Oral docetaxel plus encequidar - A pharmacokinetic model and evaluation against IV docetaxel.

The development of optimized dosing regimens plays a crucial role in oncology drug development. This study focused on the population pharmacokinetic modelling and simulation of docetaxel, comparing the pharmacokinetic exposure of oral docetaxel plus encequidar (oDox + E) with the standard of care intravenous (IV) docetaxel regimen. The aim was to evaluate the feasibility of oDox + E as a potential alternative to IV docetaxel. The article demonstrates an approach which aligns with the FDA's Project Optimus which aims to improve oncology drug development through model informed drug development (MIDD). The key question answered by this study was whether a feasible regimen of oDox + E existed. The purpose of this question was to provide an early GO / NO-GO decision point to guide drug development and improve development efficiency. METHODS:  A stepwise approach was employed to develop a population pharmacokinetic model for total and unbound docetaxel plasma concentrations after IV docetaxel and oDox + E administration. Simulations were performed from the final model to assess the probability of target attainment (PTA) for different oDox + E dose regimens (including multiple dose regimens) in relation to IV docetaxel using AUC over effective concentration (AUCOEC) metric across a range of effective concentrations (EC). A Go / No-Go framework was defined-the first part of the framework assessed whether a feasible oDox + E regimen existed (i.e., a PTA ≥ 80%), and the second part defined the conditions to proceed with a Go decision. RESULTS:  The overall population pharmacokinetic model consisted of a 3-compartment model with linear elimination, constant bioavailability, constant binding mechanics, and a combined error model. Simulations revealed that single dose oDox + E regimens did not achieve a PTA greater than 80%. However, two- and three-dose regimens at 600 mg achieved PTAs exceeding 80% for certain EC levels. CONCLUSION:  The study demonstrates the benefits of MIDD using oDox + E as a motivating example. A population pharmacokinetic model was developed for the total and unbound concentration in plasma of docetaxel after administration of IV docetaxel and oDox + E. The model was used to simulate oDox + E dose regimens which were compared to the current standard of care IV docetaxel regimen. A GO / NO-GO framework was applied to determine whether oDox + E should progress to the next phase of drug development and whether any conditions should apply. A two or three-dose regimen of oDox + E at 600 mg was able to achieve non-inferior pharmacokinetic exposure to current standard of care IV docetaxel in simulations. A Conditional GO decision was made based on this result and further quantification of the "effective concentration" would improve the ability to optimise the dose regimen.

Ketamine for treatment-resistant major depressive disorder: Double-blind active-controlled crossover study.

BACKGROUND: The N-methyl-D-aspartate antagonist ketamine has rapid onset antidepressant activity in treatment-resistant depression (TRD). AIMS: To evaluate mood rating, safety and tolerability data from patients with TRD treated with ketamine and the psychoactive control fentanyl, as part of a larger study to explore EEG biomarkers associated with mood response. METHODS: We evaluated the efficacy and safety of intramuscular racemic ketamine in 25 patients with TRD, using a double-blind active-controlled randomized crossover design. Ketamine doses were 0.5 and 1 mg/kg, and the psychoactive control was fentanyl 50 mcg, given at weekly intervals. RESULTS/OUTCOMES: Within 1 h of ketamine dosing, patients reported reduced depression and anxiety ratings, which persisted for up to 7 days. A dose-response profile for ketamine was noted for dissociative side effects, adverse events and changes in blood pressure; however, changes in mood ratings were broadly similar for both ketamine doses. Overall, 14/25 patients (56%) were responders (⩾50% reduction at 24 h compared with baseline) for either ketamine dose for the Hospital Anxiety and Depression Scale (HADS), and 18/25 (72%) were responders for the HADS-anxiety scale. After fentanyl, only 1/25 (HADS-depression) and 3/25 (HADS-anxiety) were responders. Ketamine was generally safe and well tolerated in this population. CONCLUSIONS: Our findings add to the literature confirming ketamine's activity against depressive and anxiety symptoms in patients with TRD.

Pharmacokinetics in Penguins Compared to Other Avian Species: A Review of Enrofloxacin and Voriconazole.

Australasia is home to unique and endangered avian species. Drug administration to this group of animal patients for prophylaxis and treatment is challenging from a number of different perspectives. A key limitation for optimal drug dosing in birds is the lack of published pharmacokinetic studies to guide dose requirements. The aim of this review was to systematically investigate published literature on pharmacokinetics in penguin species and compare that with the pharmacokinetics of other avian species with a focus on two drugs: enrofloxacin and voriconazole. The review was conducted following PRISMA guidelines. A systematic literature search was performed in Pubmed, Embase, Scopus, and Web of Science databases. A key finding is that penguin pharmacokinetics differs from other avian species, with weight-adjusted AUC and Cmax values higher than most other avian species (e.g., for enrofloxacin, the AUC in the African penguin is 85.7 µg h/mL, which is more than double the other bird species). Doses for some avian species may be successfully extrapolated from other avian species; however, it appears important to consider factors other than just body weight (e.g., clearance mechanism and drug physicochemical characteristics). Consequently, there is an important need for robust pharmacokinetic data in wildlife species to ensure optimal therapy for this special group of patients. As part of this review, we identify key aspects that should be considered when estimating dose in species for which there is limited pharmacokinetic information available.

Pharmacists in zoos? A qualitative study investigating the potential for pharmacist involvement in wildlife health care in Aotearoa, New Zealand.

BACKGROUND: The importance of wildlife health has been critically emphasized by the current global pandemic. Pharmacists play a valuable role in the health care of companion animals and livestock; however, their involvement in exotic animal health is largely unexplored. OBJECTIVES: This project consulted with zoo vets in New Zealand and investigated their practices around prescribing and dispensing of medicines to explore the opportunities for the involvement of pharmacists. METHODS: A mixed methods approach was used where data were initially collected through an online survey distributed to 26 veterinarians and animal keepers working in zoos, wildlife parks, and sanctuaries. An optional semistructured interview followed the survey. RESULTS: The facilities surveyed housed New Zealand native animal species and 85% also housed exotic animals. Veterinarians dispensed 75% of medicines at their animal facility, whereas the remaining 25% were dispensed by veterinary nurses. On average, 5-10 medications were dispensed at each animal facility per day. Common medicines dispensed were antibiotics, pain relievers, and antifungals. Most respondents felt that they could benefit from working alongside pharmacists in veterinary care. Compounding, access to medicines and identification of tailored formulations were identified as areas where collaboration would be valued. Limitations in the knowledge of pharmacists in animal medicine were distinguished as an area enhancement to assist in collaborative relationships. CONCLUSIONS: There are opportunities for the skills of pharmacists to be incorporated into the care of animals in zoos and wildlife parks in New Zealand. Strengthening the pharmacist-veterinarian relationship can enhance the health outcomes of animals in animal facilities through this interprofessional interaction.