A summary of the current drug interaction guidance from the European Medicines Agency and considerations of future updates.

The current EMA drug interaction guideline was published in 2012. This guideline gives important recommendations on the information required to elucidate the interaction potential of an investigational drug, both as effects of the investigational drug on the PK of other drugs and effects of other medicinal products on the PK of the investigational drug. Additional information on the use of PBPK modelling to inform drug interaction information, is also available in the guideline on the reporting of physiologically based modelling and simulation (2018).

The Importance of the Human Mass Balance Study in Regulatory Submissions.

The human mass balance study is a key study in the Clinical Pharmacology package of new drug applications. This study, along with the mass balance studies in toxicology species, provides essential information on the exposure of the parent compound and metabolites. Despite current regulatory guidance and previous publications, a lack of this study, or deficiencies in the study, are still seen in regulatory submissions today.

Evaluation of a novel chemokine receptor 2 (CCR2)-antagonist in painful diabetic polyneuropathy.

Background and aims Preclinical data suggest that the chemokine receptor 2 (CCR2) is involved in the pathophysiology of neuropathic pain through modulation of neuronal excitability, synaptic transmission and activation of spinal cord microglia. CCR2-antagonists have shown to be effective in preclinical models of neuropathic pain. The aim of this study was to evaluate the analgesic efficacy, safety and tolerability of a novel CCR2-antagonist, AZD2423, in patients with painful diabetic neuropathy (PDN).

Assessment of interaction potential of AZD2066 using in vitro metabolism tools, physiologically based pharmacokinetic modelling and in vivo cocktail data.

Purpose: Static and dynamic (PBPK) prediction models were applied to estimate the drug-drug interaction (DDI) risk of AZD2066. The predictions were compared to the results of an in vivo cocktail study. Various in vivo measures for tolbutamide as a probe agent for cytochrome P450 2C9 (CYP2C9) were also compared.

AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans.

Abnormal tau phosphorylation resulting in detachment of tau from microtubules and aggregation are critical events in neuronal dysfunction, degeneration, and neurofibrillary pathology seen in Alzheimer's disease. Glycogen synthase kinase-3β (GSK3β) is a key target for drug discovery in the treatment of Alzheimer's disease and related tauopathies because of its potential to abnormally phosphorylate proteins and contribute to synaptic degeneration. We report the discovery of AZD1080, a potent and selective GSK3 inhibitor that demonstrates peripheral target engagement in Phase 1 clinical studies.

MEPS as a rapid sample preparation method to handle unstable compounds in a complex matrix: determination of AZD3409 in plasma samples utilizing MEPS-LC-MS-MS.

The aim of the present investigation is to develop a simple, fast, and sensitive method for the determination of a new candidate drug, AZD3409, in rat, dog, and human plasma samples. AZD3409 is stable in aqueous solutions at low pH (< 4) but not in whole blood or in plasma. In rat plasma at 25 degrees C, more than 90% of the compound is degraded within 40 min.

Effect of a dental cream containing amorphous cream phosphate complexes on white spot lesion regression assessed by laser fluorescence.

Purpose: To investigate and compare the effects of a dental cream containing complexes of casein phosphoprotein-amorphous calcium phosphate (CPP-ACP) and fluoride mouthwashes on the regression of white spot lesions (WSL).

Materials And Methods: The study group consisted of 26 healthy adolescents (mean age 14.6 years) exhibiting 60 teeth with 152 visible WSL sites on incisors and canines immediately after debonding of fixed orthodontic appliances.