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Background Volenrelaxin is a half-life-extended recombinant human relaxin protein developed for improving kidney perfusion and cardiorenal function. This study assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of volenrelaxin following single- and multiple-ascending doses (SAD and MAD) administration. Methods In this Phase 1, four-part, randomized, double-blinded, placebo-controlled SAD and MAD study in healthy participants, SAD participants (n  = 56) received an intravenous or subcutaneous dose of volenrelaxin or placebo in a dose-ascending manner. MAD participants (n  = 77) received volenrelaxin or placebo subcutaneously once weekly for 5 weeks. Effective renal plasma flow (ERPF) and measured glomerular filtration rate (mGFR) were determined by para-aminohippurate and iohexol clearance, respectively. Results Volenrelaxin demonstrated an extended half-life and increased acute and chronic placebo-adjusted ERPF change from baseline by 50% and 44%, respectively (P  < .0001). mGFR was unchanged, while filtration fraction and afferent/efferent renal arteriolar resistances were reduced. Systolic and diastolic blood pressures decreased, and pulse rate increased with increasing volenrelaxin exposures, demonstrating maximal model-derived placebo-adjusted changes (90% confidence interval) of –6.16 (–8.04, –4.28) mmHg, –6.10 (–7.61, –4.58) mmHg and +4.39 (+3.38, +5.39) bpm, respectively. Adverse events were mild, with no difference in orthostatic hypotension between volenrelaxin and placebo. Conclusion Volenrelaxin was well-tolerated, safe and suitable for weekly subcutaneous dosing. Volenrelaxin showed a sustained improvement in kidney perfusion upon repeated dosing, supporting further clinical development in chronic kidney disease and chronic heart failure. Clinical trial registration NCT04768855. [ABSTRACT FROM AUTHOR]

Dulaglutide 3.0 and 4.5 mg weekly doses were approved for additional glycemic control in adult patients with type 2 diabetes inadequately controlled with metformin and 0.75 or 1.5 mg weekly doses of dulaglutide. Effects such as nausea and vomiting are commonly reported with dulaglutide and other glucagon‐like peptide‐1 receptor agonist therapies. Based on a pharmacokinetic/pharmacodynamic model‐informed approach, a stepwise dose‐escalation scheme with 4‐week intervals between dose increments was suggested to mitigate gastrointestinal events for dulaglutide. These gastrointestinal events are dose dependent and attenuate over time with repeated dosing. A Markov chain Monte Carlo pharmacokinetic/pharmacodynamic joint model was developed using AWARD‐11 data (N = 1842) to optimize dulaglutide dose escalation to 3.0 and 4.5 mg to mitigate gastrointestinal events. Model simulations evaluated probabilities of nausea and vomiting events for various dosing scenarios in patients needing higher doses for additional glycemic control. The model indicated that patients may dose escalate from 1.5 to 3.0 mg, then 4.5 mg weekly after at least 4 weeks on each dose. No clinically meaningful differences in nausea or vomiting events were expected when patients escalated to 3.0 or 4.5 mg following initiation at 0.75 or 1.5 mg dulaglutide. Based on the findings of this model, a minimum 4‐week duration at each dose before escalation was appropriate to reduce gastrointestinal events of dulaglutide, consistent with observed gastrointestinal events data from the AWARD‐11 study and supporting the currently recommended dose‐escalation regimen of dulaglutide doses of 3.0 and 4.5 mg for additional glycemic control. [ABSTRACT FROM AUTHOR]

Aim: To evaluate HbA1c and body weight changes when semaglutide 0.5‐ or 1.0‐mg once‐weekly (QW) is switched to dulaglutide 3.0‐ or 4.5‐mg QW via exposure‐response modelling. Methods: HbA1c and body weight time‐course models were developed and validated with data from the SUSTAIN 1 to 10 trials for semaglutide and the AWARD‐11 trial for dulaglutide. Simulations were conducted for HbA1c and body weight over 52 weeks. In the initial 26 weeks, semaglutide was initiated at 0.25‐mg and titrated to 0.5‐ or 1.0‐mg QW via 4‐weekly stepwise titration, followed by 26 weeks of dulaglutide initiated at 0.75‐ or 1.5‐mg QW and escalated to 3.0‐ or 4.5‐mg QW via 4‐weekly stepwise titration. Results: At 26 weeks, model‐predicted mean changes from baseline in HbA1c and weight for semaglutide 0.5 mg were up to −1.55% and −3.44 kg, respectively. After switching to dulaglutide 3.0 mg, further reductions were 0.19% and 1.40 kg, respectively, at 52 weeks. Predicted mean HbA1c and weight changes for semaglutide 1.0 mg at 26 weeks were −1.84% and −4.96 kg, respectively; after switching to dulaglutide 4.5 mg, HbA1c was maintained with additional weight reduction of up to 0.57 kg at 52 weeks. Glycaemic control was preserved when switching from semaglutide 1.0 mg to dulaglutide 3.0 mg. Conclusion: Switching from semaglutide 0.5 mg to dulaglutide 3.0 or 4.5 mg with dose escalation potentially yields additional HbA1c and weight reductions; switching from semaglutide 1.0 mg to dulaglutide 4.5 mg may enhance weight loss. [ABSTRACT FROM AUTHOR]

Insulin replacement therapy is a fundamental treatment for glycemic control for managing diabetes. The engineering of insulin analogues has focused on providing formulations with action profiles that mimic as closely as possible the pattern of physiological insulin secretion that normally occurs in healthy individuals without diabetes. Hence, it may be helpful to practitioners to visualize insulin concentration profiles and associated glucose action profiles. Expanding on a previous analysis that established a pharmacokinetic (PK) model to describe typical profiles of insulin concentration over time following subcutaneous administration of various insulin formulations, the goal of the current analysis was to link the PK model to an integrated glucose‐insulin (IGI) systems pharmacology model. After the pharmacokinetic‐pharmacodynamic (PK‐PD) model was qualified by comparing model predictions with clinical observations, it was used to project insulin (PK) and glucose (PD) profiles of common insulin regimens and dosing scenarios. The application of the PK‐PD model to clinical scenarios was further explored by incorporating the impact of several hypothetical factors together, such as changing the timing or frequency of administration in a multiple‐dosing regimen over the course of a day, administration of more than 1 insulin formulation, or insulin dosing adjusted for carbohydrates in meals. Visualizations of insulin and glucose profiles for commonly prescribed regimens could be rapidly generated by implementing the linked subcutaneous insulin PK‐IGI model using the R statistical program (version 3.4.4) and a contemporary web‐based interface, which could enhance clinical education on glycemic control with insulin therapy. [ABSTRACT FROM AUTHOR]

Objective: To investigate the pharmacogenetic effect of SLCO1B1 *1a, *1b, *5 and *15 polymorphisms on irinotecan disposition in Asian cancer patients., Experimental Design: Irinotecan was administered over 90 min either at 100 mg/m on days 1, 8 and 15 with the regimen being repeated every 28 days (N=28) or at 375 mg/m once every three weeks (N=43). Plasma concentrations of irinotecan, 7-ethyl-10-hydroxycamptothecin and 7-ethyl-10-hydroxycamptothecinG were analysed after the first dose of the first cycle and the influence of SLCO1B1 *1a, *1b, *5 and *15 polymorphisms on the disposition of irinotecan and its metabolites were evaluated., Results: Pharmacokinetic parameters were obtained from 71 cancer patients. Genotypic-phenotypic correlates showed the clearance of irinotecan to be 3-fold lower in patients carrying the *15 haplotype than cancer patients with the reference genotype *1a/*1a (9.57+/-3.15 vs. 28.86+/-10.97 l/h/m; P=0.001). The area under the plasma concentration-time curve from zero to infinity and normalized by dose and body surface area (AUC0-nf/dose/BSA) were significantly higher in patients harbouring the *15 haplotype than patients with the reference genotype for irinotecan (39.27+/-15.17 vs. 17.32+/-6.30 h/m; P=0.003) and 7-ethyl-10-hydroxycamptothecin (1.28+/-0.53 vs. 0.69+/-0.32 h/m; P=0.021). The exposure levels to 7-ethyl-10-hydroxycamptothecinG also showed a statistically significant trend among the SLCO1B1 haplotype pairs, being approximately 10-fold lower in patients with *15 haplotype than with patients harbouring the reference genotype (3.57+/-1.95 vs. 12.0+/-6.09 h/m; P=0.016)., Conclusion: These findings suggest that (1) SLCO1B1 haplotypes may have a significant influence on the disposition of irinotecan and its metabolites in Asian cancer patients, and (2) patients with SLCO1B1*15 haplotype may be susceptible to increased sensitivity to irinotecan, which may manifest itself either by increased efficacy or toxicity or both owing to the increased exposure levels to 7-ethyl-10-hydroxycamptothecin.