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Verinurad, a uric acid transporter 1 (URAT1) inhibitor, lowers serum uric acid by promoting its urinary excretion. Co-administration with a xanthine oxidase inhibitor (XOI) to simultaneously reduce uric acid production rate reduces the potential for renal tubular precipitation of uric acid, which can lead to acute kidney injury. The combination is currently in development for chronic kidney disease and heart failure. The aim of this work was to apply and extend a previously developed semi-mechanistic exposure–response model for uric acid kinetics to include between-subject variability to verinurad and its combinations with XOIs, and to provide predictions to support future treatment strategies. The model was developed using data from 12 clinical studies from a total of 434 individuals, including healthy volunteers, patients with hyperuricemia, and renally impaired subjects. The model described the data well, taking into account the impact of various patient characteristics such as renal function, baseline fractional excretion of uric acid, and race. The potencies (EC50s) of verinurad (reducing uric acid reuptake), febuxostat (reducing uric acid production), and oxypurinol (reducing uric acid production) were: 29, 128, and 13,030 ng/mL, respectively. For verinurad, symptomatic hyperuricemic (gout) subjects showed a higher EC50 compared with healthy volunteers (37 ng/mL versus 29 ng/mL); while no significant difference was found for asymptomatic hyperuricemic patients. Simulations based on the uric acid model were performed to assess dose–response of verinurad in combination with XOI, and to investigate the impact of covariates. The simulations demonstrated application of the model to support dose selection for verinurad. Supplementary Information The online version contains supplementary material available at 10.1007/s10928-021-09747-y.

AZD9567 is a potent and selective nonsteroidal oral glucocorticoid receptor modulator. It is developed as an anti-inflammatory drug with improved safety profile compared with steroids like prednisolone. Throughout the clinical development of AZD9567, dose selection and data interpretation require a method for determining doses with the same anti-inflammatory effect as prednisolone. Equipotent doses of AZD9567 and prednisolone were defined by the same average inhibition of TNFα release, a biomarker of anti-inflammatory effect, measured in a lipopolysaccharide-stimulated whole blood ex vivo assay. Based on pharmacokinetic-pharmacodynamic models, TNFα dose-response relationships for AZD9567 and prednisolone were established. A comparison of the dose-response curves enabled estimation of an equipotency relationship. Specifically, 20 mg prednisolone was estimated to be equipotent to 40 mg AZD9567 (95% confidence interval: 29-54 mg). Static concentration-response analyses showed that the relative potencies for inhibition of TNFα release of AZD9567 and prednisolone were well aligned with several other pro-inflammatory cytokines.

Summary Background Glucocorticoids are highly effective and widely used anti-inflammatory drugs, but their use is limited by serious side-effects, including glucocorticoid-induced hyperglycaemia and diabetes. AZD9567 is a non-steroidal, selective glucocorticoid receptor modulator that aims to reduce side-effects. We aimed to assess the safety, tolerability, and pharmacokinetics of AZD9567 in healthy volunteers. Methods Two phase 1 clinical studies were done. First, a randomised, placebo-controlled, single-blind, single-ascending dose study was done in healthy men who received single oral doses of AZD9567 2 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 125 mg, or 155 mg, or prednisolone 60 mg (n=8 per dose group, randomly assigned [6:2] to receive active drug or placebo). Second, a randomised, active-controlled, single-blind, multiple-ascending dose study was done, in which men and women received oral AZD9567 or prednisolone once daily for 5 days. One cohort of volunteers with prediabetes received AZD9567 10 mg (n=7) or prednisolone 20 mg (n=2). All other cohorts comprised healthy volunteers, receiving AZD9567 20 mg, 40 mg, 80 mg, or 125 mg (n=7 per dose group), or prednisolone 5 mg (n=13), 20 mg (n=16), or 40 mg (n=13). Participants and study centre staff were masked to treatment assignment for each cohort, although data were unmasked for safety review between cohorts. The primary outcome of the single-ascending dose study was the safety, tolerability, and pharmacokinetics of single ascending doses of AZD9567; for the multiple-ascending dose study it was the safety and tolerability of AZD9567 following multiple ascending doses. As a secondary outcome, effects on glycaemic control were ascertained with oral glucose tolerance tests (OGTTs) done at baseline and on day 1 of the single-ascending dose study, and at baseline and on day 4 of the multiple-ascending dose study. These trials are registered at ClinicalTrials.gov, NCT02512575 and NCT02760316. Findings In the single-ascending dose study, between Nov 18, 2015, and Sept 26, 2016, 72 healthy white men were enrolled, and all completed the study. In the multiple-ascending dose study, between May 2, 2016, and Sept 13, 2017, 77 predominantly white male volunteers (including nine individuals with prediabetes and eight women) were enrolled and 75 completed the study. All doses of AZD9567 and prednisolone were well tolerated, with no serious adverse events or events suggesting adrenal insufficiency. In the single-ascending dose study, nine adverse events of mild intensity were reported (five with AZD9567 and four with placebo); no adverse event was reported by more than one person. In the multiple-ascending dose study, 44 adverse events of mild or moderate intensity were reported (18 with AZD9567 and 26 with prednisolone). The most common were headache and micturition. Apparent clearance, volume of distribution, and half-life of AZD9567 were consistent across doses and for single versus repeated dosing. In the multiple-ascending dose study, OGTTs showed no significant difference with AZD9567 doses up to 80 mg compared with prednisolone 5 mg in glucose area under the curve from 0 h to 4 h post-OGTT (AUC0–4h) from baseline to day 4; the increase in glucose AUC0–4h from baseline to day 4 was significantly lower with all AZD9567 doses versus prednisolone 20 mg (AZD9567 20 mg p Interpretation AZD9567 appears to be safe and well tolerated in healthy, predominantly white male volunteers and shows promising initial evidence for improved post-prandial glucose control. Studies of longer duration, with a greater proportion of women and other ethnic groups, and in patients requiring anti-inflammatory treatment are needed to characterise the clinical efficacy and safety profile of AZD9567. Funding AstraZeneca.

Home‐based measures of lung function, inflammation, symptoms, and medication use are frequently collected in respiratory clinical trials. However, new statistical approaches are needed to make better use of the information contained in these data‐rich variables. In this work, we use data from two phase III asthma clinical trials demonstrating the benefit of benralizumab treatment to develop a novel longitudinal mixed effects model of peak expiratory flow (PEF), a lung function measure easily captured at home using a hand‐held device. The model is based on an extension of the mixed effects modeling framework to incorporate stochastic differential equations and allows for quantification of several statistical properties of a patient's PEF data: the longitudinal trend, long‐term fluctuations, and day‐to‐day variability. These properties are compared between treatment groups and related to a patient's exacerbation risk using a repeated time‐to‐event model. The mixed effects model adequately described the observed data from the two clinical trials, and model parameters were accurately estimated. Benralizumab treatment was shown to improve a patient's average PEF level and reduce long‐term fluctuations. Both of these effects were shown to be associated with a lower exacerbation risk. The day‐to‐day variability was neither significantly affected by treatment nor associated with exacerbation risk. Our work shows the potential of a stochastic model‐based analysis of home‐based lung function measures to support better estimation and understanding of treatment effects and disease stability. The proposed analysis can serve as a complement to descriptive statistics of home‐based measures in the reporting of respiratory clinical trials.

Febuxostat is a xanthine oxidase inhibitor indicated for gout and hyperuricemia. This work investigates potential clinically relevant covariates for febuxostat pharmacokinetics with a special focus on Asian race and bodyweight. Febuxostat plasma concentrations from 141 male subjects were obtained from two phase II studies in patients with hyperuricemia/gout (NCT02246673, NCT02317861) and one study in healthy volunteers (NCT01883167). Subjects were administered febuxostat oral doses from 10 to 80 mg. The pharmacokinetics of febuxostat was analyzed using non-linear mixed-effects modeling as implemented in NONMEM 7.3.0. The dataset consisted of racially diverse subjects, 40% being Japanese, 10% of unknown Asian origin, 39% Caucasian, and 10% Black. Most subjects (n = 92, 63%) had normal creatinine clearance (90 mL/min), while 52 subjects (36%) had mild renal impairment (creatinine clearance > 60 to

AZD9898 is an oral small molecule inhibitor of LTC4 synthase (LTC4s) developed for the treatment of asthma driven by cysteinyl leukotrienes (CysLTs). It is expected to inhibit the downstream production of leukotrienes LTC4, LTD4 and LTE4, which are important mediators of airway inflammation and bronchoconstriction. The leukotriene LTE4 is a stable metabolite, measurable in urine and has been used as a proof of mechanism biomarker in several clinical studies. We planned to evaluate AZD9898 in an integrated, multi-part, randomized, single-blind, placebo controlled, first-in-human (FIH), Phase I (Ph I) study. In Part 1, single ascending dosing in four cohorts (3 mg, 9 mg, 15 mg and 45 mg) versus placebo was evaluated in healthy subjects to assess safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. Overall, single doses of AZD9898 were well tolerated in Part 1 and no safety concerns were raised. Measurement of urinary LTE4 (uLTE4) normalised to creatinine was included as a PD marker to evaluate inhibition of LTC4s. The PD data showed that, at the highest dose tested (45 mg), AZD9898 reduced uLTE4 levels for 14 hours post dose with a maximum reduction at 6 hours post dose. The 45 mg dose was the highest dose possible due to exposure limitation margins. The required magnitude and duration of PD effect at a dose of 45 mg was lower than expected. Furthermore, modelling and simulation of data did not support that the required level of effect on uLTE4 inhibition could be reached even with twice daily dosing. Therefore, the decision was made to stop the multi-part Ph I study after only Part 1 and not progress into multiple dosing in healthy subjects or single dosing in asthmatic patients. These data provide an example of how early evaluation of a PD biomarker can be utilized for decision making in early clinical development.

Background: AZD9567 is a novel oral selective glucocorticoid receptor modulator (SGRM) developed to have an improved safety profile versus prednisolone while maintaining efficacy. Objectives: To show clinical evidence of safety differentiation for AZD9567 compared to prednisolone with respect to glucose homeostasis and to investigate the underlying effects on the glucose metabolism in human cell systems in vitro. Methods: In a dose escalation study (NCT02760316), healthy volunteers were randomized to a 5-day once-daily treatment with AZD9567 (20, 40, 80, 125 mg) or prednisolone (5, 20, 40 mg). We monitored the anti-inflammatory effect by TNFα release from ex vivo LPS stimulated whole blood and modelled the relationship with pharmacokinetics (PKPD). Plasma glucose was measured (AUC0–4h) during an oral glucose tolerance test (OGTT) before and after four days of treatment. We also studied the effects of AZD9567 and prednisolone on mRNA expression of key gluconeogenesis enzymes (tyrosine aminotransferease (TAT), phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase)) in primary human hepatocytes as well as on insulin secretion in human islets microtissues. Results: The inhibition of TNFα release increased with the plasma concentrations of AZD9567. PKPD modeling of TNFα inhibition data showed that 40 mg AZD9567 results in an anti-inflammatory activity similar to that predicted for 20 mg prednisolone. A significantly smaller increase of the glucose AUC was observed following treatment with 20 to 125 mg AZD9567 compared to 20 mg prednisolone (p We found significant induction of TAT, PEPCK, and G6Pase mRNA in hepatocytes after prednisolone treatment. In contrast, AZD9567 did not change the expression of these enzymes and inhibited the effect of prednisolone when co-administered. Furthermore, AZD9567 showed less suppression of insulin secretion in human islets microtissues compared to prednisolone at concentrations with comparable inhibition of TNFα release, resulting in a 12-fold better therapeutic ratio. Conclusions: In healthy individuals, AZD9567 showed significantly reduced effect on glucose homeostasis versus prednisolone at doses with similar anti-inflammatory activity. Thus, AZD9567 shows potential as an anti-inflammatory treatment with an improved metabolic safety profile compared to prednisolone. Disclosure of Interest: T. Hegelund Myrback Employee of: AstraZeneca, S. Prothon Employee of: AstraZeneca, M. Dearman Employee of: AstraZeneca, G. Edenro Employee of: AstraZeneca (former emplyee), J. Leander Employee of: AstraZeneca, M. Hashemi Employee of: AstraZeneca, G. de Miquel Employee of: AstraZeneca (former emplyee), R. Fuhr Employee of: Parexel International GmbH, T. Kornicke Employee of: Parexel International GmbH, Z. Tahib Employee of: AstraZeneca, E.-M. Andersson Employee of: AstraZeneca, P. Svanberg Employee of: AstraZeneca, K. Edman Employee of: AstraZeneca, R. Hendrickx Employee of: AstraZeneca, C. Keen Employee of: AstraZeneca, M. Kraan Employee of: AstraZeneca (former emplyee), K. Johansson Employee of: AstraZeneca (former emplyee), U. Eriksson Employee of: AstraZeneca, B. Carlsson Employee of: AstraZeneca, O. Vaarala Employee of: AstraZeneca

Background: Glucocorticoids (GC) are highly effective in the treatment of inflammatory diseases but chronic treatment is limited by severe adverse effects including hyperglycemia and bone re-modelling. AZD9567 is a novel, orally delivered, non-steroidal Selective Glucocorticoid Receptor Modulator (SGRM) with the potential to demonstrate an improved therapeutic ratio (TR) compared to steroidal GC such as prednisolone. Objectives: To investigate the effects of AZD9567 and prednisolone on biomarkers of inflammation, glucose metabolism and bone re-modelling in pre-clinical models. To confirm the inhibition of inflammatory biomarker production and to evaluate safety and pharmacokinetics (PK) of AZD9567 in a first clinical study. Methods: The effects on biomarkers of gluconeogenesis (tyrosine aminotransferase, TAT mRNA), bone re-modelling (osteoprotegerin, OPG mRNA) and anti-inflammatory activity (TNFα) were evaluated in vitro using human hepatocytes, an osteoblast cell line and whole blood, respectively. In vivo, effects on plasma insulin and osteocalcin levels were compared with inhibition of whole blood TNFα release in rats. Efficacy was evaluated in an adjuvant-induced rat arthritis model. In a human single ascending dose study the effect of AZD9567 on TNFα inhibition was investigated, together with assessment of safety profile and PK. Results: Potent in vitro anti-inflammatory activity (IC50,u6.2 nM, 7-fold more potent than prednisolone) was observed, whilst no effect on TAT mRNA expression in human hepatocytes was detected for AZD9567 (prednisolone EC5092 nM). This resulted in a substantially better TR compared to prednisolone. Furthermore, AZD9567 showed a 7-fold superior TR compared to prednisolone based on OPG mRNA expression in human osteoblasts. An improved profile for AZD9567 was also demonstrated in vivo in the rat (TR of 7.5 for osteocalcin and 3.6 for insulin). Efficacy was demonstrated in the rat arthritis model where an inhibition of joint inflammation was observed (ED500.1 mg/kg). In human, AZD9567 was safe and well tolerated after single doses (2–155 mg). The PK properties showed a fast absorption with a median tmax of 0.50 to 1.25 hour and a dose-dependent increase in exposure, with a mean terminal half-life of 3.9 to 6.4 hours, suitable for a once daily dosing regimen. TNFa release was inhibited in a concentration-dependent manner (IC50,u5.2 nM), consistent with pre-clinical findings. Conclusions: In pre-clinical models, AZD9567 demonstrated anti-inflammatory activity with a reduced effect on gluconeogenesis and biomarkers of bone re-modelling compared to prednisolone. Single oral dosing of AZD9567 was well tolerated and showed good PK properties in healthy subjects. These results support that AZD9567 has the potential to improve the treatment of several inflammatory diseases with a better TR compared to prednisolone. AZD9567 is currently in clinical evaluation in rheumatoid arthritis. Disclosure of Interest: R. Hendrickx Employee of: AstraZeneca, T. Hegelund-Myrback Employee of: AstraZeneca, M. Dearman Employee of: AstraZeneca, S. Prothon Employee of: AstraZeneca, G. Edenro Employee of: AstraZeneca (former employee), J. Leander Employee of: AstraZeneca, R. Fuhr Employee of: Parexel International GmbH, T. Kornicke Employee of: Parexel International GmbH, P. Svanberg Employee of: AstraZeneca, A. Berggren Employee of: AstraZeneca, T. Drmota Employee of: AstraZeneca (former employee), C. Keen Employee of: AstraZeneca, U. Eriksson Employee of: AstraZeneca

Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague–Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague–Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration–response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the “degree of disease” can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2571–2584, 2014