Safety, tolerability and toxicokinetics of the novel mitochondrial drug SUL-138 administered orally to rat and minipig.

Noncommunicable Chronic Diseases (NCD) are a socioeconomic burden and considered one of the major health challenges for coming decades. Mitochondrial dysfunction has been implicated mechanistically in their pathophysiology. Therefore, targeting mitochondria holds great promise to improve clinical outcomes in NCDs. SUL-138, an orally bioavailable small molecule efficacious from 0.5 mg/kg, improves mitochondrial function during disease in several preclinical animal models. As preparation for a First-in-Human (FIH) trial, SUL-138 was investigated in 30-day GLP repeated dose toxicity studies in rat and minipig, selected based on their comparability with human metabolism, to determine toxicokinetics, potential toxicity and its reversibility. Rats were allocated to either vehicle, 27, 136 or 682 mg/kg SUL-138 dose groups and minipigs were allocated to either vehicle, 16, 82 or 409 mg/kg. Treatment occurred orally for 30 days followed by a recovery period of 14 days. During these studies clinical observations, toxicokinetic, clinical pathology, necropsy and histopathology evaluations were performed. There was significant systemic exposure to SUL-138 and toxicokinetics was characterized by a rapid absorption and elimination. In the rat, toxicokinetics was dose-proportional and AUC0-tlast ratios in both species indicated that SUL-138 does not accumulate in vivo. No treatment-related adverse effects were observed for dose levels up to 136 and 82 mg/kg/day in rat and minipig respectively. In conclusion, these preclinical studies demonstrate that SUL-138 is well tolerated after repeated administration in rat and minipig, with NOAELs of 136 and 82 mg/kg/day, respectively.

Gait and dynamic pedobarographic analyses in hallux rigidus patients treated with Keller's arthroplasty, arthrodesis or cheilectomy 22 years after surgery.

Background: Keller's arthroplasty, arthrodesis and cheilectomy are well-known surgical interventions for hallux rigidus. This study aimed to evaluate the effects of these surgical interventions on gait, plantar pressure distribution and clinical outcome in patients treated for hallux rigidus 22 years after surgery. Methods: Spatio-temporal gait parameters and plantar pressure distribution, determined as pressure time integrals (PTIs) and peak pressures (PPs), were analyzed using a 7-foot tone analysis model. Patient-reported outcome was assessed using the Manchester-Oxford Foot Questionnaire (MOXFQ). Of the 73 patients (89 feet) from the original study, 27 patients (33 feet) and 13 healthy controls (26 feet) were available for evaluation 22 years after hallux rigidus surgery. Results: Spatio-temporal gait parameters were comparable between all groups and were in line with healthy controls (P > 0.05). No differences (P > 0.05) in PTIs and PPs were found in the seven plantar zones between groups and as compared to healthy controls. MOXFQ scores in all domains (walking/standing, range 21.4-24.1; pain, range 16.5-22.2 and social interaction, range 23.8-35.4) were not clinically and statistically different (P > 0.05) between the three different surgical interventions. Conclusion: These results suggest no long-term functional and biomechanical differences after these surgical interventions for hallux rigidus correction. The interventions seem to be appropriate treatment options for a selective group of patients with symptomatic hallux rigidus.

Exposure-Response Analysis of the Sodium-Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve markers for renal and cardiovascular outcomes in patients with and without type 2 diabetes (T2D). To assess whether individual differences in plasma drug exposure can explain inter-individual response variation, we characterized the exposure-response relationship for two SGLT2 inhibitors on several clinical and kidney hemodynamic variables. Data were obtained from two studies, RED and RECOLAR, assessing the effects of once-daily 10 mg dapagliflozin or empagliflozin, respectively, on kidney hemodynamics in patients with T2D. Individual plasma exposure was estimated using non-compartmental analyses and exposure-response relationships were assessed using linear mixed-effects models. In 23 patients participating in RED, the dapagliflozin geometric mean apparent area under the concentration-time curve during one dosing interval at steady state (AUC0-tau,ss) was 1153.1 µg/L*h (coefficient of variation (CV) 81.8%) and associated, per doubling, with decreases in body weight (0.29 kg, p < 0.001), systolic blood pressure (0.80 mmHg, p = 0.002), measured glomerular filtration rate (mGFR) (0.83 mL/min, p = 0.03), and filtration fraction (0.09%, p = 0.04). In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC0-tau,ss was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight (0.13 kg, p = 0.002), systolic blood pressure (0.65 mmHg, p = 0.045), and mGFR (0.78 mL/min, p = 0.002). To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables.

Glycemic Control and Effects of Canagliflozin in Reducing Albuminuria and eGFR: A Post Hoc Analysis of the CREDENCE Trial.

BACKGROUND: In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin improved kidney and cardiovascular outcomes and reduced the rate of estimated glomerular filtration decline (eGFR slope) in patients with type 2 diabetes and CKD. In other clinical trials of patients with CKD or heart failure, the protective effects of SGLT2 inhibitors on eGFR slope were greater in participants with versus participants without type 2 diabetes. This post hoc analysis of the CREDENCE trial assessed whether the effects of canagliflozin on eGFR slope varied according to patient subgroups by baseline glycated hemoglobin A1c (HbA1c). METHODS: CREDENCE ( ClinicalTrials.gov [ NCT02065791 ]) was a randomized controlled trial in adults with type 2 diabetes with an HbA1c of 6.5%-12.0%, an eGFR of 30-90 ml/min per 1.73 m 2 , and a urinary albumin-to-creatinine ratio of 300-5000 mg/g. Participants were randomly assigned to canagliflozin 100 mg once daily or placebo. We studied the effect of canagliflozin on eGFR slope using linear mixed-effects models. RESULTS: The annual difference in total eGFR slope was 1.52 ml/min per 1.73 m 2 (95% confidence interval [CI], 1.11 to 1.93) slower in participants randomized to canagliflozin compared with placebo. The rate of eGFR decline was faster in those with poorer baseline glycemic control. The mean difference in total eGFR slope between canagliflozin and placebo was greater in participants with poorer baseline glycemic control (difference in eGFR slope of 0.39, 1.36, 2.60, 1.63 ml/min per 1.73 m 2 for HbA1c subgroups 6.5%-7.0%, 7.0%-8.0%, 8.0%-10.0%, 10.0%-12.0%, respectively; Pinteraction = 0.010). The mean difference in change from baseline in urinary albumin-to-creatinine ratio between participants randomized to canagliflozin and placebo was smaller in patients with baseline HbA1c 6.5%-7.0% (-17% [95% CI, -28 to -5]) compared with those with an HbA1c of 7.0%-12% (-32% [95% CI, -40 to -28]; Pinteraction = 0.03). CONCLUSIONS: The effect of canagliflozin on eGFR slope in patients with type 2 diabetes and CKD was more pronounced in patients with higher baseline HbA1c, partly because of the more rapid decline in kidney function in these individuals. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.

Feasibility Study to Assess Canagliflozin Distribution and Sodium-Glucose Co-Transporter 2 Occupancy Using [18 F]Canagliflozin in Patients with Type 2 Diabetes.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, including canagliflozin, reduce the risk of cardiovascular and kidney outcomes in patients with and without type 2 diabetes, albeit with a large interindividual variation. The underlying mechanisms for this variation in response might be attributed to differences in SGLT2 occupancy, resulting from individual variation in plasma and tissue drug exposure and receptor availability. We performed a feasibility study for the use of [18 F]canagliflozin positron emission tomography (PET) imaging to determine the association between clinical canagliflozin doses and SGLT2 occupancy in patients with type 2 diabetes. We obtained two 90-minute dynamic PET scans with diagnostic intravenous [18 F]canagliflozin administration and a full kinetic analysis in 7 patients with type 2 diabetes. Patients received 50, 100, or 300 mg oral canagliflozin (n = 2:4:1) 2.5 hours before the second scan. Canagliflozin pharmacokinetics and urinary glucose excretion were measured. The apparent SGLT2 occupancy was derived from the difference between the apparent volume of distribution of [18 F]canagliflozin in the baseline and post-drug PET scans. Individual canagliflozin area under the curve from oral dosing until 24-hours (AUCP0-24h ) varied largely (range 1,715-25,747 µg/L*hour, mean 10,580 µg/L*hour) and increased dose dependently with mean values of 4,543, 6,525, and 20,012 µg/L*hour for 50, 100, and 300 mg, respectively (P = 0.046). SGLT2 occupancy ranged between 65% and 87%, but did not correlate with canagliflozin dose, plasma exposure, or urinary glucose excretion. We report the feasibility of [18 F]canagliflozin PET imaging to determine canagliflozin kidney disposition and SGLT2 occupancy. This suggests the potential of [18 F]canagliflozin as a tool to visualize and quantify clinically SGLT2 tissue binding.

Studying Telmisartan Plasma Exposure, Kidney Distribution, Receptor Occupancy, and Response in Patients With Type 2 Diabetes Using [11 C]Telmisartan.

The angiotensin receptor blocker telmisartan slows progression of kidney disease in patients with type 2 diabetes (T2D), yet many patients remain at high risk for progressive kidney function loss. The underlying mechanisms for this response variation might be attributed to differences in angiotensin-1 receptor occupancy (RO), resulting from individual variation in plasma drug exposure, tissue drug exposure, and receptor availability. Therefore, we first assessed the relationship between plasma telmisartan exposure and urinary-albumin-to-creatinine-ratio (UACR) in 10 patients with T2D and albuminuria (mean age 66 years, median UACR 297 mg/g) after 4 weeks treatment with 80 mg telmisartan once daily. Increasing telmisartan exposure associated with a larger reduction in UACR (Pearson correlation coefficient (PCC) = -0.64, P = 0.046, median change UACR: -40.1%, 95% confidence interval (CI): -22.9 to -77.4%, mean telmisartan area under the curve (AUC) = 2927.1 ng·hour/mL, 95% CI: 723.0 to 6501.6 ng·hour/mL). Subsequently, we assessed the relation among plasma telmisartan exposure, kidney distribution, and angiotensin-1 RO in five patients with T2D (mean age 60 years, median UACR 72 mg/g) in a separate positron emission tomography imaging study with [11 C]Telmisartan. Individual plasma telmisartan exposure correlated with telmisartan distribution to the kidneys (PCC = 0.976, P = 0.024). A meaningful RO could be calculated in three patients receiving 120 mg oral telmisartan, and although high exposure seems related to higher RO, with AUC0-last of 31, 840, and 274 ng·hour/mL and corresponding RO values 5.5%, 44%, and 59%, this was not significant (P = 0.64). Together these results indicate, for the first time, a relationship among interindividual differences in plasma exposure, kidney tissue distribution, RO, and ultimately UACR response after telmisartan administration.

Gait analysis of foot compensation in symptomatic Hallux Rigidus patients.

BACKGROUND: Compensatory motion of foot joints in hallux rigidus (HR) are not fully known. This study aimed to clarify the kinematic compensation within the foot and to detect whether this affects plantar pressure distribution. METHODS: Gait characteristics were assessed in 16 patients (16 feet) with HR and compared with 15 healthy controls (30 feet) with three-dimensional gait analysis by using the multi-segment Oxford Foot Model, measuring spatio-temporal parameters, joint kinematics and plantar pressure. RESULTS: HR subjects showed less hallux plantar flexion during midstance and less hallux dorsiflexion during push-off, while increased forefoot supination was detected during push-off. No significant differences in plantar pressure were detected. Step length was significantly smaller in HR subjects, while gait velocity was comparable between groups. CONCLUSIONS: HR significantly affects sagittal hallux motion, and the forefoot compensates by an increased supination during push-off. Despite this kinematic compensatory mechanism, no significant differences in plantar loading were detected.

Current Use and Complementary Value of Combining in Vivo Imaging Modalities to Understand the Renoprotective Effects of Sodium-Glucose Cotransporter-2 Inhibitors at a Tissue Level.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) were initially developed to treat diabetes and have been shown to improve renal and cardiovascular outcomes in patients with- but also without diabetes. The mechanisms underlying these beneficial effects are incompletely understood, as is the response variability between- and within patients. Imaging modalities allow in vivo quantitative assessment of physiological, pathophysiological, and pharmacological processes at kidney tissue level and are therefore increasingly being used in nephrology. They provide unique insights into the renoprotective effects of SGLT2i and the variability in response and may thus contribute to improved treatment of the individual patient. In this mini-review, we highlight current work and opportunities of renal imaging modalities to assess renal oxygenation and hypoxia, fibrosis as well as interaction between SGLT2i and their transporters. Although every modality allows quantitative assessment of particular parameters of interest, we conclude that especially the complementary value of combining imaging modalities in a single clinical trial aids in an integrated understanding of the pharmacology of SGLT2i and their response variability.

Treatment Outcomes of Childhood Tuberculous Meningitis in a Real-World Retrospective Cohort, Bandung, Indonesia.

We retrospectively evaluated clinical features and outcomes in children treated for tuberculous meningitis (TBM) at Hasan Sadikin Hospital, Bandung, Indonesia, during 2011-2020. Among 283 patients, 153 (54.1%) were <5 years of age, and 226 (79.9%) had stage II or III TBM. Predictors of in-hospital death (n = 44 [15.5%]) were stage III TBM, hydrocephalus, male sex, low-income parents, seizures at admission, and lack of bacillus Calmette-Guérin vaccination. Predictors of postdischarge death (n = 18 [6.4%]) were hydrocephalus, tuberculoma, and lack of bacillus Calmette-Guérin vaccination. At treatment completion, 91 (32.1%) patients were documented to have survived, of whom 33 (36.3%) had severe neurologic sequelae and 118 (41.7%) had unknown outcomes. Predictors of severe neurologic sequelae were baseline temperature >38°C, stage III TBM, and baseline motor deficit. Despite treatment, childhood TBM in Indonesia causes substantial neurologic sequelae and death, highlighting the importance of improved early diagnosis, better tuberculosis prevention, and optimized TBM management strategies.

Metallic hemiarthroplasty or arthrodesis of the first metatarsophalangeal joint as treatment for hallux rigidus: A systematic review and meta-analysis.

BACKGROUND: Arthrodesis and metallic hemiarthroplasty are two surgical interventions for the treatment of end-stage osteoarthritis of the first metatarsophalangeal (MTP1) joint. This systematic review and meta-analysis aims to compare the two operations with regards to patient-reported outcomes, pain reduction, complications and revision rates. METHODS: A systematic literature search identified all relevant studies. The methodological quality was assessed using two validated tools. Data of interest were derived and presented. For non-comparative studies, data was assessed for trends, while for comparative studies pooling statistics were performed. RESULTS: A total of 33 studies were included for analysis. The majority of studies (>75%) reported an AOFAS-HMI score greater than 80 points after both metallic hemiarthroplasty and arthrodesis. The lowest VAS pain score was observed after arthrodesis (weighted mean difference -1.58, 95% confidence interval (CI) -2.16 to -1.00 P< 0.00001). Comparable numbers of complications (odds radio 1.48, 95% CI 0.81 to 2.73, P = 0.21, favoring: hemiarthroplasty) and revisions (odds ratio 1.16, 95% CI 0.62 to 2.15 P = 0.64, favoring: hemiarthroplasty) were observed after both interventions. The included non-comparative studies seem to confirm these findings of the comparative studies. CONCLUSION: Metallic hemiarthroplasty and arthrodesis have excellent clinical outcomes and acceptable complication- and revision rates. Arthrodesis seems to be superior in pain reduction, while metallic hemiarthroplasty is a suitable alternative for patients performing activities that requires motion in the first metatarsophalangeal joint.

GMP Compliant Synthesis of [18F]Canagliflozin, a Novel PET Tracer for the Sodium-Glucose Cotransporter 2.

Inhibition of the sodium-glucose cotransporter 2 (SGLT2) by canagliflozin in type 2 diabetes mellitus results in large between-patient variability in clinical response. To better understand this variability, the positron emission tomography (PET) tracer [18F]canagliflozin was developed via a Cu-mediated 18F-fluorination of its boronic ester precursor with a radiochemical yield of 2.0 ± 1.9% and a purity of >95%. The GMP automated synthesis originated [18F]canagliflozin with a yield of 0.5-3% (n = 4) and a purity of >95%. Autoradiography showed [18F]canagliflozin binding in human kidney sections containing SGLT2. Since [18F]canagliflozin is the isotopologue of the extensively characterized drug canagliflozin and thus shares its toxicological and pharmacological characteristics, it enables its immediate use in patients.

Simplified Iohexol-Based Method for Measurement of Glomerular Filtration Rate in Goats and Pigs.

The preclinical evaluation of novel therapies for chronic kidney disease requires a simple method for the assessment of kidney function in a uremic large animal model. An intravenous bolus of iohexol was administered to goats (13 measurements in n = 3 goats) and pigs (23 measurements in n = 5 pigs) before and after induction of kidney failure, followed by frequent blood sampling up to 1440 min. Plasma clearance (CL) was estimated by a nonlinear mixed-effects model (CLNLME) and by a one-compartmental pharmacokinetic disposition model using iohexol plasma concentrations during the terminal elimination phase (CL1CMT). A simple method (CLSM) for the calculation of plasma clearance was developed based on the most appropriate relationship between CLNLME and CL1CMT. CLSM and CLNLME showed good agreement (CLNLME/CLSM ratio: 1.00 ± 0.07; bias: 0.03 ± 1.64 mL/min; precision CLSM and CLNLME: 80.9% and 80.7%, respectively; the percentage of CLSM estimates falling within ±30% (P30) or ±10% (P10) of CLNLME: 53% and 12%, respectively). For mGFRNLME vs. mGFRSM, bias was -0.25 ± 2.24 and precision was 49.2% and 53.6%, respectively, P30 and P10 for mGFR based on CLSM were 71% and 24%, respectively. A simple method for measurement of GFR in healthy and uremic goats and pigs was successfully developed, which eliminates the need for continuous infusion of an exogenous marker, urine collection and frequent blood sampling.

A Review of the Dose Justification of Phase 3 Trials to Regulatory Authorities for Drugs Intended for the Treatment of Type 2 Diabetes in Europe.

Aims: Cardiovascular outcome trials with anti-diabetic drugs suggest that additional cardiovascular benefit can be achieved independent of improving glycaemic control. Nonetheless, dose selection of anti-diabetic drugs is typically based solely on glycaemic effects. We evaluated whether off-target drug effects are currently considered for dose justification to regulatory agencies. Methods: In the European Union, anti-diabetic drugs are registered by the European Medicines Agency. We extracted available information regarding dose selection from public assessment reports and marketing application dossiers. Descriptive statistics were used to summarise the extracted information. Results: In total, 14 drugs of three drug classes were included; sodium-glucose co-transporter-2 inhibitors (n = 4), dipeptidyl peptidase-4 inhibitors (n = 4) and glucagon-like peptide-1 receptor agonists (n = 6). For these drugs, 21 dose-finding trials were submitted including results of multiple off-target effects, of which body weight (n = 18) and low-density lipoprotein cholesterol (n = 14) were most frequently reported. Dose-response curves for off-target effects appeared to be different compared to the glycaemic dose-response curve. Glycated hemoglobin (100%) and fasting plasma glucose (42.9%), were used most frequently for the dose justification, but generally off-target effects (<25%) were not. Conclusions: Dose justification to regulatory authorities was mainly based on glycaemic effects. The dose-response relationship for the off-target effects did not necessarily follow the dose-response relationship of the on-target effects suggesting that selection of the optimal anti-diabetic dose could benefit from including off-target effects in the dose selection process as well.

Safety, pharmacokinetics and pharmacodynamics of HTL0009936, a selective muscarinic M1 -acetylcholine receptor agonist: A randomized cross-over trial.

AIMS: HTL0009936 is a selective M1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF). METHODS: Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests. RESULTS: Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine. CONCLUSIONS: HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.

The power of modelling pulsatile profiles.

The quantitative description of individual observations in non-linear mixed effects models over time is complicated when the studied biomarker has a pulsatile release (e.g. insulin, growth hormone, luteinizing hormone). Unfortunately, standard non-linear mixed effects population pharmacodynamic models such as turnover and precursor response models (with or without a cosinor component) are unable to quantify these complex secretion profiles over time. In this study, the statistical power of standard statistical methodology such as 6 post-dose measurements or the area under the curve from 0 to 12 h post-dose on simulated dense concentration-time profiles of growth hormone was compared to a deconvolution-analysis-informed modelling approach in different simulated scenarios. The statistical power of the deconvolution-analysis-informed approach was determined with a Monte-Carlo Mapped Power analysis. Due to the high level of intra- and inter-individual variability in growth hormone concentrations over time, regardless of the simulated effect size, only the deconvolution-analysis informed approach reached a statistical power of more than 80% with a sample size of less than 200 subjects per cohort. Furthermore, the use of this deconvolution-analysis-informed modelling approach improved the description of the observations on an individual level and enabled the quantification of a drug effect to be used for subsequent clinical trial simulations.

Evaluation of the Pharmacokinetics and Exposure-Response Relationship of Dapagliflozin in Patients without Diabetes and with Chronic Kidney Disease.

BACKGROUND AND OBJECTIVE: Dapagliflozin, a sodium-glucose co-transporter inhibitor, was originally developed as an oral glucose-lowering drug for the treatment of type 2 diabetes mellitus. Emerging data suggest that cardiovascular and kidney benefits extend to patients without diabetes. Limited pharmacological data are, however, available in patients without diabetes. We aimed to characterise the pharmacokinetic profile of dapagliflozin in patients with chronic kidney disease without type 2 diabetes. METHODS: Plasma samples were collected in a randomised, placebo-controlled, double-blind, cross-over trial (DIAMOND, NCT03190694, n = 53) that assessed the effects of 10 mg of dapagliflozin in patients with a glomerular filtration rate ≥ 25 mL/min/1.73 m2 and proteinuria > 500 mg/day. Mixed-effects models were used to develop a pharmacokinetic model and to evaluate the association between plasma exposure and response. RESULTS: Plasma concentrations (n = 430 observations) from 48 patients (mean age 50.8 years, mean glomerular filtration rate 57.9 mL/min/1.73 m2, median proteinuria 1115 mg/24 h) were best described using a two-compartment model with first-order elimination. Apparent clearance and volume of distribution were 11.7 (95% confidence interval 10.7-12.7) L/h and 44.9 (95% confidence interval 39.0-50.9) L, respectively. Median dapagliflozin plasma exposure was 740.9 ng h/mL (2.5th-97.5th percentiles: 434.0-1615.3). Plasma exposure increased with decreasing kidney function. Every 100-ng h/mL increment in dapagliflozin plasma exposure was associated with a decrease in the urinary albumin:creatinine ratio (ß = - 2.8%, p = 0.01), glomerular filtration rate (ß = - 0.5 mL/min/1.73 m2, p < 0.01) and systolic blood pressure (ß = - 0.4 mmHg, p = 0.03). CONCLUSIONS: The dapagliflozin plasma concentration-time profile in patients with non-diabetic kidney disease appears similar to the profile of patients with diabetic kidney disease described in the literature. Furthermore, the plasma exposure was associated with changes in risk markers for kidney disease.

Hallux rigidus affects lower limb kinematics assessed with the Gait Profile Score.

BACKGROUND: Previous research showed that hallux rigidus (HR) affects foot and ankle kinematics during gait. It is unclear if HR affects lower limb kinematics as well. RESEARCH QUESTION: Does HR affect lower limb kinematics, and if so, is gait deviation correlated with patient-reported outcome? METHODS: This was a retrospective case-control study, including 15 HR patients and 15 healthy controls who underwent three-dimensional gait analysis by using the Plug-in Gait lower body model. The Gait Profile Score (GPS), a gait index score describing gait deviation and composed out of nine Gait Variable Scores (GVS), and intersegmental range of motion of lower limb joints were assessed. Patient-reported outcome was assessed with the Foot Function Index (FFI) and Manchester-Oxford Foot Questionnaire (MOXFQ). Data were analysed with Student t-tests and Spearman rank correlations. RESULTS: HR significantly affects gait, reflected by a higher GPS in HR subjects as compared to healthy controls. Gait deviation was seen in ankle flexion (GVSankle flexion) and to a lesser extent in pelvic rotation (GVSpelvic rotation). Interestingly, these differences were not detected when lower limb kinematics were evaluated by comparing the intersegmental ranges of motion of these joints. Positive correlations were present between patient-reported outcomes and GPS, especially functional subdomains, were positively correlated with GPS and GVSankle flexion. SIGNIFICANCE: This study demonstrated that HR, next to foot kinematics, additionally affects lower limb kinematics evaluated with an objective gait index score, i.e. GPS. The positive correlation between the GPS and patient-reported outcome can be seen as the first step in defining whether objectively measured gait indices can be used in considering surgery since most of the benefit of surgery will be expected in the patients with most gait deviation.

Individual Atrasentan Exposure is Associated With Long-term Kidney and Heart Failure Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease.

Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long-term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time-to-event models were used to quantify the association between plasma exposure and long-term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI): 0.28-0.85) for kidney events and 1.13 (95% CI: 1.03-2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population.

Inter-individual variability in atrasentan exposure partly explains variability in kidney protection and fluid retention responses: A post hoc analysis of the SONAR trial.

AIM: To evaluate whether atrasentan plasma exposure explains between-patient variability in urinary albumin-to-creatinine ratio (UACR) response, a surrogate for kidney protection, and B-type natriuretic peptide (BNP) response, a surrogate for fluid expansion. METHODS: Type 2 diabetic patients with chronic kidney disease (n = 4775) received 0.75 mg atrasentan for 6 weeks in the active run-in period. Individual area under the concentration-time-curve (AUC) was estimated using a population pharmacokinetic model. The association between atrasentan AUC, other clinical characteristics, and UACR and BNP response, was estimated using linear regression. RESULTS: The median atrasentan AUC was 43.8 ng.h/mL with a large variation among patients (2.5th-97.5th percentiles [P]: 12.6 to 197.5 ng.h/mL). Median UACR change at the end of enrichment was -36.0% and median BNP change was 8.7%, which also varied among patients (UACR, 2.5th-97.5th P: -76.2% to 44.5%; BNP, 2.5th-97.5th P: -71.5% to 300.0%). In the multivariable analysis, higher atrasentan AUC was associated with greater UACR reduction (4.88% per doubling in ng.h/mL [95% confidence interval {CI}: 6.21% to 3.52%], P < .01) and greater BNP increase (3.08% per doubling in ng.h/mL [95% CI: 1.12% to 4.11%], P < .01) independent of estimated glomerular filtration rate, haemoglobin or BNP. Caucasian patients compared with black patients had greater UACR reduction (7.06% [95% CI: 1.38% to 13.07%]) and also greater BNP increase (8.75% [95% CI: 1.65% to 15.35%]). UACR response was not associated with BNP response (r = 0.06). CONCLUSION: Atrasentan plasma exposure varied among individual patients and partially explained between-patient variability in efficacy and safety response.