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Nayak A.S.,Wheeze and Itch Associates LLC | Atiee G.J.,ICON Development Solutions | Dige E.,ALK Abello | Maloney J.,Merck And Co. | Nolte H.,Merck And Co.
Allergy and Asthma Proceedings

A sublingually administered allergy immunotherapy tablet (AIT) is under development to treat ragweed (Ambrosia artemisiifolia)-induced allergic rhinoconjunctivitis (ARC). This study investigates the optimal tolerable dose of oncedaily ragweed pollen AIT. Subjects 18-50 years old with ragweed-induced ARC were enrolled at two U.S. centers in a double-blind, placebo-controlled, dose-escalation study outside ragweed season. Groups (12 subjects each) were to be randomized 3:1 to 28 days of active treatment (groups assigned in sequence to 3, 6, 12, 24, 50, or 100 Amb a 1 U, without dose buildup at any level) or matching placebo. Recruitment to 50 Amb a 1-U was discontinued because of adverse events (AEs) after four AIT subjects were enrolled; 100 1 unit of ambrosia artemislifolia major allergen 1 was not initiated. Fifty-three subjects were randomized (AIT, n = 40; placebo, n = 13); four discontinued, all because of AEs (AIT, n = 3; placebo, n = 1). Treatment-related AEs (TRAEs) were more frequent with AIT (73%) than placebo (31%), increasing with dose level. AIT TRAEs were mostly mild (94%) or moderate (5%). No serious TRAEs or anaphylactic shock occurred. The most common TRAEs with AIT were localized pruritus, nasal irritation, and throat irritation. Median onset for common AIT application site reactions was ≤24 hours after first treatment (median duration, 15-50 minutes). AIT increased immunoglobulin (Ig) significantly more than placebo (ragweed-specific IgE [6, 12, and 24 Amb a 1-U]; IgG4 [all doses]; p < 0.05). Three subjects in dose groups ≥24 Amb a 1-U experienced symptoms suggestive of systemic reaction. Of tested doses, ragweed AIT <24 Amb a 1-U once-daily was well tolerated in subjects with ragweed-induced ARC. Clinical trial registration URL and registration number: www.clinicaltrials.gov/ct2/show/ NCT01134705. Copyright © 2012, OceanSide Publications, Inc., U.S.A. Source

The reanalysis of incurred bioanalytical samples (incurred sample reanalysis) provides additional data that help us to ensure that a 'validated bioanalytical method' is reproducible. While the guidelines for the conduct of incurred sample reanalysis evaluations have been well described, published information pertaining to the occurrence of failures and the manner in which they are resolved has not received the same amount of attention. The purpose of this manuscript is to describe two case studies where incurred sample reanalysis failures were encountered for small molecules, the approaches that were taken to elucidate the root cause of the failures, and the remedial actions that were implemented to prevent such failures from recurring. Source

Silverman J.A.,TALON THERAPEUTICS | Reynolds L.,ICON Development Solutions | Deitcher S.R.,TALON THERAPEUTICS
Journal of Clinical Pharmacology

Vincristine sulfate liposome injection (VSLI,) is a sphingomyelin and cholesterol nanoparticle formulation of vincristine sulfate (VCR) that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. In contrast to the rapid CL and wide tissue distribution of non]liposomal VCR, VSLI circulates in plasma for a prolonged period of time, with a slow CL of 345 mL/h and relatively small Vd of 3,570 mL. This facilitates enhanced and prolonged tumor]tissue delivery of VCR. The maximum tolerated dose of VSLI, 2.25 mg/m2 once per week without a dose cap, enables individual and cumulative VCR exposure unachievable with non]liposomal VCR at its labeled dose of 1.4 mg/m2. VSLI is associated with a dose]dependent peripheral neurotoxicity albeit at doses that are two to three times that of standard VCR. VCR dose intensification with VSLI correlated with an increased probability of overall response and a strong trend towards increased complete response in adults with relapsed and/or refractory acute lymphoblastic leukemia. Overall, VSLI improves the therapeutic index by facilitating increased dose intensification while maintaining a predictable and manageable safety profile. © 2013, The American College of Clinical Pharmacology. Source

Tang D.,ICON Development Solutions | Thomas E.,Manchester Laboratories

There is a consensus in industry that there is a need to assess the impact of hemolysis on the bioanalytical method. However, due to the difficulty to prepare standardized hemolyzed QC samples and the fact that no apparent conclusion can be made from hemolysis assessments during method validation, we propose that the assessments are conducted during method development and sample analysis. The use of a stable-labeled internal standard is highly recommended to identify the hemolyzed samples with potential issues of matrix effects. When an internal standard response is abnormal, dilution or standard addition can be used to confirm the data accuracy of the hemolyzed samples. An incurred sample reanalysis test is also recommended for hemolyzed samples to ensure the reproducibility of a hemolysis-'insensitive' method. The number of hemolyzed samples selected for incurred sample reanalysis is study dependent. All these additional steps can determine the 'reportability' of the bioanalytical data. For regulated studies, it is important to document all hemolysis tests in appropriate ways based on GLP requirement. © 2012 Future Science Ltd. Source

Pentikis H.S.,SAJE Consulting LLC | Matson M.,PRISM Research Inc. | Atiee G.,ICON Development Solutions | Boehlecke B.,Rho Inc. | And 5 more authors.
Antimicrobial Agents and Chemotherapy

FV-100 is the prodrug of the highly potent anti-varicella zoster virus bicyclic nucleoside analogue CF-1743. To characterize the pharmacokinetics and safety of oral FV-100, 3 randomized, double-blind, placebo-controlled clinical trials were conducted: (i) a single-ascending-dose study in 32 healthy subjects aged 18 to 55 years (100-, 200-, 400-, and 800-mg doses) with an evaluation of the food effect in the 400-mg group; (ii) a multiple-ascending-dose study in 48 subjects aged 18 to 55 years (100 mg once daily [QD], 200 mg QD, 400 mg QD, 400 mg twice a day, and 800 mg QD for 7 days); and (iii) a 2-part study in subjects aged 65 years and older with a single 400-mg dose in 15 subjects and a 400-mg QD dosing regimen for 7 days in 12 subjects. FV-100 was rapidly and extensively converted to CF-1743, the concentration of which remained above that required to reduce viral activity by 50% for the 24-hour dosing period. Renal excretion of CF-1743 was very low. A high-fat meal reduced exposure to CF-1743; a low-fat meal did not. Pharmacokinetic parameters for the elderly subjects were comparable to those for the younger subjects. FV-100 was well tolerated by all subjects. The pharmacokinetic and safety profiles of FV-100 support its continued investigation for the treatment of herpes zoster and prevention of postherpetic neuralgia with once-daily dosing and without dose modifications for elderly or renally impaired patients. Copyright © 2011, American Society for Microbiology. All Rights Reserved. Source

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