Pharmaceutical Product Development

About: Pharmaceutical Product Development is a company organization based out in Wilmington, North Carolina, United States. It is known for research contribution in the topics: Immunotoxin & Fusion protein. The organization has 402 authors who have published 353 publications receiving 16396 citations.

GSK2878175, a pan-genotypic non-nucleoside NS5B polymerase inhibitor, in healthy and treatment-naïve chronic hepatitis C subjects.

Abstract: Summary GSK2878175 is a potent, pan-genotypic, non-nucleoside, non–structural protein 5B palm polymerase inhibitor being developed for the treatment of chronic hepatitis C (CHC). A first-in-human, randomized, placebo-controlled, dose escalation study, evaluated the safety and pharmacokinetics of GSK2878175 administered as single and repeat oral doses (once daily for 14 days) to healthy volunteers. A separate proof-of-concept, placebo-controlled, repeat dose (once daily for 2 days) study evaluated the safety, pharmacokinetics, and antiviral activity of GSK2878175 monotherapy in treatment naive, non-cirrhotic, subjects with HCV genotype 1 [1a and 1b], 2, or 3. No deaths or SAEs were reported in either study and treatment was well-tolerated. Across all the HCV genotypes, GSK2878175 monotherapy at doses of 10, 30 or 60 mg once daily for 2 days produced a statistically significant multi-log reduction (p<0.001) in plasma HCV RNA log10 IU/mL from Baseline to 24, 48, and 72 hours after the first dose of GSK2878175 compared to placebo. The reduction in HCV RNA was sustained for a prolonged period across all of the active treatment groups, consistent with the long apparent half-life of GSK2878175 that was observed (mean t1/2 range: 60-63 hours in the CHC subjects). In summary, GSK2878175, when administered to healthy subjects and subjects with CHC, did not reveal any safety concerns that would limit or preclude further clinical development. GSK2878175 monotherapy across a wide dose range produced substantial reduction in HCV RNA, irrespective of HCV genotype. The results from these studies support further evaluation of GSK2878175-based regimens. This article is protected by copyright. All rights reserved.

A CD-MEKC Method Utilizing a Neutral Surfactant for Enantiomeric Purity Determination of an Oxazolidinone Drug Candidate

Abstract: A method based on cyclodextrin-mediated micellar electrokinetic chromatography (CD-MEKC) was developed and validated for quantification of the minor, undesired enantiomer (distomer) in the drug candidate PHA-549184, an oxazolidinone that was under development as an antibiotic. The low intrinsic solubility of the compound (0.24 mg mL−1), combined with the poor solution concentration sensitivity of capillary electrophoresis, required extensive method development to enhance the solubility of PHA-549184 while minimally degrading electrophoretic performance. A number of approaches were investigated, including inclusion of neutral and charged cyclodextrins in the background electrolyte (BGE) and addition of both charged and neutral surfactants. The final BGE contains the nonionic surfactant Brij 35: pH 2.5, 18.8 mM lithium phosphate buffer/5% highly sulfated-γ-CD/7.5 mM Brij 35. Quantitation is versus an external standard in the presence of an internal standard. The assay is selective for the distomer and proved linear with a mean recovery of 104.0% over the range 0.25–2.0%. The LOD was 0.1, and the LOQ 0.2%, both slightly higher than customary in chiral analysis, a consequence of an upper bound of 1.5 mg mL−1 placed on the sample concentration in order to maintain high efficiency for the system. Precision examined over the range 0.2–1.0% varied between 3.8% and 8.0%. No batch of drug substance registered above the detection limit for the distomer.

Targeting the fetal acetylcholine receptor in rhabdomyosarcoma

Abstract: Introduction: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. Recent efforts to enhance overall survival of patients with clinically advanced RMS have failed and there is a demand for conceptually novel treatments. Immune therapeutic options targeting the fetal nicotinic acetylcholine receptor (fnAChR), which is broadly expressed on RMS, are novel approaches to overcome the therapeutic resistance of RMS. Expression of the fnAChR is restricted to developing fetal muscles, some apparently dispensable ocular muscle fibers and thymic myoid cells. Therefore, after-birth fnAChR is a tumor-associated and almost tumor-specific antigen on RMS cells. Areas covered: This review gives an overview on nAChR function and expression pattern in RMS tumor cells, and deals with the immunological significance of fnAChR-expressing cells, including the risk of anti-nAChR autoimmunity as a potential side effect of fnAChR-directed immunotherapies. The article also addresses the advanta...

Implementation of highly sophisticated flow cytometry assays in multicenter clinical studies: considerations and guidance

Abstract: Flow cytometry is increasingly becoming an important technology for biomarkers used in drug discovery and development. Within clinical development flow cytometry is used for the determination of PD biomarkers, disease or efficacy biomarkers or patient stratification biomarkers. Significant differences exist between flow cytometry methodology and other widely used technologies measuring soluble biomarkers including ligand binding and mass spectrometry. These differences include the very heavy reliance on aspects of sample processing techniques as well as sample stabilization to ensure viable samples. These differences also require exploration of new approaches and wider discussion regarding method validation requirements. This paper provides a review of the current challenges, solutions, regulatory environment and recommendations for the application of flow cytometry to measure biomarkers in clinical development.