tumor growth and the effect of anticancer treatments on tumors in animals are of limited use within the drug industry. A simple and effective model would allow applying quantitative thinking to the preclinical development of oncology drugs. In this article, a minimal pharmacokinetic-pharmacodynamic model is presented, based on a system of ordinary differential equations that link the dosing regimen of a compound to the tumor growth in animal models. The growth of tumors in nontreated animals is described by an exponential growth followed by a linear growth. In treated animals, the tumor growth rate is decreased by a factor proportional to both drug concentration and number of proliferating tumor cells. A transit compartmental system is used to model the process of cell death, which occurs at later times. The parameters of the pharmacodynamic model are related to the growth characteristics of the tumor, to the drug potency, and to the kinetics of the tumor cell death. Therefore, such parameters can be used for ranking compounds based on their potency and for evaluating potential differences in the tumor cell death process. The model was extensively tested on discovery candidates and known anticancer drugs. It fitted well the experimental data, providing reliable parameter estimates. On the basis of the parameters estimated in a first experiment, the model successfully predicted the response of tumors exposed to drugs given at different dose levels and/or schedules. It is, thus, possible to use the model prospectively, optimizing the design of new experiments.

An automated method to position prosthetic components within multiple anatomical spaces.

The level of fit and fill of a stem in the host femur is the most critical factor for the mechanical stability and success of the prosthesis. It would be useful to have a simulation tool able to investigate the anatomical compatibility of a new implant in a large library of femoral anatomies in the early phases of the design process. In order to realise this tool, it is necessary to develop an automatic method for the positioning of the stem in a database of anatomies. The aim of this study was to develop and evaluate a method for the automatic positioning of the stem geometry in the anatomical CT dataset. Two different strategies were considered: a completely automatic registration technique and a semi-automatic method based on an anatomical referencing. The two procedures were compared to the manual positioning obtained by an expert surgeon in a set of nine CT datasets. For both methods in each femur the positioning and the orientation of the stem were good. The results showed a better level of fitting for the automatic method, while the shift of the hip joint centre was lower for the anatomical referencing technique. However, the anatomical referencing method requires a higher computational effort without being significantly better than the automatic method. For this reason, the automatic method should be chosen to develop the automatic positioning of a stem in a database of anatomies.