In antidiabetic drug development, phase I studies usually involve short-term glucose provocations. Multiple designs are available for these provocations (e.g., meal tolerance tests (MTTs) and graded glucose infusions (GGIs)). With a highly nonlinear, complex system as the glucose homeostasis, the various provocations will contribute with different information offering a rich choice. Here, we investigate the most appropriate study design in phase I for several hypothetical mechanisms of action of a study drug. Five drug effects in diabetes therapeutic areas were investigated using six study designs. Power to detect drug effect was assessed using the likelihood ratio test, whereas precision and accuracy of the quantification of drug effect was assessed using stochastic simulation and estimations. An overall summary was developed to aid designing the studies of antihyperglycemic drug development using model-based analysis. This guidance is to be used when the integrated glucose insulin model is used, involving the investigated drug mechanisms of action.
In antihyperglycemic drug development, drug effects are usually characterized using glucose provocations. Analyzing provocation data using pharmacometrics has shown powerful, enabling small studies. In preclinical drug development, high power is attractive due to the experiment sizes; however, insulin is not always available, which potentially impacts power and predictive performance. This simulation study was performed to investigate the implications of performing model-based drug characterization without insulin. The integrated glucose-insulin model was used to simulate and re-estimated oral glucose tolerance tests using a crossover design of placebo and study compound. Drug effects were implemented on seven different mechanisms of action (MOA); one by one or in two-drug combinations. This study showed that exclusion of insulin may severely reduce the power to distinguish the correct from competing drug effect, and to detect a primary or secondary drug effect, however, it did not affect the predictive performance of the model.
Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted ∼4% malaria incidence per year compared to ∼8% for dosing regimen of two tablets weekly and ∼10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.