Parenteral naloxone has been approved to treat opiate overdose for over 4 decades. Intranasal naloxone, administered "off label" using improvised devices, has been widely used by both first responders and the lay public to treat overdose. However, these improvised devices require training for effective use, and the recommended volumes (2 to 4 mL) exceed those considered optimum for intranasal administration. The present study compared the pharmacokinetic properties of intranasal naloxone (2 to 8 mg) delivered in low volumes (0.1 to 0.2 mL) using an Aptar Unit-Dose device to an approved (0.4 mg) intramuscular dose. A parallel study assessed the ease of use of this device in a simulated overdose situation. All doses of intranasal naloxone resulted in plasma concentrations and areas under the curve greater than those observed following the intramuscular dose; the time to reach maximum plasma concentrations was not different following intranasal and intramuscular administration. Plasma concentrations of naloxone were dose proportional between 2 and 8 mg and independent of whether drug was administered to 1 or both nostrils. In a study using individuals representative of the general population, >90% were able to perform both critical tasks (inserting nozzle into a nostril and pressing plunger) needed to deliver a simulated dose of naloxone without prior training. Based on both pharmacokinetic and human use studies, a 4-mg dose delivered in a single device (0.1 mL) was selected as the final product. This product can be used by first responders and the lay public, providing an important and potentially life-saving intervention for victims of an opioid overdose.

Metabolism by cytochrome P4503A (CYP3A) is the most prevalent clearance pathway for drugs. Designation of metabolism by CYP3A commonly refers to the potential contribution by one or both of two enzymes, CYP3A4 and CYP3A5. The metabolic turnover of 32 drugs known to be largely metabolized by CYP3A was examined in human liver microsomes (HLMs) from CYP3A5 expressers (*1/*1 genotype) and nonexpressers (*3/*3 genotype) in the presence and absence of ketoconazole and CYP3cide (a selective CYP3A4 inactivator) to calculate the contribution of CYP3A5 to metabolism. Drugs with the highest contribution of CYP3A5 included atazanavir, vincristine, midazolam, vardenafil, otenabant, verapamil, and tacrolimus, whereas 17 of the 32 tested showed negligible CYP3A5 contribution. For specific reactions in HLMs from *1/*1 donors, CYP3A5 contributes 55% and 44% to midazolam 19-and 4-hydroxylation, 16% to testosterone 6b-hydroxylation, 56% and 19% to alprazolam 19-and 4-hydroxylation, 10% to tamoxifen N-demethylation, and 58% to atazanavir p-hydroxylation.Comparison of the in vitro observations to clinical pharmacokinetic data showed only a weak relationship between estimated contribution by CYP3A5 and impact of CYP3A5 genotype on oral clearance, in large part because of the scatter in clinical data and the low numbers of study subjects used in CYP3A5 pharmacogenetics studies. These data should be useful in guiding which drugs should be evaluated for differences in pharmacokinetics and metabolism between subjects expressing CYP3A5 and those who do not express this enzyme.

The clinical development of fedratinib, a Janus kinase (JAK2) inhibitor, was terminated after reports of Wernicke's encephalopathy in myelofibrosis patients. Since Wernicke's encephalopathy is induced by thiamine deficiency, investigations were conducted to probe possible mechanisms through which fedratinib may lead to a thiamine-deficient state. In vitro studies indicate that fedratinib potently inhibits the carrier-mediated uptake and transcellular flux of thiamine in Caco-2 cells, suggesting that oral absorption of dietary thiamine is significantly compromised by fedratinib dosing. Transport studies with recombinant human thiamine transporters identified the individual human thiamine transporter (hTHTR2) that is inhibited by fedratinib. Inhibition of thiamine uptake appears unique to fedratinib and is not shared by marketed JAK inhibitors, and this observation is consistent with the known structure-activity relationship for the binding of thiamine to its transporters. The results from these studies provide a molecular basis for the development of Wernicke's encephalopathy upon fedratinib treatment and highlight the need to evaluate interactions of investigational drugs with nutrient transporters in addition to classic xenobiotic transporters.

PK/PD evaluations for aztreonam/avibactam in HFIM yielded a single target across strains with a wide MIC range. This integrated approach could be easily applied for forecasting clinically efficacious doses for β-lactam/β-lactamase inhibitor combinations.