Itraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose- and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and sample size estimation, which are important aspects of clinical trial design of bioequivalence studies.

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that can lead to permanent disability and deformity. Despite current treatment modalities, many patients are still unable to reach remission. Interleukin-1 receptor-associated kinase 4 (IRAK-4) inhibitors are novel agents designed to suppress immune signalling pathways involved in inflammation and joint destruction in RA. Four IRAK-4 inhibitors have entered clinical trials. Areas covered: This review summarizes the current stage of development of IRAK-4 inhibitors in clinical trials, detailing their chemistry, pharmacokinetics and therapeutic potential in the treatment of RA. PubMed, Embase and restricted Google searches were conducted using the term ‘IRAK-4ʹ, and publicly accessible clinical trial databases were reviewed. Expert opinion: IRAK-4 inhibitors are an exciting therapeutic option in RA management because unlike other targeted disease modifying agents, they target the innate immune system. The role of IRAK-4 as a key component of Toll/Interleukin-1 receptor signalling and its potential for a low rate of infectious complications is particularly exciting and this may facilitate their use in combination treatment. A key aspect of upcoming clinical trials will be the identification of biomarkers predictive of treatment efficacy, which will help to define if and how they will be used in the clinic.

While many studies have evaluated the relationship between BMI and breast cancer outcomes, it is unclear whether this relationship is consistent between early breast cancer (BC) and advanced BC. The study included 5099 patients with HER2 positive early BC (EBC) and 3496 with HER2 positive advanced BC (ABC). In the EBC cohort, higher BMI was associated with worse overall survival (OS) (HR [95% CI]: overweight = 1.30 [1.13–1.51]; obese = 1.37 [1.14–1.64], P = < 0.001), and worse disease-free survival (overweight = 1.10 [0.98–1.24]; obese = 1.20 [1.04–1.39], P = 0.061). In contrast, for the ABC cohort, higher BMI was significantly associated with improved OS (overweight = 0.85 [0.76–0.96]; obese = 0.82 [0.72–0.95], P = 0.014), and progression-free survival (overweight = 0.91 [0.83–1.01]; obese = 0.87 [0.77–0.98], P = 0.034). In this large high-quality dataset, higher BMI was independently associated with worse survival in EBC, paradoxically in ABC higher BMI was independently associated with improved survival.