FR104 is a monovalent pegylated Fab' Ab, antagonist of CD28, under development for treatment of transplant rejection and autoimmune diseases. In contrast to CD80/86 antagonists (CTLA4-Ig), FR104 selectively blunts CD28 costimulation while sparing CTLA-4 and PD-L1 coinhibitory signals. In the present work, FR104 has been evaluated in a first-in-human study to evaluate the safety, pharmacokinetics, pharmacodynamics, and potency of i.v. administrations in healthy subjects. Sixty-four subjects were randomly assigned to four single ascending dose groups, two double dose groups and four single ascending dose groups challenged with keyhole limpet hemocyanin. Subjects were followed up over a maximum of 113 d. Overall, the pharmacokinetics of FR104 after a single and double infusions was approximately linear at doses ≥0.200 mg/kg. CD28 receptor occupancy by FR104 was saturated at the first sampling time point (0.5 h) at doses above 0.02 mg/kg and returned to 50% in a dose-dependent manner, by day 15 (0.020 mg/kg) to 85 (1.500 mg/kg). FR104 was well tolerated, with no evidence of cytokine-release syndrome and no impact on blood lymphocyte subsets. Inhibition of anti-keyhole limpet hemocyanin Ab response was dose-dependent in FR104 recipients and was already apparent at a dose of 0.02 mg/kg. Abs to FR104 were detected in 22/46 (48%) of FR104 recipients and only 1/46 (2.2%) was detected during drug exposure. In conclusion, selective blockade of CD28 with FR104 was safe and well tolerated at the doses tested. The observed immunosuppressive activity indicated that FR104 has potential to show clinical activity in the treatment of immune-mediated diseases.
Moxidectin is a macrocyclic lactone drug derived from the actinomycete Streptomyces cyanogriseus and is currently being used as a veterinary product for the prevention of canine heartworm disease and for the treatment of internal and external parasites in cattle, sheep, goats, and horses. It is being developed by the World Health Organization (WHO) as a potential macrofilaricidal agent for mass drug administration for the elimination of onchocerciasis (river blindness) in humans caused by the parasitic worm Onchocerca volvulus. Ivermectin (Stromectol; Merck & Co., Inc.) is currently used in mass drug administration programs, but an alternative agent would potentially offer a choice in treatment. Mass drug administration is a process that would call for administration of single doses of medicine, under the supervision of a community health worker, to an entire community at one time.Knowing the extent of excretion of moxidectin into breast milk and the pharmacokinetics of the drug in lactating women will help the community health worker make appropriate decisions about dosing, hence the need for this study. Preclinical studies have shown that the absolute bioavailability of moxidectin is variable, ranging from 19% in rats to 90% in dogs (9). After oral administration, moxidectin is quickly absorbed, with the time to peak plasma concentration (t max ) being 3.7 Ϯ 1.5 h in 27 fasting healthy volunteers receiving an 8-mg dose. Administration of moxidectin with food has been shown to increase the mean peak plasma concentration (C max ) and total area under the concentration-time curve (AUC) by 34% and 39%, respectively (8).The apparent volume of distribution (V z /F) of moxidectin is large (2,000 to 3,500 liters), and moxidectin has a low clearance (CL) (2.37 to 3.50 liters/h) and undergoes very slow elimination, with the terminal-phase elimination half-life (t 1/2 ) being 485 to 842 h (4).A study in lactating dairy sheep showed that after administration of a single oral dose of 200 g/kg of body weight of moxidectin, 2.1% Ϯ 0.33% of the administered dose was excreted in milk for more than 35 days after dosing (7). The ratio of the total AUC curve for moxidectin in breast milk (AUC milk ) to the AUC was 14.3 Ϯ 1.88, indicating that although the total amount of drug that entered the breast milk was small, moxidectin preferentially entered breast milk compared to results for plasma. Similar results were seen in a study in goats (1), where 5.7% Ϯ 1.0% of an orally administered dose of 0.2
Objective. To develop diagnostic criteria for a familial form of antiphospholipid antibody syndrome (APS), identify families with >1 affected member, examine possible modes of inheritance, and determine linkage to potential candidate genes.Methods. Family members of probands with primary APS were analyzed for clinical and laboratory abnormalities associated with APS. Families with >2 affected members were analyzed by segregation analysis and typed for candidate genetic markers.Results. Seven families were identified. Thirty of 101 family members met diagnostic criteria for APS.Segregation studies rejected both environmental and autosomal recessive models, and the data were best fit by either a dominant or codominant model. Linkage analysis showed independent segregation of APS and several candidate genes.Conclusion. Clinical and laboratory criteria are essential to identify the spectrum of disease associated with APS. We believe a set of criteria was developed that can precisely define affected family members with APS. Modeling studies utilizing these criteria strongly support a genetic basis for disease in families with APS and suggest that a susceptibility gene is inherited in an autosomal dominant pattern. However, in these families, APS was not linked with HLA, Fas, or other candidate genes, including  2 -glycoprotein I, HLA, T cell receptor  chain, Ig heavy chain, antithrombin III, Fas ligand, factor V, complement factor H, IgK, and Fas.
The objective of this study was to assess the effect of a high-fat meal on the pharmacokinetics of moxidectin. Healthy male subjects were randomized to receive single oral 8 mg doses of moxidectin after an overnight fast or high-fat breakfast. In fasted subjects (N = 27), mean [SD] parameters were Cmax: 58.9 [12.5] ng/mL; tmax: 3.7 [1.5] h; area under concentration-time curve (AUC): 3,387 [1,328] ng/h/mL; Vλz/F: 2,829 [1,267] L; CL/F: 2.76 [1.28] L/h; and t½: 784 [347] h. Compared with fasted subjects, fed subjects (N = 27) exhibited a 34% increase in Cmax, delay in tmax to 5.3 [2.1] h, 44% increase in AUC, 40% decrease in Vλz/F, and a 35% decrease in CL/F. There was no significant change in t½. The changes are consistent with an increase in moxidectin bioavailability following administration with food. There were no clinically relevant changes in vital signs, laboratory tests, or electrocardiograms.
In order to evaluate the potential for CYP3A4 induction by moxidectin, midazolam pharmacokinetic (PK) parameters were compared before and after moxidectin administration. Healthy subjects received a single 8 mg dose of moxidectin and 3 single 7.5 mg doses of midazolam 3 days before, and 7 and 89 days after the moxidectin. Blood samples were taken for 24 hours to measure midazolam and metabolites in plasma, and for 89 days to measure moxidectin in plasma after dose administration. Noncompartmental PK analyses were performed for each analyte. Analysis of variance was performed on log-transformed midazolam parameters with treatment day as a fixed effect. Adverse events were recorded and laboratory tests, physical examinations, pulse oximetry monitoring, vital sign measurement, and electrocardiograms performed. Thirty-nine subjects were enrolled in the study; PK data were available for 37 subjects. Moxidectin PK parameters were similar to previous studies. There were no significant changes in PK for midazolam or its metabolites 7 or 89 days after moxidectin administration. Adverse events were generally mild and there were no relevant changes in safety assessments. Thus, 8 mg moxidectin does not induce CYP3A4 activity and other CYP3A4 substrates are unlikely to be affected by moxidectin co-administration.
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