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Peripheral and axial manifestations of psoriatic arthritis (PsA) can lead to irreversible structural damage and chronic disability. Our objective was to explore predictors of radiographic progression and to increase our understanding of treatment effects in subgroups of patients with different rates of structural damage progression.We analysed data from two large Phase-3 trials of secukinumab in PsA patients, FUTURE-1 (NCT01392326, n=606) and FUTURE-5 (NCT02404350, n=996), where different posologies ranging from 75 mg to 300 mg were used. We applied a longitudinal Bayesian mixture model with random effects to account for the variability in the repeated radiographic assessments. "Fast progressors" were defined post hoc as patients with a 50% model-estimated probability to progress at least 0.5 mTSS/year faster than an average patient.Higher baseline inflammation and higher body weight were identified as significant predictors of radiographic progression (multivariate model). Model-estimated structural damage progression in an average patient treated with secukinumab 150 mg subcutaneous (s.c.) was slower (0.04 mTSS/year; 95% CI -0.28, 0.34) compared to a patient treated with placebo (0.94 mTSS/year; 95% CI 0.45, 1.45). According to the model, the subgroup of "fast progressors" (hsCRP ≥26 mg/L, body weigth ≥94 kg, inadequate response to prior anti-TNF-alpha, structural damage ≥42 mTSS) treated with secukinumab 150 mg s.c. progressed at 0.56 mTSS/year (95% CI 0.02, 1.09) and 1.46 mTSS/year (95% CI 0.81, 2.11) when treated with placebo.Greater systemic inflammation and higher body weight at baseline were identified as significant predictors of progression. Even patients with fast radiographic progression could experience a beneficial effect with secukinumab that holds promise to prevent further mobility loss.

Demand for healthcare services is unprecedented. Society is struggling to afford the cost. Pricing of biopharmaceutical products is under scrutiny, especially by payers and Health Technology Assessment agencies. As we discuss here, rapidly advancing technologies, such as Real-World Data (RWD), are being utilized to increase understanding of disease. RWD, when captured and analyzed, produces the Real-World Evidence (RWE) that underpins the economic case for innovative medicines. Furthermore, RWD can inform the understanding of disease, help identify new therapeutic intervention points, and improve the efficiency of research and development (R&D), especially clinical trials. Pursuing precompetitive collaborations to define shared requirements for the use of RWD would equip service-providers with the specifications needed to implement cloud-based solutions for RWD acquisition, management and analysis. Only this approach would deliver cost-effective solutions to an industry-wide problem.

Sphingosine 1-phosphate (S1P) receptor agonists are associated with cardiovascular effects in humans. This study aims to develop a systems pharmacology model to identify the site of action (i.e., primary hemodynamic response variable) of S1P receptor agonists, and to predict, in a quantitative manner, the cardiovascular effects of novel S1P receptor agonists in vivo. The cardiovascular effects of once-daily fingolimod (0, 0.1, 0.3, 1, 3, and 10 mg/kg) and siponimod (3 and 15 mg/kg) were continuously recorded in spontaneously hypertensive rats and Wistar-Kyoto rats. The results were analyzed using a recently developed systems cardiovascular pharmacology model, i.e. the CVS model; total peripheral resistance and heart rate were identified as the site of action for fingolimod. Next, the CVS model was interfaced with an S1P agonist pharmacokinetic-pharmacodynamic (PKPD) model. This combined model adequately predicted, in a quantitative manner, the cardiovascular effects of siponimod using in vitro binding assays. In conclusion, the combined CVS and S1P agonist PKPD model adequately describes the hemodynamic effects of S1P receptor agonists in rats and constitutes a basis for the prediction, in a strictly quantitative manner, of the cardiovascular effects of novel S1P receptor agonists.

Background: Ankylosing spondylitis (AS) is an inflammatory disease resulting in progressive disability due to structural damage in the spine. The identification of predictors of progression would allow treating physicians to personalize treatments but requires an approach accounting for a relatively short follow-up of clinical studies, large between-patient variability, and low sensitivity of X-ray images which generate intra-patient variability when repeated measurements are taken. Objectives: 1) To identify patient characteristics predicting faster structural damage progression. 2) To quantify the progression over four years of secukinumab treatment, depending on dose/exposure. Methods: Data came from the phase 3 randomized placebo-controlled trial MEASURE 1 (NCT01358175)1 in which patients were treated with secukinumab (intravenous loading of 10 mg/kg at weeks 0, 2, and 4, followed by secukinumab subcutaneously at a dose of either 75 mg or 150 mg every 4 weeks) over 208 weeks. Only patients treated with secukinumab with at least two assessments of structural damage were included. We explored the effect of multiple baseline demographic traits, disease stage, severity, bone cartilage biomarkers as well as prior and current treatment on change in modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) using a longitudinal Bayesian mixture model with random effects, which accounted simultaneously for the probability of progression, magnitude of progression and inter-patient variability. Posterior predictive check was performed. Results: Out of 249 patients randomized to secukinumab, 167 had their structural damage assessed at least twice. These patients contributed in total 409 assessments of change in structural damage between weeks 0, 52, 104 and 208. Of the factors tested, a higher baseline BASMI score was associated with faster progression rate in a statistically significant way (+0.60 in mSASSS/year for each additional standard deviation of baseline BASMI (SD=1.74), 95% interval 0.03 to 1.14). Trends were also detected for association between faster mSASSS progression and younger age, prior exposure to TNFα inhibitor, HLA-B27 positivity, and higher osteocalcin levels. Increased exposure to secukinumab was associated with slower structural damage progression (-0.23 in mSASSS/year for each additional standard deviation in exposure, 95% interval -0.58 to 0.10). Model estimation suggested that secukinumab 150 mg was associated with a yearly progression of -0.2 (95% interval -1.2 to 0.8) in the first two years of treatment and 0.1 mSASSS (95% interval -0.8 to 1.0) in the third and fourth year of treatment. Analogously, secukinumab 75mg (currently not approved for clinical use) was associated with a progression of -0.2 mSASSS/year (95% interval -1.3 to 0.9) in the first two years of treatment and 0.5 mSASSS/year (95% interval -0.5 to 1.6) in the third and fourth year of treatment. Conclusion: Potential predictors of structural progression suggested by the model were higher baseline BASMI, younger age, prior exposure to TNFα inhibitor, HLA-B27 positivity, and higher osteocalcin at baseline, although only baseline BASMI showed statistical significance. Further analyses using larger, deeper and real-world data are needed to confirm these findings and to estimate progression rates in AS patients in daily practice. Reference [1] Baeten D, Sieper J, Braun J, et al. Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis. N Engl J Med. 2015;373(26):2534-2548. Disclosure of Interests: Olivier Luttringer Shareholder of: Novartis, Employee of: Employee of Novartis Pharma AG, Todd Fox Employee of: Novartis, Brian Porter Shareholder of: Novartis, Employee of: Novartis, Abhijit Shete Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG, Hanno Richards Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG, Witold Wiecek Consultant for: Employee of CERTARA Strategic Consulting., Zuzanna Angehrn Shareholder of: Owns funds which might occassionaly invest in pharmaceutical companies’ stocks., Consultant for: Employee of CERTARA strategic consulting., Helene Karcher Consultant for: Former employee of Analytica Laser, a Certara company. Former independent consultant. Current employee of PAREXEL., Employee of: Former employee of Novartis., Billy Amzal Consultant for: Employee of CERTARA Strategic Consulting., Employee of: Former employee of Novartis.

Background and purpose The homeostatic control of arterial BP is well understood with changes in BP resulting from changes in cardiac output (CO) and/or total peripheral resistance (TPR). A mechanism-based and quantitative analysis of drug effects on this interrelationship could provide a basis for the prediction of drug effects on BP. Hence, we aimed to develop a mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model in rats that could be used to characterize the effects of cardiovascular drugs with different mechanisms of action (MoA) on the interrelationship between BP, CO and TPR. Experimental approach The cardiovascular effects of six drugs with diverse MoA, (amlodipine, fasudil, enalapril, propranolol, hydrochlorothiazide and prazosin) were characterized in spontaneously hypertensive rats. The rats were chronically instrumented with ascending aortic flow probes and/or aortic catheters/radiotransmitters for continuous recording of CO and/or BP. Data were analysed in conjunction with independent information on the time course of drug concentration using a mechanism-based PKPD modelling approach. Key results By simultaneous analysis of the effects of six different compounds, the dynamics of the interrelationship between BP, CO and TPR were quantified. System-specific parameters could be distinguished from drug-specific parameters indicating that the model developed is drug-independent. Conclusions and implications A system-specific model characterizing the interrelationship between BP, CO and TPR was obtained, which can be used to quantify and predict the cardiovascular effects of a drug and to elucidate the MoA for novel compounds. Ultimately, the proposed PKPD model could be used to predict the effects of a particular drug on BP in humans based on preclinical data.

Background and Purpose Previously, a systems pharmacology model was developed characterizing drug effects on the interrelationship between mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR). The present investigation aims to (i) extend the previously developed model by parsing CO into heart rate (HR) and stroke volume (SV) and (ii) evaluate if the mechanism of action (MoA) of new compounds can be elucidated using only HR and MAP measurements. Experimental Approach Cardiovascular effects of eight drugs with diverse MoAs (amiloride, amlodipine, atropine, enalapril, fasudil, hydrochlorothiazide, prazosin and propranolol) were characterized in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats following single administrations of a range of doses. Rats were instrumented with ascending aortic flow probes and aortic catheters/radiotransmitters for continuous recording of MAP, HR and CO throughout the experiments. Data were analysed in conjunction with independent information on the time course of the drug concentration following a mechanism-based pharmacokinetic-pharmacodynamic modelling approach. Key Results The extended model, which quantified changes in TPR, HR and SV with negative feedback through MAP, adequately described the cardiovascular effects of the drugs while accounting for circadian variations and handling effects. Conclusions and Implications A systems pharmacology model characterizing the interrelationship between MAP, CO, HR, SV and TPR was obtained in hypertensive and normotensive rats. This extended model can quantify dynamic changes in the CVS and elucidate the MoA for novel compounds, with one site of action, using only HR and MAP measurements. Whether the model can be applied for compounds with a more complex MoA remains to be established.

A complicating factor in the translational pharmacology of sphingosine 1-phosphate agonists is that they exert their pharmacological effect through their respective phosphate metabolites, which are formed by the enzyme sphingosine kinase (S1PHK). In this investigation, we present a semimechanistic pharmacokinetic model for the interconversion of S1PHK substrates and their respective phosphates in rats and humans with the aim of investigating whether characterization of the rate of phosphorylation in blood platelets constitutes a basis for interspecies scaling using fingolimod as a model compound. Data on the time course of fingolimod and fingolimod-phosphate (fingolimod-P) blood concentrations after intravenous and oral administration of fingolimod and/or fingolimod-P in rats and after oral administration of fingolimod in doses of 0.5, 1.25, and 5 mg once daily in healthy volunteers were analyzed in conjunction with data on the ex vivo interconversion and blood-plasma distribution in rat and human blood, respectively. Integrating the data from the ex vivo and in vivo studies enabled simulation of fingolimod and fingolimod-P concentrations in plasma rather than blood, which are more relevant for characterizing drug effects. Large interspecies differences in the rate of phosphorylation between rats and humans were quantified. In human, phosphorylation of fingolimod in the platelets was four times slower compared with rat, whereas the dephosphorylation rates were comparable in both species. This partly explained the 10-12-fold overprediction of fingolimod-P exposure in human when applying a dose-by-factor approach on the developed rat model. Additionally, differences in presystemic phosphorylation should also be taken into account.

The objective of this study was to use in synergy physiologically based and empirical approaches to estimate the drug-specific input parameters of PBPK models of disposition to simulate the plasma concentration-time profile of epiroprim in human. The estimated input parameters were the tissue:plasma partition coefficients (Pt:p) for distribution and the blood clearance (CL) for the in vivo conditions. Epiroprim represents a challenge for such methods, because it shows large interspecies differences in its pharmacokinetic properties. Two approaches were used to predict the human Pt:p values: the tissue composition model (TCM) and the "Arundel approach" based on the volume of distribution at steady state (Vdss) determined in vivo in the rat. CL in human was predicted by (1) conventional allometric scaling of in vivo animal clearances (CAS), (2) physiologically based direct scaling up of in vitro hepatocyte data (DSU), and (3) allometric scaling of animal intrinsic in vivo blood CL normalized by the ratios of animal:human intrinsic clearances determined in vitro with hepatocytes (NAS). The performance of prediction was assessed by comparing separately the above pharmacokinetic parameters (Vdss estimated from the Pt:p values and blood CL) with the corresponding in vivo data obtained from the plasma kinetic profiles. These input parameters were used in PBPK models, and the resulting plasma concentration-time profiles of epiroprim were compared with those observed in rat and human. Previously to the construction of the human PBPK model, a model for the rat was also developed to gain more confidence on the model structure and assumptions. Overall, using the TCM and the NAS for the parameterization of the distribution and clearance, respectively, the PBPK model gave the more accurate predictions of epiroprim's disposition in human. This study represents therefore an attractive approach, which may potentially help the clinical candidate selection.

The influence of the isolation procedure of hepatocytes, extracellular matrix (ECM) configuration and incubation medium supplementation by dexamethasone (DEX) on the cell morphology and on the gene expression of membrane transporters was examined in rat hepatocytes. The mRNA levels were determined using oligonucleotide microarrays, in liver, in suspension and in primary culture in monolayer (CPC), and in collagen gels sandwich (SPC) in absence and presence of DEX (100 and 1000 nM). The results indicated pronounced morphological differences between CPC and SPC in response to DEX demonstrating that the hepatocytes re-formed, as in vivo, multicellular arrays with extensive bile canalicular network only in SPC in presence of DEX. The mRNA levels of membrane transporters were not affected significantly during isolation procedure. However, plating hepatocytes in CPC resulted in a decrease of major basolateral transporters mRNA level whereas mRNA levels of mdr1b and mrp3 were increased (>100-fold). Similar observations were made in SPC in the absence of DEX demonstrating that the ECM configuration alone did not play a critical role in the regulation of membrane transporters. However, adding DEX to the incubation medium in SPC resulted in an up-regulation of mdr2, oatp2 and mrp2 in a concentration-dependent way for the two latter genes, whereas mdr1b and mrp3 expression were maintained to their baseline liver levels. These data suggested therefore that the combination of ECM and DEX supplementation is essential for the formation of the bile canalicular network and is a determinant factor in the regulation of membrane transporters in cultured rat hepatocytes.

Background Canakinumab, a fully human, selective anti-interleukin-1β (IL-1β) monoclonal antibody, has demonstrated rapid and sustained efficacy in systemic juvenile idiopathic arthritis (SJIA) patients, 1 and is approved in >30 countries including USA, EU, Canada, UK and Russia. Given the nature of the disease (pediatric population, rare condition), the phase 3 program only included limited placebo data. In such a context, the safety profile of canakinumab has been characterized via a model-based analysis of the dose-exposure-safety event relationship. Objectives To explore the relationship between canakinumab concentration and the occurrence of AEs of interest and clinically meaningful lab abnormalities. Methods The analysis considered the first portion of the phase III trial where SJIA patients received canakinumab 4mg/kg (300 mg max.) every 4 weeks for a maximum of 8 consecutive doses (n=188). Individual canakinumab concentration time-profiles have been predicted for those patients, by combining the patients9 canakinumab and IL-1β concentration-time data and an established population PK model. This model is a PK-binding model parameterized in terms of clearance of drug and ligand (IL-1β), central and peripheral volume for the drug, interstitial flow rate, ligand production rate and binding affinity which has been developed using all the data available from the entire canakinumab program. The average serum canakinumab concentration (Cavg) was calculated from the concentration time profiles for each patient and dosing interval. In each dosing interval, Cavg were compared between patients with and without the following safety events of interest: AEs of abdominal pain, cough, headache, infection, serious AE infection, pyrexia, and vomiting, as well as lab abnormalities of thrombocytopenia (>3XULN [upper limit normal]), leukopenia (≤0.8 XLLN [lower limit normal]), >20g/L decrease from baseline hemoglobin, neutropenia ( 3XLLN), elevated total cholesterol (≥1.5XULN), triglycerides (≥5.7 mmol/L), and ≥25% decrease from baseline estimated glomerular filtration rate for 2 consecutive visits. Results For all AEs and lab abnormalities, except neutropenia, Cavg was not different for patients who experienced an event compared with those who did not. The mean Cavg for patients with neutropenia was comparable to the 74th percentile of those patients without neutropenia, however this higher Cavg was not found to be associated with more infection. Conclusions A pharmacometric based analysis in SJIA patients treated with a therapeutic dose of canakinumab, did not find, in the range of canakinumab exposure observed, any relationship between average canakinumab exposure and the occurrence of any specific safety events, except for neutropenia. This increased Cavg in patients with neutropenia was not associated with increased infections. These data support the effective and safe use of canakinumab 4mg/kg every 4 week for the treatment of SJIA in patients >2 years old. References Ruperto N. et al. N Engl J Med 2012;367 (25):2396-406. Disclosure of Interest T. Dumortier Shareholder of: Novartis, Employee of: Novartis, N. Ruperto Grant/research support: Gaslini Hospital: Abbott, Astrazeneca, BMS, Centocor Research & Development, Eli Lilly and Company, “Francesco Angelini”, Glaxo Smith & Kline, Italfarmaco, Novartis, Pfizer Inc., Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals Inc., Speakers bureau: Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V., Roche, Wyeth/Pfizer, H. Brunner Consultant for: Novarits, Roche, Astrazeneca, Celgene, Pfizer, Janssen, UCB, GSK, BMS, Speakers bureau: Novartis, O. Luttringer Employee of: Novartis DOI 10.1136/annrheumdis-2014-eular.4016