Phase I study of daily and weekly regimens of the orally administered MDM2 antagonist idasanutlin in patients with advanced tumors.

Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days.

Noteworthy idiosyncrasies of 1α,25-dihydroxyvitamin D kinetics for extrapolation from mouse to man: Commentary.

Calcitriol or 1,25-dihydroxyvitamin D [1,25(OH) D ] is the active ligand of the vitamin D receptor (VDR) that plays a vital role in health and disease. Vitamin D is converted to the relatively inactive metabolite, 25-hydroxyvitamin D [25(OH)D ], by CYP27A1 and CYP2R1 in the liver, then to 1,25(OH) D by a specific, mitochondrial enzyme, CYP27B1 (1α-hydroxylase) that is present primarily in the kidney. The degradation of both metabolites is mostly carried out by the more ubiquitous mitochondrial enzyme, CYP24A1.

Tranexamic Acid Dosing for Cardiac Surgical Patients With Chronic Renal Dysfunction: A New Dosing Regimen.

Background: Tranexamic acid (TXA) is a common antifibrinolytic agent used to minimize bleeding in cardiac surgery. Up to 50% cardiac surgical patients have chronic renal dysfunction (CRD). Optimal dosing of TXA in CRD remains poorly investigated.

Highlighting Vitamin D Receptor-Targeted Activities of 1,25-Dihydroxyvitamin D in Mice via Physiologically Based Pharmacokinetic-Pharmacodynamic Modeling.

We expanded our published physiologically based pharmacokinetic model (PBPK) on 1,25-dihydroxyvitamin D [1,25(OH)D], ligand of the vitamin D receptor (VDR), to appraise VDR-mediated pharmacodynamics in mice. Since 1,25(OH)D kinetics was best described by a segregated-flow intestinal model (SFM) that described a low/partial intestinal (blood/plasma) flow to enterocytes, with feedback regulation of its synthesis (Cyp27b1) and degradation (Cyp24a1) enzymes, this PBPK(SFM) model was expanded to describe the VDR-mediated changes (altered/basal mRNA expression) of target genes/responses with the indirect response model. We examined data on 1) renal Trpv5 (transient receptor potential cation channel, subfamily V member 5) and Trpv6 and intestinal Trpv6 (calcium channels) for calcium absorption; 2) liver 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (Hmgcr) and cytochrome 7-hydroxylase (Cyp7a1) for cholesterol synthesis and degradation, respectively; and 3) renal and brain Mdr1 (multidrug-resistance protein that encodes the P-glycoprotein) for digoxin disposition after repetitive intraperitoneal doses of 120 pmol 1,25(OH)D Fitting, performed with modeling software, yielded reasonable prediction of a dominant role of intestinal Trpv6 in calcium absorption, circadian rhythm that is characterized by simple cosine models for Hmgcr and Cyp7a1 on liver cholesterol, and brain and renal Mdr1 on tissue efflux of digoxin.

Comparing early liver graft function from heart beating and living-donors: A pilot study aiming to identify new biomarkers of liver injury.

The liver and kidney functions of recipients of liver transplantation (LT) surgery with heart beating (HBD, n = 13) or living donors (LD, n = 9) with different cold ischemia times were examined during the neohepatic phase for the elimination of rocuronium bromide (ROC, cleared by liver and kidney) and tranexamic acid (TXA, cleared by kidney). Solid phase micro-extraction and LC-MS/MS was applied to determine the plasma concentrations of ROC and TXA, and creatinine was determined by standard laboratory methods. Metabolomics and the relative expressions of miR-122, miR-148a and γ-glutamyltranspeptidase (GGT), liver injury biomarkers, were also measured.

Unequivocal evidence supporting the segregated flow intestinal model that discriminates intestine versus liver first-pass removal with PBPK modeling.

Merits of the segregated flow model (SFM), highlighting the intestine as inert serosa and active enterocyte regions, with a smaller fractional (f < 0.3) intestinal flow (Q ) perfusing the enterocyte region, are described. Less drug in the circulation reaches the enterocytes due to the lower flow (f Q ) in comparison with drug administered into the gut lumen, fostering the idea of route-dependent intestinal removal.

Metabolite Kinetics: The Segregated Flow Model for Intestinal and Whole Body Physiologically Based Pharmacokinetic Modeling to Describe Intestinal and Hepatic Glucuronidation of Morphine in Rats In Vivo.

We used the intestinal segregated flow model (SFM) versus the traditional model (TM), nested within physiologically based pharmacokinetic (PBPK) models, to describe the biliary and urinary excretion of morphine 3β-glucuronide (MG) after intravenous and intraduodenal dosing of morphine in rats in vivo. The SFM model describes a partial (5%-30%) intestinal blood flow perfusing the transporter- and enzyme-rich enterocyte region, whereas the TM describes 100% flow perfusing the intestine as a whole. For the SFM, drugs entering from the circulation are expected to be metabolized to lesser extents by the intestine due to the segregated flow, reflecting the phenomenon of shunting and route-dependent intestinal metabolism.

Physiologically-Based Pharmacokinetic-Pharmacodynamic Modeling of 1α,25-Dihydroxyvitamin D3 in Mice.

1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3] concentrations are regulated by renal CYP27B1 for synthesis and CYP24A1 for degradation. Published plasma and tissue 1,25(OH)2D3 concentrations and mRNA fold change expression of Cyp24a1 and Cyp27b1 following repetitive i.p.

Pharmacokinetic modeling of tranexamic acid for patients undergoing cardiac surgery with normal renal function and model simulations for patients with renal impairment.

Tranexamic acid (TXA), an effective anti-fibrinolytic agent that is cleared by glomerular filtration, is used widely for cardiopulmonary bypass (CPB) surgery. However, an effective dosing regimen has not been fully developed in patients with renal impairment. The aims of this study were to characterize the inter-patient variability associated with pharmacokinetic parameters and to recommend a new dosing adjustment based on the BART dosing regimen for CPB patients with chronic renal dysfunction (CRD).

PBPK modeling to unravel nonlinear pharmacokinetics of verapamil to estimate the fractional clearance for verapamil N-demethylation in the recirculating rat liver preparation.

We applied physiologically based pharmacokinetic (PBPK) modeling to study the dose-dependent metabolism and excretion of verapamil and its preformed metabolite, norverapamil, to unravel the kinetics of norverapamil formation via N-demethylation. Various initial verapamil (1, 50, and 100 μM) and preformed norverapamil (1.5 and 5 μM) concentrations, perfused at 12 ml/min, were investigated in the perfused rat liver preparation.