PNO Consultants (Netherlands)

Obesity has become a major public health concern worldwide. Pharmacological interventions with the glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have shown promising results in facilitating weight loss and improving metabolic outcomes in individuals with obesity. Quantifying drug effects of GLP‐1RAs on energy intake (EI) and body weight (BW) using a QSP modeling approach can further increase the mechanistic understanding of these effects, and support obesity drug development. An extensive literature‐based dataset was created, including data from several diet, liraglutide and semaglutide studies and their effects on BW and related parameters. The Hall body composition model was used to quantify and predict effects on EI. The model was extended with (1) a lifestyle change/placebo effect on EI, (2) a weight loss effect on activity for the studies that included weight management support, and (3) a GLP‐1R agonistic effect using in vitro potency efficacy information. The estimated reduction in EI of clinically relevant dosages of semaglutide (2.4 mg) and liraglutide (3.0 mg) was 34.5% and 13.0%, respectively. The model adequately described the resulting change in BW over time. At 20 weeks the change in BW was estimated to be −17% for 2.4 mg semaglutide and −8% for 3 mg liraglutide, respectively. External validation showed the model was able to predict the effect of semaglutide on BW in the STEP 1 study. The GLP‐1RA body composition model can be used to quantify and predict the effect of novel GLP‐1R agonists on BW and changes in underlying processes using early in vitro efficacy information.

This paper builds on the literature on mission-oriented innovation policy, governance, transition studies and innovation systems, and develops a structural-functional approach to formatively evaluate mission governance from a Mission-oriented Innovation Systems (MIS) perspective. Central to this MIS approach is the mission arena, a governance structure where actors formulate and govern the mission, by mobilizing and directing other, preexisting system components. Their goal is to meet the mission by developing and diffusing innovative mission solutions and destabilizing harmful practices. The MIS approach involves a problem-solutions diagnosis and an analysis of structural, functional, and systemic barriers. To provide formative mission governance recommendations, the systemic barriers are then contrasted with the mission arena’s governance tasks. To illustrate the value of the MIS approach, we use a case study of the Dutch mission for sustainable maritime shipping. This case study illustrates a mission arena striving to increase coherence amongst different innovation system structures in semblance of a MIS. The mission arena configuration of actors shaped the mission formulation and negotiated governance actions. Dominant industry networks negotiated green growth as problem direction and non-committal governance actions, which are likely ineffective for inherently transformative sustainability missions. The paper concludes by identifying directions for further developing the MIS approach and the mission arena concept.

AimRegorafenib is an oral multikinase inhibitor with clinical efficacy in a range of advanced solid tumours. A population pharmacokinetic (PK) model was developed to evaluate the variability of the PK of regorafenib and its pharmacologically active metabolites M‐2 and M‐5 in solid tumours.MethodsThe model was initially developed using densely sampled phase 1 data and information on food intake to incorporate enterohepatic circulation (EHC) that was identified to considerably contribute to the PK of regorafenib. This was then applied to sparsely sampled data from four phase 3 studies in patients with advanced solid tumours. The need for exact food intake data to estimate individual drug exposure was evaluated.ResultsBy incorporating EHC, the model adequately described the PK profiles of regorafenib, M‐2 and M‐5 after single and multiple doses in patients from phase 1 studies. Individual exposure in phase 3 studies was adequately described based on assumptions on the time and frequency of food intake, although exact food intake data are recommended to improve the estimation. Covariate analysis identified sex and body mass index (BMI) as impacting exposure to regorafenib, and sex as strongly impacting exposure to M‐2 and M‐5 (also influenced by the BMI effect on parent regorafenib in the joint model developed); however, these factors accounted for a small portion of the overall variability in exposure.ConclusionsThe adequate description of regorafenib PK after multiple dosing requires the incorporation of EHC. Neither single nor combined covariates predicted exposures that would warrant a priori regorafenib dose adjustment.

When applied to a pure component suspension in an apolar solvent, a strong inhomogeneous electric field induces particle movement, and the particles are collected at the surface of one of the two electrodes. This new phenomenon was used to separately isolate two organic crystalline compounds, phenazine and caffeine, from their suspension in 1,4-dioxane. First, crystals of both compounds were collected at different electrodes under the influence of an electric field. Subsequent cooling crystallization enabled the immobilization and growth of the particles on the electrodes, which were separately collected after the experiment with purities greater than 91 %. This method can be further developed into a technique for crystal separation and recovery in complex multicomponent suspensions of industrial processes.

e13580 Background: The multikinase inhibitor regorafenib (REG) has shown clinical efficacy in metastatic colorectal cancer and advanced gastrointestinal stromal tumors. REG is primarily metabolized in the liver to 2 pharmacologically active metabolites, M-2 and M-5. Methods: A popPK model for REG, M-2, and M-5 is based on 14 clinical studies with rich and sparse PK sampling and doses ranging from 10 to 220 mg QD. Covariate effects (formulation, gender, weight, body-mass index [BMI], height, age, ethnic group, baseline kidney and liver function, protein levels, and hematocrit/hemoglobin) were evaluated for their influence on exposure. The popPK model was applied to the PK data of all studies to derive individual exposure estimates for the 902 subjects: Cavp (average concentration in ng/mL of REG over 24h) and Cavtot (average of sum of the molar concentration of REG, M-2, and M-5). Both exposures were estimated after 21 daily doses of 160 mg. Results: The modelled availability of REG in plasma from the oral formulation decreased linearly by 3.9% per 10 mg and was 48% higher after a single dose than after repeated doses > 120 mg. The relative amount of REG metabolized to M-2 increased linearly by 4.0% per 10 mg. The elimination of M-5 decreased linearly by 3.1% per 10 mg. The net result of this nonlinear model was a less than proportional increase in REG and a more than proportional increase in M-2 and M-5, keeping the molar sum exposure almost proportional with dose. Cavp and Cavtot were about 45% lower in healthy volunteers vs cancer patients. Cavp and Cavtot were 11% and 34% higher in females vs males, respectively. Cavp and Cavtot were 11% and 23% lower in Asians vs non-Asians, respectively. Cavtot but not Cavp was 19% lower in patients also taking UGT1A9 inhibitors. Cavp and Cavtot were positively correlated with age, hemoglobin, and plasma albumin. Cavp but not Cavtot increased with BMI. Cavtot but not Cavp decreased with body weight. Simulated patients with extreme covariate combinations were still within the borders of the 90% confidence interval of observed exposures (Cavp 1.2 to 4.7 mg/L, Cavtot 5 to 39 µM). Conclusions: None of the listed covariates or any extreme combinations thereof warrant any dosage adjustments in the absence of compelling clinical reasons.

The new European Commission's funding programme Horizon 2020 represents a unique chance to assemble innovative projects. In recognition of the importance of photonics research, the program has made it one of its most significant funding opportunities. With this paper, PNO Consultants offers the possibility of those interested to benefit from their extensive track record in idea development, project build up, consortium formation, proposal writing, project management and compliance.

The homeostatic control of arterial BP is well understood with changes in BP resulting from changes in cardiac output (CO) and/or total peripheral resistance (TPR). A mechanism-based and quantitative analysis of drug effects on this interrelationship could provide a basis for the prediction of drug effects on BP. Hence, we aimed to develop a mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model in rats that could be used to characterize the effects of cardiovascular drugs with different mechanisms of action (MoA) on the interrelationship between BP, CO and TPR. The cardiovascular effects of six drugs with diverse MoA, (amlodipine, fasudil, enalapril, propranolol, hydrochlorothiazide and prazosin) were characterized in spontaneously hypertensive rats. The rats were chronically instrumented with ascending aortic flow probes and/or aortic catheters/radiotransmitters for continuous recording of CO and/or BP. Data were analysed in conjunction with independent information on the time course of drug concentration using a mechanism-based PKPD modelling approach. By simultaneous analysis of the effects of six different compounds, the dynamics of the interrelationship between BP, CO and TPR were quantified. System-specific parameters could be distinguished from drug-specific parameters indicating that the model developed is drug-independent. A system-specific model characterizing the interrelationship between BP, CO and TPR was obtained, which can be used to quantify and predict the cardiovascular effects of a drug and to elucidate the MoA for novel compounds. Ultimately, the proposed PKPD model could be used to predict the effects of a particular drug on BP in humans based on preclinical data.