A drug-drug interaction study and physiologically based pharmacokinetic modelling to assess the effect of an oral 5-lipoxygenase activating protein inhibitor on the pharmacokinetics of oral midazolam.

AIMS: Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre-clinical profiling suggests that time-dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co-administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time-/dose-dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity. METHODS: Open-label, fixed-sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2 mg on days 1 and 7 and single oral doses of Atuliflapon (125 mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug-drug interaction. RESULTS: Mean midazolam values of maximum plasma concentration (Cmax) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co-administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in Cmax of midazolam following its co-administrations with two predicted therapeutically relevant doses of Atuliflapon. CONCLUSIONS: Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs.

The myeloperoxidase inhibitor mitiperstat (AZD4831) does not prolong the QT interval at expected therapeutic doses.

Mitiperstat is a myeloperoxidase inhibitor in clinical development for treatment of patients with heart failure and preserved or mildly reduced ejection fraction, non-alcoholic steatohepatits and chronic obstructive pulmonary disease. We aimed to assess the risk of QT-interval prolongation with mitiperstat using concentration-QT (C-QT) modeling. Healthy male volunteers were randomized to receive single oral doses of mitiperstat 5, 15, 45, 135, or 405 mg (n = 6 per dose) or matching placebo (n = 10) in a phase 1 study (NCT02712372). Time-matched pharmacokinetic and digital electrocardiogram data were collected at the baseline (pre-dose) and at 11 time-points up to 48 h post-dose. C-QT analysis was prespecified as an exploratory objective. The prespecified linear mixed effects model used baseline-adjusted QT interval corrected for the heart rate by Fridericia's formula (ΔQTcF) as a dependent variable and plasma mitiperstat concentration as an independent variable. Initial exploratory analyses indicated that all model assumptions were met (no effect on heart rate; appropriate use of QTcF; no hysteresis; linear concentration-response relationship). Model-predicted mean baseline-corrected and placebo-adjusted ΔΔQTcF was +0.73 ms (90% confidence interval [CI]: -1.73, +3.19) at the highest anticipated clinical exposure (0.093 µmol/L) during treatment with mitiperstat 5 mg once daily. The upper 90% CI was below the established threshold of regulatory concern. The 16-fold margin to the highest observed exposure was high enough to mean that a positive control was not needed. Mitiperstat is not associated with risk of QT-interval prolongation at expected therapeutic concentrations.

Rationale and design of ENDEAVOR: A sequential phase 2b-3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction.

AIMS: Mitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity-induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b-3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF. METHODS: In phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6-min walk distance (6MWD) of 30-400 m with a <50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ-TSS. The sample size provides 85% power to detect placebo-adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ-TSS at overall two-sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo. CONCLUSION: ENDEAVOR is the first phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF.

Mass Balance and Absorption, Distribution, Metabolism, and Excretion Properties of Balcinrenone following Oral Administration in Combination with Intravenous Microtracer in Healthy Subjects.

An absorption, distribution, metabolism, and excretion study was performed to determine the basic pharmacokinetic parameters, mass balance, and metabolite profiles of balcinrenone, a mineralocorticoid receptor modulator, in humans. This open-label, single-center, nonrandomized study had a two-period design. In period 1, eight healthy male subjects were dosed with a microtracer intravenous infusion of [14C]balcinrenone shortly after receiving an oral dose of unlabeled balcinrenone in a capsule. Following a 7-day washout, the same group of subjects subsequently received an oral dose of [14C]balcinrenone as a suspension in period 2. Clearance and absolute bioavailability of balcinrenone were determined to be 14.2 l/h and 52%, respectively. Renal clearance was determined to be 5.4 l/h (>fu • glomerular filtration rate), indicating elimination via active tubular secretion, which was potentially mediated by P-glycoprotein 1 and/or organic anion transporter 3, according to in vitro transporter data. In total, 94.1% of the oral dose was recovered: 45.2% in the urine and 48.9% in the feces. Balcinrenone was primarily metabolized via oxidation, and in vitro data suggest that cytochrome P450 3A4 was the main enzyme responsible. Intact [14C]balcinrenone accounted for 55% of drug-related material in the plasma; four metabolites were identified, each representing <6% of the total plasma radioactivity. In conclusion, this two-period study has determined the basic pharmacokinetic parameters of balcinrenone in humans, including absolute bioavailability and disposition. No metabolites warranted further evaluation on account of their low representation, and any contribution to the pharmacodynamic response or potential drug-drug interactions was deemed negligible. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the pharmacokinetics, disposition, and metabolism of balcinrenone following oral and microtracer intravenous administration in humans. In vitro phenotyping and transporter data granted mechanistic insights into the absorption, distribution, metabolism, and excretion properties of balcinrenone. This knowledge will guide future nonclinical and clinical studies evaluating drug-drug interactions, organ dysfunction, and safety of metabolites.

Design of FLAIR: a Phase 2b Study of the 5-Lipoxygenase Activating Protein Inhibitor AZD5718 in Patients With Proteinuric CKD.

INTRODUCTION: Patients with chronic kidney disease (CKD) remain at risk for kidney and cardiovascular events resulting from residual albuminuria, despite available treatments. Leukotrienes are proinflammatory and vasoconstrictive lipid mediators implicated in the etiology of chronic inflammatory diseases. AZD5718 is a potent, selective, and reversible 5-lipoxygenase activating protein (FLAP) inhibitor that suppresses leukotriene production. METHODS: FLAIR (FLAP Inhibition in Renal disease) is an ongoing phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of AZD5718 in patients with proteinuric CKD with or without type 2 diabetes. Participants receive AZD5718 at 3 different doses or placebo once daily for 12 weeks, followed by an 8-week extension in which they also receive dapagliflozin (10 mg/d) as anticipated future standard of care. The planned sample size is 632 participants, providing 91% power to detect 30% reduction in urinary albumin-to-creatinine ratio (UACR) between the maximum dose of AZD5718 and placebo. The dose-response effect of AZD5718 on UACR after the dapagliflozin extension is the primary efficacy objective. Key secondary objectives are the dose-response effect of AZD5718 plus current standard of care on UACR and acute effects of treatment on the estimated glomerular filtration rate. Safety, tolerability, AZD5718 pharmacokinetics, and analyses of biomarkers that may predict or reflect response to AZD5718 are additional objectives. CONCLUSION: FLAIR will provide data on the effects of 5-lipoxygenase pathway inhibition in patients with proteinuric CKD with or without type 2 diabetes, and will form the basis for future clinical trials (ClinicalTrials.gov: NCT04492722).

Pharmacokinetics, Pharmacodynamics, and Tolerability of AZD5718, an Oral 5-Lipoxygenase-Activating Protein (FLAP) Inhibitor, in Healthy Japanese Male Subjects.

BACKGROUND AND OBJECTIVE: AZD5718, a 5-lipoxygenase-activating protein (FLAP) inhibitor, is in clinical development for treatment of coronary artery disease (CAD) and chronic kidney disease (CKD). This study evaluated AZD5718 pharmacokinetics, pharmacodynamics, and tolerability in healthy male Japanese subjects. METHODS: Four cohorts of eight Japanese subjects were randomized to receive oral doses of AZD5718 (60, 180, 360, and 600 mg) or matching placebo administered as a single dose on Day 1 and as once-daily doses from Day 3 to Day 10 in fasted conditions. Pharmacokinetic, pharmacodynamic, and safety data were collected. RESULTS: The pharmacokinetics characteristics of AZD5718 in Japanese male subjects were similar to those reported in a previous study, and the pharmacokinetics were characterized as rapid absorption with median time to reach maximum concentration (Tmax) of 1-2 h Creatine-normalized urine maximum concentration (Cmax) with mean half-lives ranging from 8 to 21 h, and supra-proportional increase in exposure over the 60-600 mg dose range evaluated. Also, an increase in steady-state area under the concentration-time curve (AUC) compared to the first dose was observed. After both single and multiple doses of AZD5718, a clear dose/concentration-effect relationship was shown for urinary leukotriene E4 (LTE4) versus AZD5718 exposure with > 80 % inhibition at plasma concentrations in the lower nM range. No clinically relevant safety and tolerability findings were observed. CONCLUSIONS: The observed pharmacokinetics and pharmacodynamics were similar to reported data for non-Japanese healthy subjects, which support further evaluation of AZD5718 at similar doses/exposures in Japanese and non-Japanese subjects for future evaluation in patients with CAD and CKD.

Early Clinical Experience With AZD4831, A Novel Myeloperoxidase Inhibitor, Developed for Patients With Heart Failure With Preserved Ejection Fraction.

We evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics of AZD4831, a novel oral myeloperoxidase (MPO) inhibitor, in a randomized, single-blind, placebo-controlled study, following once-daily multiple ascending dosing to steady-state in healthy subjects. Target engagement was measured as specific MPO activity in plasma following ex vivo zymosan stimulation of whole blood. Except for generalized maculopapular rash in 4 of 13 subjects receiving the 2 highest doses, 15 and 45 mg AZD4831, no clinically relevant safety and tolerability findings were observed. AZD4831 was rapidly absorbed and plasma concentrations declined slowly with an elimination half-life of ~ 60 hours. A dose/concentration-effect relationship between MPO inhibition vs. AZD4831 exposure was established with > 50% MPO inhibition in plasma at concentrations in the low nanomolar range. Steady-state levels were achieved within 10 days. Taken together, the PK profile, the sustained dose/concentration-dependent MPO inhibition, and available clinical data support further clinical development of AZD4831 in patients with heart failure with preserved ejection fraction.

Safety, Tolerability, and Pharmacokinetics of the Mineralocorticoid Receptor Modulator AZD9977 in Healthy Men: A Phase I Multiple Ascending Dose Study.

Excessive activation of the mineralocorticoid receptor (MR) underlies the pathophysiology of heart failure and chronic kidney disease. Hyperkalemia risk limits the therapeutic use of conventional MR antagonists. AZD9977 is a nonsteroidal, selective MR modulator that may protect nonepithelial tissues without disturbing electrolyte balance. This phase I study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of AZD9977 in healthy volunteers. Twenty-seven male participants aged 23-45 years were randomized 3:1 to receive oral AZD9977 or placebo for 8 days (with twice-daily dosing on days 2-7), in dose cohorts of 50, 150, and 300 mg (AZD9977, n = 6 per cohort; placebo, n = 3 per cohort). Adverse events occurred in 4 of 18 participants receiving AZD9977 (22.2%) and 6 of 9 receiving placebo (66.7%), all of mild or moderate severity; none were serious or led to withdrawal. AZD9977 was rapidly absorbed, with median time of maximum concentration of 0.50-0.84 hours across dose groups. Area under the curve and maximum concentration were approximately dose proportional but elimination and accumulation terminal half-life increased with dose. Steady-state was reached after 3-4 days, with dose-dependent accumulation of 1.2-1.7-fold. Renal clearance was 5.9-6.5 L/hour and 24-37% of AZD9977 was excreted in the urine. Serum aldosterone levels increased dose dependently from days -1 to 7 in participants receiving AZD9977, but serum potassium levels and urinary electrolyte excretion were unchanged. AZD9977 was generally well-tolerated with no safety concerns. Exploratory outcomes suggested reduced hyperkalemia risk compared with MR antagonists. These findings support further clinical development of AZD9977.

Phase 1 Pharmacokinetic Study of AZD5718 in Healthy Volunteers: Effects of Coadministration With Rosuvastatin, Formulation and Food on Oral Bioavailability.

AZD5718 is a first-in-class small-molecule anti-inflammatory drug with the potential to reduce the residual risk of cardiovascular events after myocardial infarction in patients receiving lipid-lowering statin therapy. Leukotrienes are potent proinflammatory and vasoactive mediators synthesized in leukocytes via 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP). AZD5718 is a FLAP inhibitor that dose-dependently reduced leukotriene biosynthesis in a first-in-human study. We enrolled 12 healthy men in a randomized, open-label, crossover, single-dose phase 1 pharmacokinetic study of AZD5718 to investigate a potential drug-drug interaction with rosuvastatin, and the effects of formulation and food intake (ClinicalTrials.gov identifier: NCT02963116). Rosuvastatin (10 mg) were absorbed more rapidly when coadministered with AZD5718 (200 mg), probably owing to weak inhibition of hepatic statin uptake, but relative bioavailability was unaffected (geometric least-squares mean ratio [GMR], 100%; 90% confidence interval [CI], 86%-116%). AZD5718 pharmacokinetics were unaffected by coadministration of rosuvastatin. AZD5718 (200 mg) was absorbed less rapidly when formulated as tablets than oral suspension, with reduced relative bioavailability (GMR, 72%; 90%CI, 64%-80%). AZD5718 absorption was slower when 200-mg tablets were taken after a high-fat breakfast than after fasting, but relative bioavailability was unaffected (GMR, 96%; 90%CI, 87%-106%). In post hoc pharmacodynamic simulations, plasma leukotriene B4 levels were inhibited by >90% throughout the day following once-daily AZD5718, regardless of formulation or administration with food. AZD5718 was well tolerated, with no severe or serious adverse events. These data supported the design of a phase 2a efficacy study of AZD5718 in patients with coronary artery disease.

Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease.

5-Lipoxygenase activating protein (FLAP) inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of proinflammatory and vasoactive leukotrienes. As such, they are hypothesized to have therapeutic benefit for the treatment of diseases that involve chronic inflammation including coronary artery disease. Herein, we disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718 (12). Multiparameter optimization included securing adequate potency in human whole blood, navigation away from Ames mutagenic amine fragments while balancing metabolic stability and PK properties allowing for clinically relevant exposures after oral dosing. The superior safety profile of AZD5718 compared to earlier frontrunner compounds allowed us to perform a phase 1 clinical study in which AZD5718 demonstrated a dose dependent and greater than 90% suppression of leukotriene production over 24 h. Currently, AZD5718 is evaluated in a phase 2a study for treatment of coronary artery disease.

Safety, tolerability, pharmacokinetics and effect on serum uric acid of the myeloperoxidase inhibitor AZD4831 in a randomized, placebo-controlled, phase I study in healthy volunteers.

AIMS: Myeloperoxidase activity can contribute to impaired vascular endothelial function and fibrosis in chronic inflammation-related cardiovascular disease. Here, we investigated the safety, tolerability and pharmacokinetics of the myeloperoxidase inhibitor, AZD4831. METHODS: In this randomized, single-blind, placebo-controlled, phase I, first-in-human study, healthy men in five sequential cohorts were randomized 3:1 to receive a single oral dose of AZD4831 (5, 15, 45, 135 or 405 mg) or placebo, after overnight fasting. After at least 7 days' washout, one cohort additionally received AZD4831 45 mg after a high-calorie meal. RESULTS: Forty men participated in the study (eight per cohort: AZD4831, n = 6; placebo, n = 2). AZD4831 distributed rapidly into plasma, with a half-life of 38.2-50.0 hours. The area under the plasma concentration-time curve (AUC) increased proportionally with dose (AUC0-∝ slope estimate 1.060; 95% confidence interval [CI] 0.9943, 1.127). Increases in maximum plasma concentration were slightly more than dose proportional (slope estimate 1.201; 95% CI 1.071, 1.332). Food intake reduced AZD4831 absorption rate but did not substantially affect overall exposure or plasma half-life (n = 4). Serum uric acid concentrations decreased by 71.77 (95% CI 29.15, 114.39) and 84.42 (58.90, 109.94) µmol L-1 with AZD4831 135 mg and 405 mg, respectively. Maculopapular rash (moderate intensity) occurred in 4/30 participants receiving AZD4831 (13.3%). No other safety concerns were identified. CONCLUSIONS: AZD4831 was generally well tolerated, rapidly absorbed, had a long plasma half-life and lowered uric acid concentrations after single oral doses in healthy men. These findings support the further clinical development of AZD4831.

Exploring the insulin secretory properties of the PGD2-GPR44/DP2 axis in vitro and in a randomized phase-1 trial of type 2 diabetes patients.

AIMS/HYPOTHESIS: GPR44 (DP2, PTGDR2, CRTh2) is the receptor for the pro-inflammatory mediator prostaglandin D2 (PGD2) and it is enriched in human islets. In rodent islets, PGD2 is produced in response to glucose, suggesting that the PGD2-GPR44/DP2 axis may play a role in human islet function during hyperglycemia. Consequently, the aim of this work was to elucidate the insulinotropic role of GPR44 antagonism in vitro in human beta-cells and in type 2 diabetes (T2DM) patients. METHODS: We determined the drive on PGD2 secretion by glucose and IL-1beta, as well as, the impact on insulin secretion by pharmacological GPR44/DP2 antagonism (AZD1981) in human islets and beta-cells in vitro. To test if metabolic control would be improved by antagonizing a hyperglycemia-driven increased PGD2 tone, we performed a proof-of-mechanism study in 20 T2DM patients (average 54 years, HbA1c 9.4%, BMI 31.6 kg/m2). The randomized, double-blind, placebo-controlled cross-over study consisted of two three-day treatment periods (AZD1981 or placebo) separated by a three-day wash-out period. Mixed meal tolerance test (MMTT) and intravenous graded glucose infusion (GGI) was performed at start and end of each treatment period. Assessment of AZD1981 pharmacokinetics, glucose, insulin, C-peptide, glucagon, GLP-1, and PGD2 pathway biomarkers were performed. RESULTS: We found (1) that PGD2 is produced in human islet in response to high glucose or IL-1beta, but likely by stellate cells rather than endocrine cells; (2) that PGD2 suppresses both glucose and GLP-1 induced insulin secretion in vitro; and (3) that the GPR44/DP2 antagonist (AZD1981) in human beta-cells normalizes insulin secretion. However, AZD1981 had no impact on neither glucose nor incretin dependent insulin secretion in humans (GGI AUC C-peptide 1-2h and MMTT AUC Glucose 0-4h LS mean ratios vs placebo of 0.94 (80% CI of 0.90-0.98, p = 0.12) and 0.99 (90% CI of 0.94-1.05, p = 0.45), despite reaching the expected antagonist exposure. CONCLUSION/INTERPRETATION: Pharmacological inhibition of the PGD2-GPR44/DP2 axis has no major impact on the modulation of acute insulin secretion in T2DM patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02367066.

Physiologically Based Pharmacokinetic Model of Itraconazole and Two of Its Metabolites to Improve the Predictions and the Mechanistic Understanding of CYP3A4 Drug-Drug Interactions.

Physiologically based pharmacokinetic (PBPK) modeling for itraconazole using a bottom-up approach is challenging, not only due to complex saturable pharmacokinetics (PK) and the presence of three metabolites exhibiting CYP3A4 inhibition, but also because of discrepancies in reported in vitro data. The overall objective of this study is to provide a comprehensive mechanistic PBPK model for itraconazole in order to increase the confidence in its drug-drug interaction (DDI) predictions. To achieve this, key in vitro and in vivo data for itraconazole and its major metabolites were generated. These data were crucial to developing a novel bottom-up PBPK model in Simcyp (Simcyp Ltd., Certara, Sheffield, United Kingdom) for itraconazole and two of its major metabolites: hydroxy-itraconazole (OH-ITZ) and keto-itraconazole (keto-ITZ). Performance of the model was validated using prespecified acceptance criteria against different dosing regimens, formulations for 29 PK, and DDI studies with midazolam and other CYP3A4 substrates. The main outcome is an accurate PBPK model that simultaneously predicts the PK profiles of itraconazole, OH-ITZ, and keto-ITZ. In addition, itraconazole DDIs with midazolam and other CYP3A4 substrates were successfully predicted within a 2-fold error. Prediction precision and bias of DDI expressed as geometric mean fold error were for the area under the concentration-time curve and peak concentration, 1.06 and 0.96, respectively. To conclude, in this paper a comprehensive data set for itraconazole and its metabolites is provided that enables bottom-up mechanism-based PBPK modeling. The presented model is applicable for studying the contribution from the metabolites and allows improved assessments of itraconazole DDI.

Initial Clinical Experience with AZD5718, a Novel Once Daily Oral 5-Lipoxygenase Activating Protein Inhibitor.

We evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD5718, a novel 5-lipooxygenase activating protein (FLAP) inhibitor, in a randomized, single-blind, placebo-controlled, first-in-human (FIH) study consisting of single and multiple ascending dosing (SAD and MAD) for 10 days in healthy subjects. Target engagement was measured by ex vivo calcium ionophore stimulated leukotriene B (LTB4 ) production in whole blood and endogenous leukotriene E (LTE4 ) in urine. No clinically relevant safety and tolerability findings were observed. The AZD5718 was rapidly absorbed and plasma concentrations declined biphasically with a mean terminal half-life of 10-12 h. Steady-state levels were achieved after ∼3 days. After both SADs and MADs, a dose/concentration-effect relationship between both LTB4 and LTE4 vs. AZD5718 exposure was observed with concentration of half inhibition (IC50 ) values in the lower nM range. Based on obtained result, AZD5718 is considered as a suitable drug candidate for future evaluation in patients with coronary artery disease (CAD).

Clinical safety, tolerability, pharmacokinetics and effects on urinary electrolyte excretion of AZD9977, a novel, selective mineralocorticoid receptor modulator.

AIMS: AZD9977 is the first mineralocorticoid receptor modulator in clinical development exerting similar organ protection as eplerenone with minimal urinary electrolyte effects in preclinical studies. The aim was to perform the initial clinical assessment of AZD9977. METHODS: A first-in-human trial explored doses from 5 to 1200 mg. To study effects on urinary electrolyte excretion an additional randomized placebo controlled cross-over four-period clinical trial was performed. Twenty-three healthy volunteers were administered fludrocortisone alone or in combination with AZD9977, eplerenone or both. AZD9977/eplerenone combination was given to assess if AZD9977 can attenuate eplerenone induced natriuresis. RESULTS: AZD9977 at doses from 5 to 1200 mg was safe and well tolerated and pharmacokinetics were compatible with further development. AZD9977 exhibited similar effects on urinary ln [Na+ ]/[K+ ] as eplerenone when using fludrocortisone as mineralocorticoid receptor agonist, and the combination had an additive effect on ln [Na+ K+ ]. CONCLUSIONS: The results in man contradict the results in rodent models driven by aldosterone, in which AZD9977 has minimal electrolyte effects. Future clinical studies with AZD9977 should be performed in presence of endogenous or exogenous aldosterone to assess potential benefit of AZD9977 in patients.

Tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator AZD1656, after single ascending doses in healthy subjects during euglycemic clamp.

OBJECTIVES: AZD1656 is a novel glucokinase activator with a postulated dual mechanism of action by activating glucokinase in both the pancreas and the liver, and with the potential to deliver effective glucose-lowering in Type 2 diabetes mellitus. Here, we present the tolerability, pharmacokinetics and pharmacodynamics of AZD1656 in two single-blind, randomized, placebo-controlled studies, one with Western and the other with Japanese healthy adult male subjects. METHODS: Both studies evaluated oral single ascending doses of AZD1656 of up to 180 mg, administered during euglycemic clamp conditions to explore a wide dose range without risking hypoglycemia. Safety, pharmacokinetics and effects on serum insulin and glucose infusion rate were assessed. A population pharmacokinetics analysis was also conducted. RESULTS: AZD1656 was well tolerated in single doses up to 180 mg in both populations. AZD1656 was rapidly absorbed, and a dose-proportional increase in total exposure was observed for AZD1656 and the equipotent metabolite, AZD5658. Taking differences in body weight into account, there were no differences in pharmacokinetic parameters between Western and Japanese subjects. A dose-dependent blood glucose lowering effect was indirectly demonstrated by the increased glucose infusion rate required to maintain euglycemia, which was of similar magnitude in both populations. Dose-dependent increases in insulin secretion were also observed. CONCLUSIONS: No safety concerns were raised. AZD1656 displayed uncomplicated pharmacokinetics and dose-dependent pharmacodynamics effects were observed. The results suggest no ethnic differences in AZD1656 tolerability, pharmacokinetics or pharmacodynamics.

The glucokinase activator AZD6370 decreases fasting and postprandial glucose in type 2 diabetes mellitus patients with effects influenced by dosing regimen and food.

AIMS: To investigate the pharmacodynamics, pharmacokinetics and safety of the glucokinase activator AZD6370 after 1 day of administration under fed and fasted conditions in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a two-part study. In Part A, patients received a single oral dose of AZD6370 (20, 60 or 180 mg) or placebo in the fasted or fed states (both n=8). In Part B, patients (n=8) received placebo and a total dose of AZD6370 180 mg given in one, two or four divided doses. Plasma glucose, insulin and C-peptide changes versus placebo were assessed. RESULTS: AZD6370 provided dose-dependent reductions in plasma glucose of up to 30% versus placebo in both fasted and fed patients (p<0.001 at 60 and 180 mg doses). Insulin secretion increased with dose, but absolute increases were relatively small in the fasted versus fed state (0-4 h). Dosing AZD6370 twice or four-times over 1 day gave a smoother 24-h glucose profile than single-dose. AZD6370 was rapidly absorbed. Pharmacokinetics of AZD6370 were dose-independent and unaffected by food. AZD6370 was generally well tolerated. CONCLUSIONS: AZD6370 produced dose-dependent glucose reductions and increased glucose-stimulated insulin secretion in patients with T2DM.

Glucokinase activators AZD6370 and AZD1656 do not affect the central counterregulatory response to hypoglycemia in healthy males.

CONTEXT: Glucokinase is expressed in the hypothalamus, but effects of glucokinase activators (GKAs) on counterregulatory responses to hypoglycemia are unknown. OBJECTIVE: Two separate studies assessed the counterregulatory hormone responses to hypoglycemia induced by the GKAs, AZD6370 and AZD1656, compared with insulin infusion. DESIGN AND SETTING: Both studies were randomized, open, two-way crossover studies, conducted in separate clinical research centers. PARTICIPANTS: Both studies involved 12 healthy adult male volunteers. INTERVENTIONS: Each subject received two treatments in randomized order, separated by a washout. In the AZD6370 study, overnight-fasted subjects received either a single oral AZD6370 dose (300 mg) or insulin infusion (0.8 mU/kg · min). In the AZD1656 study, overnight-fasted subjects received either a single oral dose of AZD1656 (80 mg) plus supporting insulin (1 mU/kg · min) or insulin alone (1 mU/kg · min). Insulin was added to support AZD1656 because AZD1656 alone did not produce the desired hypoglycemia. Plasma glucose was lowered during a stepwise hypoglycemic clamp with a glycemic nadir of 2.7 mmol/liter for 30 min. MAIN OUTCOME MEASURES: Epinephrine, norepinephrine, GH, cortisol, and glucagon plasma levels were assessed. RESULTS: No safety issues were raised. AZD6370 and AZD1656 had no effect on counterregulatory responses for norepinephrine, GH, or cortisol, but epinephrine increased slightly with AZD1656. Glucagon responses were reduced by approximately 30% with both GKAs vs. insulin. CONCLUSIONS: These data suggest the central nervous system-mediated counterregulatory response during GKA-induced hypoglycemia was preserved, whereas the glucagon response was attenuated; the latter was possibly mediated by a local pancreatic effect (intraislet hyperinsulinemia) rather than by impairment of the central nervous system-mediated response.

Mechanistic modelling of tesaglitazar pharmacokinetic data in subjects with various degrees of renal function--evidence of interconversion.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Tesaglitazar, is predominantly metabolized (to an acyl glucuronide of the parent compound) and 20% of given dose is found unchanged in the urine. Acyl glucuronides are know to be unstable and can become hydrolysed back to parent compound, a phenomena called interconversion. WHAT THIS STUDY ADDS: A likely mechanism (interconversion) for the cause of the increased exposure of tesaglitazar in subjects with impaired renal function. A possible modelling framework to evaluate interconversion without dosing of the metabolite based on the simultaneous analysis of plasma and urine data from a group of subjects with varying renal function. A mechanistic understanding of the pharmacokinetic properties of tesaglitazar and its metabolite. AIMS To develop a mechanistic pharmacokinetic (PK) model for tesaglitazar and its metabolite (an acyl glucuronide) following oral administration of tesaglitazar to subjects with varying renal function, and derive an explanation for the increased plasma exposure of tesaglitazar in subjects with impaired renal function. METHODS: Data were from a 6-week study in subjects with renal insufficiency and matched controls undergoing repeated oral dosing with tesaglitazar (n = 41). Compartmental population PK modelling was employed to describe the PK of tesaglitazar and its metabolite, in plasma and urine, simultaneously. Two hypotheses were tested to investigate the increased exposure of tesaglitazar in subjects with renal functional impairment: tesaglitazar metabolism is correlated with renal function, or metabolite elimination is reduced in renal insufficiency, leading to increased hydrolysis (interconversion) to the parent compound via biliary circulation. RESULTS: The hypothesis for interconversion was best supported by the data. The population PK model included first-order absorption, two-compartment disposition and separate renal (0.027 l h(-1)) and metabolic (1.9 l h(-1)) clearances for tesaglitazar. The model for the metabolite; one-compartment disposition with renal (saturable, V(max) = 0.19 micromol l(-1) and K(m) = 0.04 micromol l(-1)) and nonrenal clearances (1.2 l h(-1)), biliary secretion (12 h(-1)) to the gut, where interconversion and reabsorption (0.8 h(-1)) of tesaglitazar occurred. CONCLUSION: A mechanistic population PK model for tesaglitazar and its metabolite was developed in subjects with varying degrees of renal insufficiency. The model and data give insight into the likely mechanism (interconversion) of the increased tesaglitazar exposure in renally impaired subjects, and separate elimination and interconversion processes without dosing of the metabolite.