BackgroundElayta (CT1812) is a novel allosteric antagonist of the sigma-2 receptor complex that prevents and displaces binding of Aβ oligomers to neurons. By stopping a key initiating event in Alzheimer's disease, this first-in–class drug candidate mitigates downstream synaptotoxicity and restores cognitive function in aged transgenic mouse models of Alzheimer's disease.MethodsA phase 1, two-part single and multiple ascending dose study was conducted in 7 and 4 cohorts of healthy human subjects, respectively. In part A, healthy, young subjects (<65 years old) received CT1812 doses ranging from 10 to 1120 mg (6:2 active to placebo [A:P] per cohort). In part B, subjects were administered 280, 560, and 840 mg once daily for 14 days (8:2 A:P per cohort). An elderly cohort, aged 65-75 years, was dosed at 560 mg once daily for 14 days (7:2 A:P). Serum concentrations of CT1812 in part B were measured on day 3 and 14 and cerebrospinal fluid concentrations on day 7 or 9. Cognitive testing was performed in the healthy elderly cohort at baseline and at day 14 of treatment.ResultsTreatment with CT1812 was well tolerated in all cohorts. Adverse events were mild to moderate in severity and included headache and GI tract symptoms. Plasma concentrations of drug were dose proportional across two orders of magnitude with minimal accumulation over 14 days. Cognitive scores in the healthy elderly cohort were similar before and after treatment.ConclusionsCT1812 was well tolerated with single dose administration up to 1120 mg and with multiple dose administration up to 840 mg and 560 mg in healthy young and healthy elderly subjects, respectively. CT1812 is currently being studied in early phase 2 trials in patients with Alzheimer's disease.

On the basis of consistent results of 5 clinical trials in healthy volunteers, the pharmacokinetic properties of obiltoxaximab after a 16-mg/kg IV infusion can be considered adequately characterized, a criteria of the Animal Rule. Obiltoxaximab appears to be generally well tolerated. ClinicalTrials.gov identifiers: NCT00829582, NCT01453907, NCT01929226, NCT01952444, NCT01932242.

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Cefdinir (Omnicef; Abbott Laboratories) is a cephalosporin antibiotic primarily eliminated by the kidney. Nonlinear renal elimination of cefdinir has been previously reported. Cefdinir renal transport mechanisms were studied in the erythrocyte-free isolated perfused rat kidney. Studies were performed with drug-free perfusate and perfusate containing cefdinir alone to establish the baseline physiology and investigate cefdinir renal elimination characteristics. To investigate cefdinir renal transport mechanisms, inhibition studies were conducted by coperfusing cefdinir with inhibitors of the renal organic anion (probenecid), organic cation (tetraethylammonium), or dipeptide (glycylsarcosine) transport system. Cefdinir concentrations in biological samples were determined using reversed-phase high-performance liquid chromatography. Differences between treatments and controls were evaluated using analysis of variance and Dunnett's test. The excretion ratio (ER; the renal clearance corrected for the fraction unbound and glomerular filtration rate) for cefdinir was 5.94, a value indicating net renal tubular secretion. Anionic, cationic, and dipeptide transport inhibitors all significantly affected the cefdinir ER. With probenecid, the ER was reduced to 0.59, clearly demonstrating a significant reabsorptive component to cefdinir renal disposition. This finding was confirmed by glycylsarcosine studies, in which the ER was elevated to 7.95, indicating that reabsorption was mediated, at least in part, by the dipeptide transporter system. The effects of the organic cation tetraethylammonium, in which the ER was elevated to 7.53, were likely secondary in nature. The anionic secretory pathway was found to be the predominant mechanism for cefdinir renal excretion.Cefdinir (Omnicef; Abbott Laboratories) is an extendedspectrum third-generation cephalosporin approved for use in the United States, Japan, and several countries in Europe. Prescribed for use in treating mild to moderate bacterial infections in adults, children, and infants, cefdinir demonstrates excellent activity against a wide range of gram-positive and gram-negative bacteria. Cefdinir MICs have been reported to be comparable or superior to those of cephalexin, cefaclor, cefixime, cefpodoxime, cefuroxime, and ceftibuten for group A, B, C, F, and G streptococci, viridans group streptococci, Staphylococcus aureus, and Staphylococcus epidermidis. For Streptococcus pneumoniae, the in vitro activity of cefdinir has been reported to be comparable to those of cefuroxime and cefpodoxime and superior to those of other evaluated cephalosporins. Because of its hydroxyimino functionality, cefdinir is resistant to a broad variety of ␤-lactamases and exhibits a ␤-lactam stability profile generally better than those observed with cefaclor and cefuroxime (9).With respect to pharmacokinetics, cefdinir demonstrates oral bioavailability of ϳ16 to 25%. The drug is widely distributed in the body and is not appreciably metabolized once absorbed (10,20). Cefdinir elimination is primarily...

Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax under the US Food and Drug Administration's (FDA) Animal Rule. The human dose was selected and justified by comparing observed obiltoxaximab exposures in healthy and infected New Zealand White rabbits and cynomolgus macaques to observed exposures in healthy humans, to simulated exposures in healthy and infected humans, and to serum PA levels in infected animals. In humans, at 16 mg/kg intravenous, obiltoxaximab AUC was >2 times that in animals, while maximum serum concentrations were comparable to those in animals and were maintained in excess of the concentration required for PA neutralization in infected animals for 2–3 weeks. Obiltoxaximab 16 mg/kg in humans provided exposure beyond that of 16 mg/kg in animals, ensuring a sufficient duration of PA neutralization to allow for adaptive immunity development. Our approach to dose translation may be applicable to other agents being developed under the Animal Rule.