Population pharmacokinetic analysis of lanicemine (AZD6765), an NMDA channel blocker, in healthy subjects and patients with major depressive disorder.

WHAT IS KNOWN AND OBJECTIVE: Lanicemine (AZD6765) is a low-trapping N-methyl-d-aspartate receptor channel blocker that has demonstrated antidepressant efficacy in three of four clinical studies. The aim of this study was to develop a population pharmacokinetic model describing the concentration vs time profile of intravenously administered lanicemine in healthy subjects and patients with major depressive disorder (MDD) and to use the model to evaluate the impact of demographic and clinical factors and concomitant medication on the pharmacokinetics of lanicemine. METHODS: Data were derived from four studies: two Phase I trials in healthy subjects (studies 8 [NCT01069822] and 13 [NCT00785915]) and two Phase II trials in patients with MDD (studies 1 [NCT00491686] and 9 [NCT00781742]). Population pharmacokinetic analysis was performed by nonlinear mixed-effects modelling. The covariates evaluated within the model included sex, race, age and body weight parameters, clinically relevant laboratory measures, and use of concomitant medications. Goodness-of-fit plots, bootstrap and visual predictive checks were conducted to confirm concordance with observed data. RESULTS AND DISCUSSION: A total of 2531 plasma lanicemine concentrations were available for analysis from 191 healthy subjects and patients with MDD. The pharmacokinetics of lanicemine following intravenous infusion was best described by a two-compartment model with zero-order input and first-order elimination. Mean systemic clearance (CL) was estimated at 9.43 L/h (90% CI 9.12-9.77), central compartment volume of distribution (V1) was 106 L (90% CI 93.7-115), peripheral volume of distribution (V2) was 47.3 (95% CI 39.6-56.6), and intercompartmental clearance (Q) was 75.7 (90% CI 51.8-127). Lean body mass and body surface area had a statistically significant effect on CL and V1, respectively. WHAT IS NEW AND CONCLUSIONS: The population pharmacokinetic model developed adequately described the clinical observation of lanicemine in patients with MDD and healthy volunteers. Lean body mass and body surface area were identified as covariates that significantly influence the pharmacokinetics of lanicemine.

A Modified OSCE Assessing the Assimilation and Application of Ethical Principles Relevant to Obstetric and Gynaecological Practice.

OBJECTIVE: To develop and evaluate a modified OSCE assessing the assimilation and application of a range of ethical principles relevant to Obstetric and Gynecological practice. SETTING: Candidates for an SpR training rotation Methods. Twenty six candidates working in Obstetrics and Gynecology were presented with four questions covering a range of relevant ethical scenarios. Their responses were assessed using a marking schedule. The marking schedule was evaluated against a checklist developed for assessing postgraduate medical examinations. Inter-rater reliability was assessed by calculating Kappa values for each question. The items in the marking schedule were also assessed to determine the level of agreement between the two examiners. To assess the contribution of each question to the total score, the question to total score correlations were calculated. The discriminatory capacity of each question was also assessed. RESULTS: The development of the examination met almost all of the criteria in the checklist for developing a postgraduate examination. Inter-rater reliability was reasonable (4 weighted Kappas ranged from 0.53 - 0.75). There was a high level of agreement between examiners as to whether a candidate had answered an item on the marking schedule correctly. The degree of discrimination of items in the marking schedule was consistent with clinical opinion on the importance of questions. CONCLUSION: This modified OSCE examination demonstrates the feasibility of testing ethical principles relevant to practice in Obstetrics and Gynecology in candidates for postgraduate posts. It meets most of the criteria laid down in a checklist developed to assess postgraduate medical examinations.