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Aims: Use of infliximab (IFX) has improved outcomes in children with inflammatory bowel disease (IBD). However, a proportion of patients does not respond to IFX or loses response over time. Population pharmacokinetic (PopPK) modelling is a promising approach for IFX dose optimization, but with the increasing number of PopPK models in literature, model evaluation is essential. The aims of this study are: (i) to validate the predictive performance of existing IFX PopPK models using a cohort of children with IBD; and (ii) to perform a Bayesian estimation of the most suitable model to predict the next IFX concentrations. Methods: PubMed was searched for IFX PopPK models in children. Selected models were rebuilt and analysed using R. Model performance was assessed through goodness‐of‐fit‐plots, residuals against time, prediction error and prediction‐corrected visual predictive checks. The validation cohort consisted of 73 children with IBD who were treated with IFX in our centre between 2017 and 2023 (340 IFX measurements). Results: We identified 9 PopPK models. Model bias for individual predicted values ranged from −9.29% to 8.01% compared to bias for population predicted values. The model by Vande Casteele et al. demonstrated superior performance (individual predicted bias 2.13, population predicted bias −6.11); upon Bayesian estimation, it predicted induction trough levels with median error of 12.95% but had a median error of −69% predicting maintenance concentrations. Conclusion: The model by Vande Casteele et al. displayed superior performance in initial evaluations but had a high error in estimating next IFX levels and can only be used in practice to predict induction levels. [ABSTRACT FROM AUTHOR]

During ischemia and reperfusion injury (IRI), mitochondria may release mitochondrial DNA (mtDNA). mtDNA can serve as a propagator of further injury but in specific settings has anti-inflammatory capacities as well. Therefore, the aim of this study was to study the perioperative dynamics of plasma mtDNA during living donor kidney transplantation (LDKT) and its potential as a marker of graft outcome. Fifty-six donor–recipient couples from the Volatile Anesthetic Protection of Renal Transplants-1 (VAPOR-1) trial were included. Systemic venous, systemic arterial, and renal venous samples were taken at multiple timepoints during and after LDKT. Levels of mtDNA genes changed over time and between vascular compartments. Several donor, recipient, and transplantation-related variables significantly explained the course of mtDNA genes over time. mtDNA genes predicted 1-month and 24-month estimated glomerular filtration rate (eGFR) and acute rejection episodes in the two-year follow-up period. To conclude, mtDNA is released in plasma during the process of LDKT, either from the kidney or from the whole body in response to transplantation. While circulating mtDNA levels positively and negatively predict post-transplantation outcomes, the exact mechanisms and difference between mtDNA genes are not yet understood and need further exploration. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Early non-invasive detection and prediction of graft function after kidney transplantation is essential since interventions might prevent further deterioration. The aim of this study was to analyze the dynamics and predictive value of four urinary biomarkers: kidney injury molecule-1 (KIM-1), heart-type fatty acid binding protein (H-FABP), N-acetyl-β-D-glucosaminidase (NAG), and neutrophil gelatinase-associated lipocalin (NGAL) in a living donor kidney transplantation (LDKT) cohort. Biomarkers were measured up to 9 days after the transplantation of 57 recipients participating in the VAPOR-1 trial. Dynamics of KIM-1, NAG, NGAL, and H-FABP significantly changed over the course of 9 days after transplantation. KIM-1 at day 1 and NAG at day 2 after transplantation were significant predictors for the estimated glomerular filtration rate (eGFR) at various timepoints after transplantation with a positive estimate (p < 0.05), whereas NGAL and NAG at day 1 after transplantation were negative significant predictors (p < 0.05). Multivariable analysis models for eGFR outcome improved after the addition of these biomarker levels. Several donor, recipient and transplantation factors significantly affected the baseline of urinary biomarkers. In conclusion, urinary biomarkers are of added value for the prediction of graft outcome, but influencing factors such as the timing of measurement and transplantation factors need to be considered. [ABSTRACT FROM AUTHOR]

Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25–75 mL/min/1.73 m2, and a urine albumin‐to‐creatinine ratio of 300–5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin‐1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasma‐concentration time curve from zero to infinity (AUC0−inf) 41.3 ng·h/mL) or slow (atrasentan AUC0−inf 49.7 ng·h/mL, P < 0.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45–0.81) and 1.35 (95% CI: 0.84–2.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95–4.03, P‐interaction normal phenotype = 0.004), and 4.18 (95% CI: 1.37–12.7, P‐interaction normal phenotype = 0.060), respectively. OATP1B1 gene polymorphisms are associated with significant between‐patient variability in atrasentan plasma exposure and long‐term efficacy and safety. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Dapagliflozin is a sodium–glucose co‐transporter 2 inhibitor that has been developed as oral glucose lowering drug. The original dosefinding studies focused on optimal glycaemic effects. However, dapagliflozin also affects various cardiorenal risk markers and provides cardiorenal protection. To evaluate whether the currently registered doses of 5 and 10 mg are optimal for cardiorenal efficacy and safety, we characterized the relationship between dapagliflozin exposure and nonglycaemic cardiorenal risk markers as well as adverse events. Methods: Data were obtained from a pooled database of 13 24‐week randomized controlled clinical trials of the clinical development programme of dapagliflozin. The exposure–response relationship was quantified using population pharmacodynamic and repeated time‐to‐event models. Results: A dose of 10 mg dapagliflozin resulted in an average individual exposure of 638 ng h/mL (95% prediction interval [PI]: 354–1061 ng h/mL), which translated to 71.2% (95% PI: 57.9–80.5%), 61.1% (95% PI: 58.0–64.8%), 91.3% (95% PI: 85.4–94.6%) and 25.7% (95% PI: 23.5–28.3%) of its estimated maximum effect for fasting plasma glucose, haematocrit, serum creatinine and urinary albumin–creatinine ratio, respectively. Conclusion: We demonstrate that doses higher than 10 mg could provide additional beneficial effects in haematocrit, systolic blood pressure, urinary albumin–creatinine ratio and uric acid, without obvious increases in the rate of adverse events. These results raise the question whether future outcome studies assessing the benefits of higher than currently registered dapagliflozin doses are merited. [ABSTRACT FROM AUTHOR]

Aims: To quantitate the consistency of an individual's plasma exposure to dapagliflozin upon re‐exposure, and to investigate whether the individual's systemic exposure to dapagliflozin explains inter‐individual variation in response to dapagliflozin with regard to multiple renal risk markers. Methods: Data were used from a crossover randomized clinical trial that assessed the albuminuria‐lowering effect of dapagliflozin in 33 people with type 2 diabetes and elevated albuminuria. Fifteen participants were exposed twice to dapagliflozin. Trough plasma concentrations of dapagliflozin were measured for each participant at steady state. Dapagliflozin plasma concentrations were measured by liquid chromatography tandem mass spectrometry, and pharmacokinetic characteristics were simulated based on a population pharmacokinetic model. Linear mixed‐effects models were used to quantify the exposure–response relationships. Results: The median plasma concentration after first and second exposure to dapagliflozin was 5.3 ng/mL vs 4.6 ng/mL, respectively (P = 0.78). Lin's concordance correlation coefficient between occasions was 0.73 (P < 0.0021). Every 100 ng.h/mL increment in area under the dapagliflozin plasma concentration curve was associated with a decrease in log‐transformed urinary albumin:creatinine ratio (β = −5.9, P < 0.01), body weight (β = −0.3, P < 0.01) and estimated glomerular filtration rate (β = −0.7, P = 0.01) and an increase in urinary glucose excretion (β = 17.0, P < 0.001). Conclusion: An individual's exposure to dapagliflozin is consistent upon re‐exposure and correlates with pharmacodynamic response in renal risk markers. [ABSTRACT FROM AUTHOR]

Aims: The AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator‐activated receptor‐αγ agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar. Materials and Methods: The AleCardio trial enrolled 7226 patients to receive aleglitazar 150 μg or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population. Results: Concomitant administration of clopidogrel was identified as a covariate that influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma‐concentration‐time curve (AUC0–24) of 174.7 ng h/mL (SD: ±112.9 ng h/mL) versus 142.2 ng h/mL (SD: ±92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002, <0.001 and < 0.001, respectively). Conclusions: Concomitant use of clopidogrel was identified as a covariate that explained interindividual variability in exposure to aleglitazar. Patients using clopidogrel showed an additional lowering of HbA1c, at the expense of an additional decrease in haemoglobin, and an increase in serum creatinine and adiponectin. Clopidogrel is a moderate inhibitor of CYP2C8. Because aleglitazar is metabolized by CYP2C8, a pharmacokinetic interaction could explain differences in exposure and response to aleglitazar. [ABSTRACT FROM AUTHOR]

This study aimed to identify the optimal dose of the endothelin‐1 receptor antagonist atrasentan with maximal albuminuria reduction and minimal signs of sodium retention, as manifested by increase in bodyweight. Data from the RADAR‐JAPAN studies were used, evaluating the effect of 0.75 or 1.25 mg/d of atrasentan in 161 patients with type 2 diabetes and kidney disease. Individual pharmacokinetic parameters were estimated using a population pharmacokinetic approach. Subsequently, changes in the urinary albumin‐to‐creatinine ratio (UACR) and bodyweight from baseline after 2 weeks' exposure were modelled as a function of the pharmacokinetic parameters. The 0.75 and 1.25 mg doses showed a mean UACR reduction of 34.0% and 40.1%, whereas mean bodyweight increased by 0.9 and 1.1 kg, respectively. A large variation between individuals was observed in the UACR and bodyweight responses. Individual pharmacokinetic parameters correlated significantly with both individual UACR and bodyweight responses (P < .01). The individual response curves for UACR and bodyweight crossed at approximately the mean trough concentration of 0.75 mg atrasentan, indicating that 0.75 mg/d of atrasentan is the optimal dose for kidney protection with maximal efficacy (albuminuria reduction) and safety (minimal sodium retention). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]