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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]

B The Asian Pharmacometrics Network (APN) has been established to enhance regional development in pharmacometrics by holding annual regional symposiums and to provide training opportunities across Asia by hosting educational workshops. The establishment of APN was endorsed by the APN steering committee, which consists of representatives of local pharmacometrics groups of PAGJA, PAGK, PCPC, and PAGIN. PHARMACOMETRICS STATUS IN ASIA BEFORE WCOP2012 The extent of pharmacometrics development of a region can be judged by the existence of pharmacometrics groups and the experience in hosting international pharmacometrics meetings and workshops. [Extracted from the article]

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 glargine (IGlar) and LY2963016 (LY IGlar) are long‐acting insulin analogs with identical primary amino acid sequences. We conducted a randomized, open‐label, 2‐treatment, 2‐period, crossover study in healthy Chinese subjects to evaluate the relative bioavailability of LY IGlar to IGlar and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of LY IGlar. Subjects (n = 58) were randomized to receive single subcutaneous doses (0.5 U/kg) of LY IGlar and IGlar with a ≥7‐day washout period between study treatments. Serum was collected before and up to 24 hours after dosing to assess PK characteristics. PD characteristics were assessed by euglycemic clamp up to 24 hours after dosing. Linear mixed‐effects models were used to fit the log‐transformed primary PK (maximum observed concentration and area under the concentration‐time curve from time 0 to 24 hours) and PD parameters (maximum glucose infusion rate and total amount of glucose infused during clamp period). The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar for maximum observed concentration and area under the concentration‐time curve from time 0 to 24 hours were 0.961 (0.887‐1.04) and 0.941 (0.872‐1.01), respectively. The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar were 0.91 (0.85‐0.98) for maximum glucose infusion rate and 0.89 (0.82‐0.97) for total amount of glucose infused during clamp period. LY IGlar demonstrated similarity to IGlar in PK and PD characteristics following single‐dose (0.5 U/kg) administration in healthy Chinese subjects. [ABSTRACT FROM AUTHOR]

The drug–drug interaction profile of atorvastatin confirms that disposition is determined by cytochrome P450 (CYP) 3A4 and organic anion transporting polypeptides (OATPs). Drugs that affect gastric emptying, including dulaglutide, also affect atorvastatin pharmacokinetics (PK). Atorvastatin is a carboxylic acid that exists in equilibrium with a lactone form in vivo. The purpose of this work was to assess gastric acid–mediated lactone equilibration of atorvastatin and incorporate this into a physiologically‐based PK (PBPK) model to describe atorvastatin acid, lactone, and their major metabolites. In vitro acid‐to‐lactone conversion was assessed in simulated gastric fluid and included in the model. The PBPK model was verified with in vivo data including CYP3A4 and OATP inhibition studies. Altering the gastric acid–lactone equilibrium reproduced the change in atorvastatin PK observed with dulaglutide. The model emphasizes the need to include gastric acid–lactone conversion and all major atorvastatin‐related species for the prediction of atorvastatin PK. [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]

Baricitinib is an oral inhibitor of Janus kinases (JAKs), selective for JAK1 and 2. It demonstrated dose-dependent efficacy in patients with moderate-to-severe rheumatoid arthritis (RA) in a phase IIb study up to 24 weeks. Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed to characterize concentration-time profiles and dose/exposure-response (D/E-R) relationships for the key efficacy (proportion of patients achieving American College of Rheumatology 20%, 50%, or 70% response rate) and safety endpoints (incidence of anemia) for the phase IIb study. The modeling suggested that 4 mg q.d. was likely to offer the optimum risk/benefit balance, whereas 2 mg q.d. had the potential for adequate efficacy. In addition, at the same total daily dose, a twice-daily regimen is not expected to provide an advantage over q.d. dosing for the efficacy or safety endpoints. The model-based simulations formed the rationale for key aspects of dosing, such as dose levels and dosing frequency for phase III development. [ABSTRACT FROM AUTHOR]

Insulin pharmacokinetics following subcutaneous administration were modeled, simulated, and displayed through an interactive and user-friendly interface to illustrate the time course of administered insulins frequently prescribed, providing a simple tool for clinicians through a straightforward visualization of insulin regimens. Pharmacokinetic data of insulin formulations with different onset and duration of action from several clinical studies, including insulin glargine, regular insulin, neutral protamine Hagedorn (NPH), insulin lispro, and premixed preparations of NPH with regular insulin (Mix 70/30), and insulin lispro protamine suspension with insulin lispro (Mix 50/50, Mix 75/25), were used to develop a predictive population pharmacokinetic model of insulins with consideration of factors such as insulin formulation, weight-based dosing, body-weight effect on volume of distribution, and administration time relative to meals, on the insulin time-action profile. The model-predicted insulin profile of each insulin was validated and confirmed to be comparable to observed data via an external validation method. Model-based simulations of clinically relevant insulin-dosing scenarios to cater to specific initial patient and prescribing conditions were then implemented with differential equations using the R statistical program (version 3.2.2). The R package Shiny was subsequently applied to build a web browser interface to execute and visualize the model simulation outputs. The application of insulin pharmacokinetic modeling enabled informative visualization of insulin time-action profiles and provided an efficient and intuitive educational tool to quickly convey and interactively explore many insulin time-action profiles to ease the understanding of insulin formulations in clinical practice. [ABSTRACT FROM AUTHOR]

Ixekizumab (LY2439821), a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody that selectively binds and neutralizes interleukin (IL) 17A has demonstrated efficacy in the treatment of psoriasis. A population pharmacokinetics-pharmacodynamics model was developed using NONMEM 7.2 to describe the temporal relationship between ixekizumab concentrations and absolute Psoriasis Area and Severity Index (PASI) scores from a phase 2 dose-finding study in chronic plaque psoriasis. The objective was to inform dose-selection for further development. The primary endpoint, PASI 75 (75% or greater improvement from baseline PASI score) was then derived from each individual's absolute PASI score. The population pharmacokinetics of ixekizumab was characterized by a two-compartment model, while the exposure-response relationship was characterized using an indirect response model that described the pharmacological effects of ixekizumab and placebo in the form of inhibition of the formation of psoriatic skin lesions. PASI 75 responder status at the Week 12 primary endpoint was found to be a significant covariate on the concentration producing half maximal effect (EC50). While the results suggested patient may have different levels of sensitivity to ixekizumab, it is possible that nonresponder patients assigned to lower doses of ixekizumab may potentially become responders to ixekizumab if given doses that yield adequate exposures. [ABSTRACT FROM AUTHOR]

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Focuses on an incident of physical incompatibility when vancomycin was used during an elective open-heart surgery. Precipitation formed during the infusion of vancomycin.