Pharmacokinetics of Clofarabine in Patients with High-risk Inherited Metabolic Disorders Undergoing Brain-sparing Hematopoietic Cell Transplantation

Clofarabine, a newer purine analog with reduced central nervous system toxicity, may prove advantageous in hematopoietic cell transplantation in patients for whom neurotoxicity is a natural part of disease progression. This study evaluated clofarabine pharmacokinetics in adult and pediatric patients undergoing hematopoietic cell transplantation for the treatment of high-risk, inherited metabolic disorders. Clofarabine (40 mg/m(2)/d) … Continued

N1-benzoyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes: Development of 4-chlorophenylcarboxamide (calhex 231) as a New Calcium Sensing Receptor Ligand Demonstrating Potent Calcilytic Activity

A structure-activity relationship (SAR) study was performed principally at the N1 position of N1-arylsulfonyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes, a new family of calcilytics acting at the calcium sensing receptor (CaSR). The most active compound in this series was the 4-(trifluoromethoxy)benzenesulfonyl derivative 7e, which displayed an IC50 of 5.4 ± 0.5 µM with respect to the inhibition of calcium-induced tritiated … Continued

Epimerase Activity of the Human 11β-hydroxysteroid Dehydrogenase Type 1 on 7-hydroxylated C19-steroids

Cytochrome P4507B1 7α-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5α-androstane-3β,17β-diol (Adiol). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts 7α- and 7β-forms. Whether the interconversion proceeds through oxido-reductive steps or epimerase activity was investigated. Experiments using [(3)H]-labelled 7β-hydroxy-DHEA, 7β-hydroxy-EpiA and 7β-hydroxy-Adiol showed the (3)H-label to accumulate in the 7-oxo-DHEA trap but not in 7-oxo-EpiA or 7-oxo-Adiol traps. Computed … Continued

Case Studies Addressing Human Pharmacokinetic Uncertainty Using a Combination of Pharmacokinetic Simulation and Alternative First-in-human

PF-184298 ((S)-2,3-dichloro-N-isobutyl-N-pyrrolidin-3-ylbenzamide) and PF-4776548 ((3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo[2,3-c][1,7]naphthyridin-6-one)) are novel compounds which were selected to progress to human studies. Discordant human pharmacokinetic predictions arose from pre-clinical in vivo studies in rat and dog, and from human in vitro studies, resulting in a clearance prediction range of 3 to >20 mL min-1  kg-1 for PF-184298, and 5 to >20 mL min-1 … Continued

Application of PBPK Modeling to Predict Monoclonal Antibody Disposition in Plasma and Tissues in Mouse Models of Human Colorectal Cancer

This investigation evaluated the utility of a physiologically based pharmacokinetic (PBPK) model, which incorporates model parameters representing key determinants of monoclonal antibody (mAb) target-mediated disposition, to predict, a priori, mAb disposition in plasma and in tissues, including tumors that express target antigens. Monte Carlo simulation techniques were employed to predict the disposition of two mAbs, 8C2 (as a non-binding control mouse IgG1 mAb) and T84.66 (a high-affinity murine IgG1 anti-carcinoembryonic antigen … Continued

2D- and 3D-QSAR Studies on 54 Anti-tumor Rubiaceae-type Cyclopeptides

RA-VII, a bicyclic hexapeptide isolated from the roots of Rubia cordifolia, Rubia akane belongs to Rubiaceae-type cyclopeptides (RAs) and has attracted much attention for its potent anti-tumor activity and its bicyclic structure incorporating the isodityrosine moiety. In this work, hologram quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis … Continued

Certara to Participate in 19 Sessions at ACoP7

PRINCETON, NJ – Oct. 21, 2016 – Certara today announced it will be participating in 19 sessions at the Seventh American Conference on Pharmacometrics (ACoP7). This year’s conference is being held from Oct. 23-26 in Bellevue, Washington.

Therapeutic Benefit of Eletriptan Compared to Sumatriptan for the Acute Relief of Migraine Pain—Results of a Model-based Meta-analysis that Accounts for Encapsulation

A novel model-based meta-analysis was used to quantify the dose-response relationship of sumatriptan and eletriptan for the proportion of patients that achieve migraine pain relief up to 4 h after treatment. The proportion of patients that became pain free was also evaluated. This analysis includes some unique features, allowing comparison of sumatriptan and eletriptan doses … Continued

Application of Knockout Mouse Models to Investigate the Influence of FcγR on the Pharmacokinetics and Anti-platelet Effects of MWReg30, a Monoclonal Anti-GPIIb Antibody

This work evaluates the influence of FcγR on the pharmacokinetics and pharmacodynamics of a rat anti-integrin-αIIb IgG1 monoclonal antibody, MWReg30, in mice. The pharmacokinetics and pharmacodynamics of MWReg30 were investigated in C57BL/6 control mice, FcγRI/RIII knockout mice, and FcγRIIb knockout mice, following intravenous doses of 0.04-0.4mg/kg. MWReg30 treatment resulted in a dose-dependent induction of thrombocytopenia … Continued