Publications by authors named "David Taft"

38 Publications

Application of Physiologically Based Pharmacokinetic-Pharmacodynamic Modeling in Preterm Neonates to Guide Gentamicin Dosing Decisions and Predict Antibacterial Effect.

J Clin Pharmacol 2021 May 4. Epub 2021 May 4.

Samuel J. and Joan B. Williamson Institute for Pharmacometrics, Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York, 11201, USA.

Clinical studies in preterm neonates are rarely performed due to ethical concerns and difficulties associated with trials and recruitment. Consequently, dose selection in this population is primarily empirical. Scaling neonatal doses from adult doses does not account for developmental changes and may not accurately predict drug kinetics. This is especially important for gentamicin, a narrow therapeutic index aminoglycoside antibiotic. While gentamicin's bactericidal effect is associated with its peak plasma concentration, keeping trough concentrations below 1 μg/mL prevents toxicity and also helps counteracting adaptive resistance in bacteria such as Escherichia coli. In this study, physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) modeling was used to support and/or guide dosing decisions, and to predict the antibacterial effect in preterm neonates. A gentamicin PBPK model was successfully verified in healthy adults and preterm neonates across all gestational ages. Clinical data from a neonatal intensive care unit at NYU Langone Long Island hospital was used to identify dosing regimens associated with increased incidence of elevated gentamicin trough concentrations in different preterm patient cohorts. Model predictions demonstrated that a higher dose with an extended-dosing interval (Q36h) in neonates with a postmenstrual age of 30-34 weeks and ≥ 35 weeks, with postnatal age 8-28 days and 0-7 days, respectively, were more likely to have a trough < 1 μg/mL when compared with once-daily (Q24h) dosing. PBPK-PD modeling suggested that a higher dose administered Q36h may provide effective antibacterial therapy. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jcph.1890DOI Listing
May 2021

Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results.

Blood 2021 Apr 7. Epub 2021 Apr 7.

City of Hope National Medical Center, Duarte, California, United States.

This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed or refractory classical Hodgkin lymphoma. In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2-4. In part 3, both study drugs were dosed same day for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (N=91) was 85%, with 67% achieving a complete response. At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI]: 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns.
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http://dx.doi.org/10.1182/blood.2020009178DOI Listing
April 2021

Physiologically based pharmacokinetic modeling of altered tizanidine systemic exposure by CYP1A2 modulation: Impact of drug-drug interactions and cigarette consumption.

Drug Metab Pharmacokinet 2021 Apr 13;37:100375. Epub 2020 Dec 13.

Samuel J. and Joan B. Williamson Institute for Pharmacometrics, Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, 11201, USA. Electronic address:

Tizanidine is an alpha2-adrenergic agonist, used to treat spasticity associated with multiple sclerosis and spinal injury. Tizanidine is primarily metabolized by CYP1A2 and is considered a sensitive index substrate for this enzyme. The physiologically based pharmacokinetic (PBPK) modeling platform Simcyp® was used to evaluate the impact of CYP1A2 modulation on tizanidine exposure through drug-drug interactions (DDIs) and host-dependent habits (cigarette smoking). A PBPK model was developed to predict tizanidine disposition in healthy volunteers following oral administration. The model was verified based on agreement between model-simulated and clinically observed systemic exposure metrics (C, AUC). The model was then used to carry-out DDI simulations to predict alterations in tizanidine systemic exposure when co-administered with various CYP1A2 perpetrators including competitive inhibitors (fluvoxamine, ciprofloxacin), a mechanism-based inhibitor (rofecoxib), and an inducer (rifampin). Additional simulations were performed to evaluate the impact of cigarette smoking on systemic exposure. Under each scenario, the PBPK model was able to capture the observed fold changes in tizanidine C and AUC of tizanidine when coadministered with CYP1A2 inhibitors or inducers. These results add to the available research findings in the literature on PBPK predictions of drug-drug interactions and illustrate the potential application in drug development, specifically to support product labeling.
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http://dx.doi.org/10.1016/j.dmpk.2020.100375DOI Listing
April 2021

Erratum to: Rapid, modular, and cost-effective generation of donor DNA constructs for CRISPR-based gene knock-in.

Biol Methods Protoc 2020 18;5(1):bpaa021. Epub 2020 Nov 18.

Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.

[This corrects the article DOI: 10.1093/biomethods/bpaa006.].
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http://dx.doi.org/10.1093/biomethods/bpaa021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673287PMC
November 2020

Rapid, modular, and cost-effective generation of donor DNA constructs for CRISPR-based gene knock-in.

Biol Methods Protoc 2020 20;5(1):bpaa006. Epub 2020 Mar 20.

Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.

Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing techniques find applications in many fields, such as molecular biology, cancer biology, and disease modeling. In contrast to the knock-out procedure, a key step of CRISPR knock-in experiments is the homology-directed repair process that requires donor constructs as repair templates. Therefore, it is desirable to generate a series of donor templates efficiently and cost-effectively. In this study, we developed a new strategy that combines (i) Gibson assembly reaction, (ii) a linker pair composed of eight in silico screened restriction enzyme sites, and (iii) a hierarchical framework, to remarkably improve the efficiency of producing donor constructs for common genes as well as for the genes containing unbalanced guanine-cytosine content and requiring a selectable marker. Furthermore, the approach provides the ability of inserting additional elements into the donor templates, such as single guide RNA recognition sites that have been reported to enhance the efficiency of homology-directed repair. Conclusively, our modularized process is simple, fast, and cost-effective for making donor constructs and benefits the application of CRISPR knock-in methods.
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http://dx.doi.org/10.1093/biomethods/bpaa006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211398PMC
March 2020

Learn to segment single cells with deep distance estimator and deep cell detector.

Comput Biol Med 2019 05 8;108:133-141. Epub 2019 Apr 8.

Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA, 15260, USA; UPMC-Hillman Cancer Center, University of Pittsburgh, Pittsburgh, 15232, PA, USA. Electronic address:

Single cell segmentation is a critical and challenging step in cell imaging analysis. Traditional processing methods require time and labor to manually fine-tune parameters and lack parameter transferability between different situations. Recently, deep convolutional neural networks (CNN) treat segmentation as a pixel-wise classification problem and have become a general and efficient method for image segmentation. However, cell imaging data often possesses characteristics that adversely affect segmentation accuracy: absence of established training datasets, few pixels on cell boundaries, and ubiquitous blurry features. We developed a strategy that combines strengths of CNN and traditional watershed algorithm. First, we trained a CNN to learn Euclidean distance transform (EDT) of the mask corresponding to the input images (deep distance estimator). Next, we trained a faster R-CNN (Region with CNN) to detect individual cells in the EDT image (deep cell detector). Then, the watershed algorithm performed the final segmentation using the outputs of previous two steps. Tests on a library of fluorescence, phase contrast and differential interference contrast (DIC) images showed that both the combined method and various forms of the pixel-wise classification algorithm achieved similar pixel-wise accuracy. However, the combined method achieved significantly higher cell count accuracy than the pixel-wise classification algorithm did, with the latter performing poorly when separating connected cells, especially those connected by blurry boundaries. This difference is most obvious when applied to noisy images of densely packed cells. Furthermore, both deep distance estimator and deep cell detector converge fast and are easy to train.
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http://dx.doi.org/10.1016/j.compbiomed.2019.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781873PMC
May 2019

Spatial clustering and common regulatory elements correlate with coordinated gene expression.

PLoS Comput Biol 2019 03 1;15(3):e1006786. Epub 2019 Mar 1.

Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America.

Many cellular responses to surrounding cues require temporally concerted transcriptional regulation of multiple genes. In prokaryotic cells, a single-input-module motif with one transcription factor regulating multiple target genes can generate coordinated gene expression. In eukaryotic cells, transcriptional activity of a gene is affected by not only transcription factors but also the epigenetic modifications and three-dimensional chromosome structure of the gene. To examine how local gene environment and transcription factor regulation are coupled, we performed a combined analysis of time-course RNA-seq data of TGF-β treated MCF10A cells and related epigenomic and Hi-C data. Using Dynamic Regulatory Events Miner (DREM), we clustered differentially expressed genes based on gene expression profiles and associated transcription factors. Genes in each class have similar temporal gene expression patterns and share common transcription factors. Next, we defined a set of linear and radial distribution functions, as used in statistical physics, to measure the distributions of genes within a class both spatially and linearly along the genomic sequence. Remarkably, genes within the same class despite sometimes being separated by tens of million bases (Mb) along genomic sequence show a significantly higher tendency to be spatially close despite sometimes being separated by tens of Mb along the genomic sequence than those belonging to different classes do. Analyses extended to the process of mouse nervous system development arrived at similar conclusions. Future studies will be able to test whether this spatial organization of chromosomes contributes to concerted gene expression.
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http://dx.doi.org/10.1371/journal.pcbi.1006786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415868PMC
March 2019

Using PBPK Modeling to Predict Drug Exposure and Support Dosage Adjustments in Patients With Renal Impairment: An Example with Lamivudine.

Curr Drug Discov Technol 2020 ;17(3):387-396

Samuel J. and Joan B. Williamson Institute for Pharmacometrics, Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn 11201, New York, United States.

Background: Lamivudine is a nucleoside reverse transcriptase inhibitor used to treat HIV and hepatitis B. It is primarily cleared by the kidney with renal secretion mediated by OCT2 and MATE.

Objective: To use PBPK modeling to assess the impact of renal impairment on lamivudine pharmacokinetics using the Simcyp® Simulator.

Methods: The model incorporated the Simcyp® Mechanistic Kidney Model option to predict renal disposition. The model was initially verified using the Simcyp® Healthy Volunteer population. Two discrete patient populations were then created for moderate (GFR 10-40 mL/min) and severe (GFR < 10 mL/min) renal failure (RF), and model simulations were compared to published data. The developed model was then utilized in a clinical study evaluating the clinical experience and plasma exposure of lamivudine when administered at higher than recommended doses to HIV-infected patients with varying degrees of renal impairment.

Results: Predicted systemic exposure metrics (Cmax, AUC) compared favorably to published clinical data for each population, with the following fold errors (FE, ratio of predicted and observed data) for Cmax/AUC: Healthy Volunteers 1.04/1.04, Moderate RF 1.03/0.78, Severe RF 0.89/0.79. The model captured lamivudine plasma concentrations measured pre- and post-dose (0.5-1.5hr) in study participants (n = 34). Model simulations demonstrated comparable systemic profiles across patient cohorts, supporting the proposed dosage adjustment scheme.

Conclusion: This study illustrates how PBPK modeling can help verify dosing guidelines for patients with varying levels of renal impairment. This approach may also be useful for predicting potential changes in exposure during renal insufficiency for compounds undergoing clinical development.
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http://dx.doi.org/10.2174/1570163816666190214164916DOI Listing
January 2020

Effect of Gender on the Pharmacokinetics of ON 123300, A Dual Inhibitor of ARK5 and CDK4/6 for the Treatment of Cancer, in Rats.

Eur J Drug Metab Pharmacokinet 2019 Aug;44(4):531-538

Onconova Therapeutics, Inc., Newtown, PA, USA.

Background And Objectives: ON 123300, a small molecule dual inhibitor of the c-MYC activated kinases ARK5 and CDK4/6, is being developed as a novel drug candidate for the treatment of cancer. The objective of this research was to evaluate gender differences in the in vitro metabolism and in vivo systemic exposure of ON 123300 in rats.

Methods: In vitro metabolism experiments (n = 2/group) were performed in rat liver microsomes from male and female donors. ON 123300 bislactate (final concentration 10 µM) was incubated with 0.5 mg/mL microsomes, and samples (100 µL) were withdrawn at specified incubation times over a period of 60 min, and immediately quenched and centrifuged. The supernatant was analyzed for ON 123300 and its metabolites by HPLC. ON 123300 (bislactate salt) pharmacokinetics were evaluated following intravenous (i.v.) (30 s infusion, 5 and 10 mg/kg) or oral administration (25 and 100 mg/kg) to male and female Sprague-Dawley rats (250-300 g). Following dosing, blood samples were collected over a time period up to 24 h. ON 123300 plasma concentrations were measured by LC-MS/MS. Pharmacokinetic parameters were estimated by non-compartmental analysis. Plasma and microsomal binding of ON 123300 and blood:plasma ratio were also determined.

Results: ON 123300 displayed more rapid microsomal degradation in vitro in males compared to females, as reflected in intrinsic clearance (181 vs 53.1 µL/min/mg). This translated into a significantly higher exposure of ON 123300 following oral administration to female rats, with the area under the curve (AUC) increasing nearly 3-fold (5617 ± 1914 ng·h/mL) compared to males (AUC = 1965 ± 749 ng·h/mL). This gender effect was less pronounced following i.v. dosing, where the AUC was ~ 2-fold higher in females. Based on these results, the higher plasma exposure observed in females can be primarily attributed to reductions in both hepatic clearance and presystemic metabolism compared to males.

Conclusions: This investigation demonstrated a significantly lower metabolism of ON 123300 in female rats, which resulted in high systemic exposure. Additional testing is warranted to assess the potential clinical implications of these findings.
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http://dx.doi.org/10.1007/s13318-019-00542-2DOI Listing
August 2019

Real-World Experience With Higher-Than-Recommended Doses of Lamivudine in Patients With Varying Degrees of Renal Impairment.

Open Forum Infect Dis 2018 Oct 10;5(10):ofy225. Epub 2018 Sep 10.

Division of Pharmacy Practice, The Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York.

Background: Although nucleoside reverse transcriptase inhibitors have been associated with lactic acidosis, lamivudine (3TC) has not been reported to have an increased risk with elevated concentrations. Therefore, some recommend that the lowest tablet strength of 3TC be considered in patients with kidney disease to avoid the inconvenience of liquid formations. Our institution avoids dose-adjusting 3TC until creatinine clearance (CrCl) <30 mL/min and uses 100-150-mg tablets daily in hemodialysis. The aim of this study was to describe the use of higher-than-recommended doses of 3TC in a real-world setting.

Methods: Blood samples were collected before and 0.5-1.5 hours after 3TC administration in HIV+ adults. Predose (C) and postdose (C) samples were measured by high-performance liquid chromatography. Physiologically based pharmacokinetic modeling was utilized to simulate areas under the curve (AUCs) and profiles by CrCl. Lactic acid levels and patient-reported adverse events were obtained to monitor for safety, and viral suppression was assessed for efficacy.

Results: Thirty-four patients with varying degrees of renal function were enrolled. Observed 3TC C values were comparable among CrCl cohorts. Simulated 3TC AUC values in patients with CrCl 30-49, 15-29, and 0-15 mL/min were consistent with historical data, and fold-errors were between 0.5 and 2.0. All lactic acid levels were within normal limits, and no adverse effects were reported.

Conclusions: This study is the first to describe the use of higher-than-recommended doses of 3TC in a real-world setting. 3TC was well tolerated across all levels of renal function. These results can guide providers in their selection of higher 3TC dosing in select patients with renal dysfunction to maximize adherence.
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http://dx.doi.org/10.1093/ofid/ofy225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171568PMC
October 2018

Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma.

Blood 2018 03 11;131(11):1183-1194. Epub 2017 Dec 11.

Stanford University Medical Center, Palo Alto, CA.

In this phase 1/2 study, brentuximab vedotin (BV) and nivolumab (Nivo) administered in combination were evaluated as initial salvage therapy in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL). Patients received up to 4 cycles of combination treatment, with BV administered on day 1 and Nivo on day 8 of the first cycle. For cycles 2 to 4, BV and Nivo were both administered on day 1. After study treatment, responses were evaluated by investigators per the 2014 Lugano classification, and patients could proceed to autologous stem cell transplantation (ASCT). Sixty-two patients were enrolled; the complete response rate among all treated patients (n = 61) was 61%, with an objective response rate of 82%. Before ASCT, adverse events (AEs) occurred in 98% of patients, mostly grades 1 and 2. Infusion-related reactions (IRRs) occurred in 44% of patients overall, with 41% of patients experiencing an IRR during at least 1 infusion of BV. Five patients (8%) were treated with systemic steroids for immune-related AEs. A reduction of peripheral T-cell subsets including regulatory T cells was observed after the first dose of BV, and reduced serum levels of thymus- and activation-regulated chemokine concurrent with an increase in proinflammatory cytokines and chemokines were seen after the first BV plus Nivo infusions. The combination of BV plus Nivo was an active and well-tolerated first salvage regimen, potentially providing patients with R/R HL an alternative to traditional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT02572167.
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http://dx.doi.org/10.1182/blood-2017-10-811224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855021PMC
March 2018

Application of physiologically based pharmacokinetic modeling to predict drug disposition in pregnant populations.

Biopharm Drug Dispos 2017 Oct 13;38(7):426-438. Epub 2017 Jul 13.

Samuel J. and Joan B. Williamson Institute for Pharmacometrics, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York, USA.

Pregnancy is associated with numerous physiological changes that influence absorption, distribution, metabolism and excretion. Moreover, the magnitude of these effects changes as pregnancy matures. For most medications, there is limited information available about changes in drug disposition that can occur in pregnant patients, yet most women are prescribed one or more medications during pregnancy. In this investigation, PBPK modeling was used to assess the impact of pregnancy on the pharmacokinetic profiles of three medications (metformin, tacrolimus, oseltamivir) using the Simcyp® simulator. The Simcyp pregnancy-PBPK model accounts for the known physiological changes that occur during pregnancy. For each medication, plasma concentration-time profiles were simulated using Simcyp® virtual populations of healthy volunteers and pregnant patients. The predicted systemic exposure metrics (C , AUC) were compared with published clinical data, and the fold error (FE, ratio of predicted and observed data) was calculated. The PBPK model was able to capture the observed changes in C and AUC across each trimester of pregnancy compared with post-partum for metformin (FE range 0.86-1.19), tacrolimus (FE range 1.03-1.64) and oseltamivir (FE range 0.54-1.02). Simcyp model outputs were used to correlate these findings with pregnancy-induced alterations in renal blood flow (metformin, oseltamivir), hepatic CYP3A4 activity (tacrolimus) and reduced plasma protein levels and hemodilution (tacrolimus). The results illustrate how PBPK modeling can help to establish appropriate dosing guidelines for pregnant patients and to predict potential changes in systemic exposure during pregnancy for compounds undergoing clinical development.
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http://dx.doi.org/10.1002/bdd.2081DOI Listing
October 2017

Evaluating the Potential for Delivery of Irinotecan via the Buccal Route: Physicochemical Characterization and In Vitro Permeation Assessment Across Porcine Buccal Mucosa.

AAPS PharmSciTech 2017 Apr 30;18(3):867-874. Epub 2016 Jun 30.

Division of Pharmaceutical Sciences, Long Island University, Brooklyn, New York, 11201, USA.

Irinotecan (CPT-11) is used to treat advanced colorectal cancer as an intravenous therapy. Depending on pH, CPT-11 exists in either a lactone (active) or carboxylate (inactive) form, or both. In this investigation, the feasibility for systemic delivery of CPT-11 through the buccal route was evaluated. Permeation of CPT-11 across porcine buccal mucosa was studied in vitro using side-by-side flow through diffusion cells at 37°C. Experiments were performed over a pH range from 4 to 9, and the permeability of both the lactone and carboxylate forms of CPT-11 was measured. CPT-11 steady state flux was determined over a range of donor concentrations at pH 4 (0.5, 1, 5, 10, 15, 20 mg/ml) and pH 6.8 (0.5, 5, 10 mg/ml). Steady state flux increased linearly with increasing donor concentration of CPT-11 at pH 4 (r  = 0.9935) and at pH 6.8 (r  = 0.9886). CPT-11 permeability was independent of pH, although the distribution coefficient increased with increasing pH. Estimates of permeability for the lactone and carboxylate forms were 4.16 × 10 cm/s and 2.6 × 10 cm/s, respectively. These calculated permeability values were in agreement with the in vitro experimental data. Overall, CPT-11 was found to permeate through porcine buccal mucosa via passive diffusion. CPT-11 permeability was independent of pH, suggesting that the compound was transported mainly via a paracellular route. Overall, the results of this research suggest that the buccal route is a potential extravascular mode of delivery for CPT-11.
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http://dx.doi.org/10.1208/s12249-016-0578-zDOI Listing
April 2017

Phase 1 study of intravenous rigosertib (ON 01910.Na), a novel benzyl styryl sulfone structure producing G2/M arrest and apoptosis, in adult patients with advanced cancer.

Am J Cancer Res 2013 20;3(3):323-38. Epub 2013 Jun 20.

Department of Radiology and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai New York, NY, USA.

Rigosertib (ON 01910.Na), a synthetic novel benzyl styryl sulfone, was administered to 28 patients with advanced cancer in a Phase I trial in order to characterize its pharmacokinetic profile, determine the dose-limiting toxicities (DLT), define the recommended phase II dose (RPTD) and to document any antitumor activity. Patients with advanced malignant neoplasms refractory to standard therapy were given escalating doses of rigosertib (50, 100, 150, 250, 325, 400, 650, 850, 1,050, 1,375, 1,700 mg/m(2)/24h) as a 3-day continuous infusion (CI) every 2 weeks. An accelerated Fibonacci titration schedule with specified decreases for toxicities was used for escalation until grade ≥2 toxicity occurred. Intrapatient dose escalation was allowed if toxicity was grade ≤2 and the disease remained stable. Plasma pharmacokinetics (PK) and urinary PK assessments were studied in the 1st and 4th cycles. Twenty-nine patients (12 men and 17 women; age 36-87 y with a median of 63 y) were registered, but one died before study drug was given. Twenty-eight patients received a median of 3 cycles of therapy. Most common grade ≥2 toxicities attributable to rigosertib included fatigue, anorexia, vomiting and constipation. DLTs included muscular weakness, hyponatremia, neutropenia, delirium and confusional state. Risk factors for severe toxicities include pre-existing neurological dysfunction or advanced gynecologic cancer after pelvic surgery. Rigosertib pharmacokinetics showed rapid plasma distribution phases and urinary excretion. Elevations in plasma Cmax and AUC due to decreases in plasma clearance were associated with acute grade ≥3 toxicities. Of 22 evaluable patients, 9 (41%) achieved a best overall response of stable disease; all other patients (n=13; 59%) progressed. The median progression-free survival time was 50 days (95% confidence interval [CI]: 37-80 days). Nine (41%) patients survived for over 1 y. In summary, prolonged IV infusions of rigosertib were generally well tolerated. Nine (41%) patients achieved stable disease and 9 (41%) patients survived for over 1 year. The RPTD appears to be 850 mg/m(2)/24hr CI x 3 days. (ClinicalTrials.gov identifier: NCT01538537).
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696538PMC
July 2013

Phase I clinical trial of oral rigosertib in patients with myelodysplastic syndromes.

Br J Haematol 2013 Aug 21;162(4):517-24. Epub 2013 Jun 21.

Department of Hematological Malignancies, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

The multi-kinase inhibitor rigosertib (ON 01910.Na) induces mitotic arrest and apoptosis in myeloblasts, while sparing normal cells. The purpose of this study was to determine the pharmacokinetic profile, maximum-tolerated dose (MTD), safety, and clinical activity of an oral formulation of rigosertib in patients with myelodysplastic syndromes (MDS). For pharmacokinetic studies, patients received rigosertib in single escalating weekly doses. To determine the MTD, patient cohorts received escalating doses of rigosertib twice daily for 14 d of a 21-d cycle. Overall, 37 patients were treated. Rigosertib exposure increased with escalating oral doses. Mean absolute oral bioavailability ranged from 13·9% (fed) to 34·8% (fasting) in 12 patients treated at the 560 mg b.i.d. dose level. Dose-limiting toxicity (grade 3 dysuria and shortness of breath) occurred at the 700 mg b.i.d. dose. Five patients experienced grade 3 non-haematological toxicity, including symptoms of urothelial inflammation, hypotension and syncope, fatigue and abdominal pain. Encouraging signs of clinical activity included two bone marrow complete remissions in refractory anaemia with excess blasts type 1 patients previously treated with azacitidine. In addition, four patients each achieved transfusion independence and haematological improvements. In conclusion, oral rigosertib is bioavailable and well tolerated, and has clinical activity in patients with MDS.
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http://dx.doi.org/10.1111/bjh.12436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685467PMC
August 2013

Determination of intestinal permeability of rigosertib (ON 01910.Na, Estybon): correlation with systemic exposure.

J Pharm Pharmacol 2013 Jul 25;65(7):960-9. Epub 2013 Mar 25.

Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USA.

Objectives: Rigosertib (ON 01910.Na, Estybon) is a novel, anticancer agent undergoing phase 3 clinical trials for a lead indication against myelodysplastic syndromes (MDS). In this research, the permeability of rigosertib was evaluated using the in-situ perfused rat intestine (IPRI) model to support development of an oral formulation for rigosertib for treating cancer patients.

Methods: Experiments (n = 6 per group) were conducted using male Sprague-Dawley rats. Studies evaluated permeability across various intestinal segments and assessed the dose-linearity of absorption over the entire intestinal length. Drug concentrations in the portal and jugular vein were collected to correlate permeability parameters with presystemic and systemic exposure.

Key Findings: Rigosertib permeability was highest in the jejunum, although parameter estimates indicated that rigosertib was a medium permeability compound. The compound displayed nonlinear absorption in the IPRI model, suggesting a saturable transport process. Transport inhibition studies using Caco-2 cells demonstrated that rigosertib was a P-glycoprotein (P-gp) substrate. Absolute bioavailability of rigosertib (10 and 20 mg/kg, 1-h infusion) in rats was estimated to be 10-15%. However, the fraction absorbed in humans predicted from IPRI data (52%) was consistent with published clinical data for rigosertib (35% oral bioavailability).

Conclusions: The results of this research indicated that rigosertib is a promising candidate for oral delivery. Further studies are needed to evaluate the potential impact of P-gp and other intestinal transporters on the oral absorption of this promising anticancer agent.
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http://dx.doi.org/10.1111/jphp.12057DOI Listing
July 2013

Disposition of ON 01210.Na (Ex-RAD(R)), a novel radioprotectant, in the isolated perfused rat liver: probing metabolic inhibition to increase systemic exposure.

J Pharm Sci 2013 Feb 4;102(2):732-40. Epub 2012 Dec 4.

Division of Pharmaceutical Sciences, Long Island University, Brooklyn, New York 11201, USA.

ON 01210.Na (Ex-RAD) is a novel benzyl styryl sulfone analog, developed as a radioprotectant by Onconova Therapeutics Inc. The objectives of this research were to evaluate the hepatobiliary disposition of ON 01210.Na in the isolated perfused rat liver (IPRL) and to determine the effect of coadministration of ethacrynic acid (EA) on the pharmacokinetic profile of ON 01210.Na. EA acid was used as a prototypical inhibitor of glutathione-S-transferase inhibitor. ON 01210.Na was highly bound in IPRL perfusate proteins, and binding was significantly lower in the presence of EA. Dose-escalation studies (bolus dose, target concentrations 10-250 μg/mL) showed that ON 01210.Na followed nonlinear pharmacokinetics with hepatic clearance decreasing from 3.14 to 1.99 mL/min with increasing dose. ON 01210.Na underwent extensive metabolic degradation to its glutathione (GSH) adduct in liver. The GSH metabolite was mainly excreted into the bile. Coadministration of EA (1 mM) significantly inhibited the conversion of ON 01210.Na to its GSH conjugate, resulting in decreased clearance (approx. fivefold lower), and prolonged elimination from the perfusate. These preclinical studies suggest that EA is a potential pharmacoenhancer that can reduce the metabolism of ON 01210.Na in vivo, thereby increasing drug exposure and boosting radioprotective activity.
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http://dx.doi.org/10.1002/jps.23391DOI Listing
February 2013

Radioprotective effects of ON 01210.Na upon oral administration.

J Radiat Res 2012 11;53(3):368-76. Epub 2012 May 11.

Department of Biochemistry and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057-1468, USA.

ON 01210.Na (Ex-RAD), a chlorobenzylsulfone derivative was investigated for its pharmacologic and radioprotective properties when administered via oral and subcutaneous (SC) routes. The goals of the study were to assess the comparative bioavailability of ON 01210.Na when administered by oral versus SC routes and to demonstrate that the oral drug delivery of ON 01210.Na afforded survival advantage similar to SC dosing. Pharmacokinetics was studied after two doses, 24 h apart, of ON 01210.Na (500 mg/kg) administered to male C3H/Hen mice (7-9 weeks) via SC injection or oral route. The dose response (100 to 750 mg/kg) and survival advantage of ON 01210.Na administered at 24 h and 15 min prior to 7.5 or 8 Gy whole body irradiation from a ¹³⁷Cs source (dose rate 1 Gy/min) were studied in these mice. Effects on the hematopoietic system were investigated by complete blood count and granulocyte-macrophage colony forming unit assay. A significant survival advantage and hematopoietic protection were observed after prophylactic oral ON 01210.Na and results were comparable to SC administration. These findings correlated well with pharmacokinetic data. Both SC and oral ON 01210.Na showed significant survival advantage against radiation toxicity and ON 01210.Na mediated hematopoietic protection plays key role in enhanced survival of mice. Oral administration holds better clinical promise as an effective countermeasure not only for early-responders in a nuclear accident, but also for the at-risk civilian population.
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http://dx.doi.org/10.1269/jrr.11191DOI Listing
January 2013

Aristolochic acid I metabolism in the isolated perfused rat kidney.

Chem Res Toxicol 2012 Jan 14;25(1):130-9. Epub 2011 Dec 14.

Department of Biological Sciences, Florida International University , Miami, Florida 33199, United States.

Aristolochic acids are natural nitro-compounds found globally in the plant genus Aristolochia that have been implicated in the severe illness in humans termed aristolochic acid nephropathy (AAN). Aristolochic acids undergo nitroreduction, among other metabolic reactions, and active intermediates arise that are carcinogenic. Previous experiments with rats showed that aristolochic acid I (AA-I), after oral administration or injection, is subjected to detoxication reactions to give aristolochic acid Ia, aristolactam Ia, aristolactam I, and their glucuronide and sulfate conjugates that can be found in urine and feces. Results obtained with whole rats do not clearly define the role of liver and kidney in such metabolic transformation. In this study, in order to determine the specific role of the kidney on the renal disposition of AA-I and to study the biotransformations suffered by AA-I in this organ, isolated kidneys of rats were perfused with AA-I. AA-I and metabolite concentrations were determined in perfusates and urine using HPLC procedures. The isolated perfused rat kidney model showed that AA-I distributes rapidly and extensively in kidney tissues by uptake from the peritubular capillaries and the tubules. It was also established that the kidney is able to metabolize AA-I into aristolochic acid Ia, aristolochic acid Ia O-sulfate, aristolactam Ia, aristolactam I, and aristolactam Ia O-glucuronide. Rapid demethylation and sulfation of AA-I in the kidney generate aristolochic acid Ia and its sulfate conjugate that are voided to the urine. Reduction reactions to give the aristolactam metabolites occur to a slower rate. Renal clearances showed that filtered AA-I is reabsorbed at the tubules, whereas the metabolites are secreted. The unconjugated metabolites produced in the renal tissues are transported to both urine and perfusate, whereas the conjugated metabolites are almost exclusively secreted to the urine.
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http://dx.doi.org/10.1021/tx200333gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276251PMC
January 2012

Renal excretion of apricitabine in rats: ex vivo and in vivo studies.

Eur J Drug Metab Pharmacokinet 2011 Sep 6;36(3):141-50. Epub 2011 Apr 6.

College of Pharmacy, Long Island University, 75 DeKalb Avenue, Brooklyn, NY 11201, USA.

Apricitabine (ATC) is a novel nucleoside reverse transcriptase inhibitor undergoing phase 2/3 clinical development for the treatment of HIV infection. In this investigation, the renal handling of ATC was evaluated in the isolated perfused rat kidney (IPK) model with follow-up in vivo studies. IPK experiments were performed to characterize the renal excretion of ATC, to probe mechanisms of ATC excretion using known inhibitors of organic cation (cimetidine) and organic anion (probenecid) transport systems, and to screen for potential drug-drug interactions between ATC and clinically relevant medications (dapsone, metformin, pentamidine, stavudine, tenofovir and ritonavir). ATC demonstrated net tubular secretion in the IPK with a baseline excretion ratio (XR) of 2.1 ± 0.56. ATC XR decreased 3.6-fold in the presence of cimetidine and 2-fold in the presence of probenecid. Among the clinically relevant medications, metformin produced the greatest inhibitory effect on ATC excretion. In vivo studies were conducted in rats to evaluate ATC disposition upon co-administration with compounds that showed a significant effect on ATC clearance in the IPK model. Co-administration of cimetidine and trimethoprim significantly reduced ATC renal clearance, but resulted in only a moderate increase in plasma exposure. Metformin had no apparent effect on ATC clearance in rats. These findings indicate that the IPK model is more sensitive to secretory inhibition as compared to in vivo. The medications screened showed minimal effects on ATC renal excretion in the IPK, and should thus be excluded as potential in vivo interactants. Overall, this study generated important information on renal handling of ATC to support its development and commercialization.
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http://dx.doi.org/10.1007/s13318-011-0038-9DOI Listing
September 2011

Vstm3 is a member of the CD28 family and an important modulator of T-cell function.

Eur J Immunol 2011 Apr 18;41(4):902-15. Epub 2011 Mar 18.

Department of Immunology, ZymoGenetics, Inc., Seattle, WA, USA.

Members of the CD28 family play important roles in regulating T-cell functions and share a common gene structure profile. We have identified VSTM3 as a protein whose gene structure matches that of the other CD28 family members. This protein (also known as TIGIT and WUCAM) has been previously shown to affect immune responses and is expressed on NK cells, activated and memory T cells, and Tregs. The nectin-family proteins CD155 and CD112 serve as counter-structures for VSTM3, and CD155 and CD112 also bind to the activating receptor CD226 on T cells and NK cells. Hence, this group of interacting proteins forms a network of molecules similar to the well-characterized CD28-CTLA-4-CD80-CD86 network. In the same way that soluble CTLA-4 can be used to block T-cell responses, we show that soluble Vstm3 attenuates T-cell responses in vitro and in vivo. Moreover, animals deficient in Vstm3 are more sensitive to autoimmune challenges indicating that this new member of the CD28 family is an important regulator of T-cell responses.
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http://dx.doi.org/10.1002/eji.201041136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733993PMC
April 2011

Effects of formulation and route of administration on the systemic availability of Ex-RAD®, a new radioprotectant, in preclinical species.

Biopharm Drug Dispos 2011 Mar 14;32(2):99-111. Epub 2011 Jan 14.

Division of Pharmaceutical Sciences, Long Island University, Brooklyn, NY 11201, USA.

ON 01210.Na (Ex-RAD®) is a novel small molecule under development by Onconova Therapeutics, Inc. as a radiation protection agent. The purpose of this investigation was to evaluate the effect of various formulation approaches on the systemic exposure of ON 01210.Na. In vitro experiments were used to characterize the plasma binding and metabolic stability of ON 01210.Na using hepatocytes from several animal species (mouse, rat, rabbit, dog, monkey and human). In vivo studies were performed in rats, rabbits, dogs and monkeys, and involved several routes of administration (intravenous, subcutaneous, oral). Plasma protein binding was high across species (>83%), and the rate of ON 01210.Na metabolism was highest in rat and mouse hepatocytes. After intravenous administration, ON 01210.Na demonstrated biphasic elimination from the plasma. Systemic exposure parameters (Cmax, AUC) were dose-proportional up to 100 mg/kg. Following subcutaneous dosing, ON 01210.Na showed relatively low bioavailability upon administration of the suspension formulation. Developing a solution formulation significantly increased the bioavailability of the drug. This solution formulation demonstrated significant oral bioavailability in rabbit (70%) and monkey (30%). The findings from these preclinical studies provide an overview of the systemic disposition of ON 01210.Na, aiding in the development of optimal formulations and routes of administration for pivotal animal efficacy and clinical safety studies. A solution formulation of ON 01210.Na for s.c. administration is being developed, in addition to an oral dosage form for potential use of the compound as a radioprotectant and a radiation-mitigating agent in wider military and civilian populations.
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http://dx.doi.org/10.1002/bdd.741DOI Listing
March 2011

Renal excretion of clofarabine: assessment of dose-linearity and role of renal transport systems on drug excretion.

Eur J Pharm Sci 2010 Jun 25;40(3):209-16. Epub 2010 Mar 25.

Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 Dekalb Avenue, Brooklyn, NY 11201, USA.

The renal excretion of clofarabine was studied in vitro in the isolated perfused rat kidney (IPK) model and in vivo in rats. Clofarabine excretion was studied at four doses (160, 800, 2000 and 4000microg) in the IPK, targeting perfusate levels of 2, 10, 25, 50microg/mL, respectively. Clofarabine (2microg/mL) was also co-perfused with known inhibitors of the, organic cation (cimetidine, ranitidine and tyramine) and organic anion (probenecid, ellagic acid) transport systems. Additionally, the effect of medications including, itraconazole, digoxin, fludarabine and cytarabine (Ara-C) on clofarabine excretion was, evaluated. Based on IPK results, in vivo studies were performed to assess the plasma, pharmacokinetics and urinary recovery of clofarabine (6.5mg/kg, IV) pretreatment, with cimetidine (250mg/kg, IV). Clofarabine clearance was non-linear in the IPK, although at concentrations that were approximately 10- to 100-fold higher than maximum concentrations observed in humans. Excretion ratio data indicated a shift from net, secretion (XR=1.2+/-0.33) to net reabsorption (XR=0.78+/-0.40) at the highest dose, tested. Clofarabine clearance was significantly reduced upon co-administration with, cimetidine (0.83+/-0.22-->0.32+/-0.058mL/min). In vivo data correlated with IPK results as clofarabine clearance decreased 61% (20.2-7.80mL/min/kg), upon co-administration with cimetidine in rats. The results suggest that clofarabine is a substrate for a cimetidine-sensitive organic cation transporter system in the kidney, presumably OCT2. The magnitude of the cimetidine-clofarabine interaction was similar, in IPK and in vivo, demonstrating the utility of the IPK model in characterizing renal, drug excretion and assessing potential drug-drug interactions.
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http://dx.doi.org/10.1016/j.ejps.2010.03.014DOI Listing
June 2010

Comparative renal excretion of VX-702, a novel p38 MAPK inhibitor, and methotrexate in the perfused rat kidney model.

Drug Dev Ind Pharm 2010 Mar;36(3):315-22

Division of Pharmaceutical Sciences, Long Island University, Brooklyn, NY 11201, USA.

Context: VX-702 is a novel p38 mitogen-activated protein kinase inhibitor being developed to treat rheumatoid arthritis.

Objective: To characterize the renal excretion profile of VX-702 using the isolated perfused rat kidney (IPRK) model.

Methods: Studies were performed to assess the dose linearity of VX-702 excretion and to evaluate the effect of inhibitors of organic anion (probenecid) and organic cation (cimetidine) transport systems on VX-702 disposition. VX-702 excretion was studied over a range of doses targeting concentrations between 100 and 600 ng/mL. VX-702 (600 ng/mL) was also co-perfused with probenecid (1 mM) and cimetidine (2 mM). The results were compared to parallel experiments performed with methotrexate (MTX).

Results: VX-702 excretion was linear over the range of doses studied, and clearance data were consistent with net reabsorption by the kidney. Transport inhibition studies indicate that VX-702 is not a substrate for renal organic anion and organic cation transport systems. MTX (500 ng/mL) also displayed net reabsorption in the IPRK, but secretory transport was inhibited upon co-administration with probenecid. This finding is consistent with previous IPRK studies that demonstrated inhibitory effects of NSAIDS on MTX excretion.

Conclusion: Overall, this study suggests that a renal drug-drug interaction between VX-702 and MTX would be unlikely if these medications were co-administered.
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http://dx.doi.org/10.3109/03639040903154200DOI Listing
March 2010

Preclinical pharmacokinetics and in vitro activity of ON 01910.Na, a novel anti-cancer agent.

Cancer Chemother Pharmacol 2009 Dec 24;65(1):177-86. Epub 2009 May 24.

Division of Pharmaceutical Sciences, Long Island University, Brooklyn, NY 11201, USA.

Purpose: ON 01910.Na is a novel targeted anti-cancer agent under clinical investigation in Phase I and II trials. The purpose of this research was to evaluate the pharmacokinetic profile of ON 01910.Na across several species, and to evaluate the effects of protein binding and duration of exposure on its in vitro cytotoxic activity.

Methods: Data were collated from several preclinical investigations, where the plasma disposition and tissue distribution of ON 01910.Na were assessed after administration (10-150 mg/kg, IP or IV) to several species (mouse, rat, and dog). Plasma protein binding was assessed using ultrafiltration. Cytotoxic activity of ON 01910.Na was determined in DU145 cells, and activity was correlated to unbound drug concentration and the duration of exposure.

Results: ON 01910.Na exhibits extensive plasma protein binding and the compound displays rapid elimination from the circulation in all three animal species (t(1/2) range 0.404-0.870 h). Tissue distribution studies in mice revealed highest drug accumulation in the liver, followed by the kidneys. ON 01910.Na is not extensively metabolized in vivo and urinary excretion is predominant at higher doses. ON 01910.Na cytotoxicity in DU145 cells was adversely affected by protein binding in the incubation medium. Drug cytotoxicity was greatly enhanced upon extending the duration of exposure at reduced drug concentrations.

Conclusions: Due to the short half-life and rapid clearance of the drug, administration of ON 01910.Na by continuous IV infusion is a likely treatment option for cancer patients.
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http://dx.doi.org/10.1007/s00280-009-1022-9DOI Listing
December 2009

Renal excretion of emtricitabine II. effect of trimethoprim on emtricitabine excretion: In vitro and in vivo studies.

J Pharm Sci 2008 Dec;97(12):5411-20

Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 DeKalb Ave., Brooklyn, New York 11201, USA.

The potential interaction between the nucleoside analog emtricitabine (FTC) and trimethoprim (TMP) was assessed in the isolated perfused rat kidney (IPK) model and in vivo in rats. IPK experiments were performed with FTC alone (2 microg/mL) and in the presence of increasing concentrations of TMP (1-10 microg/mL). TMP inhibited FTC excretion in a concentration dependent manner. The IC(50) (TMP concentration associated with a 50% reduction in FTC excretion) was 1.86 +/- 0.37 microg/mL. The results were compared to whole animal studies in rats. Animals received an IV dose of FTC (1 mg/kg) with or without pretreatment with TMP (25 mg/kg). TMP coadministration significantly decreased FTC clearance (7.4 +/- 1.2 mL/min/kg to 2.7 +/- 0.53 mL/min/kg), and elimination half-life was significantly increased (58 +/- 12 min to 215 +/- 44 min). A good correlation was obtained between IPK findings and in vivo data, as FTC renal clearance was reduced approximately 60% in the presence of TMP in both studies. Based on this investigation, TMP would be expected to inhibit the renal excretion of FTC when the two compounds are coadministered, resulting in increased plasma exposure of FTC. However, the clinical significance of this finding remains to be elucidated.
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http://dx.doi.org/10.1002/jps.21369DOI Listing
December 2008

Renal excretion of emtricitabine I: effects of organic anion, organic cation, and nucleoside transport inhibitors on emtricitabine excretion.

J Pharm Sci 2008 Dec;97(12):5401-10

Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 DeKalb Ave., Brooklyn, New York 11201, USA.

The excretion of emtricitabine (FTC) was characterized using isolated perfused rat kidney (IPK) model. Studies were performed to assess the dose-linearity of FTC excretion, to evaluate the effect of inhibitors of organic anion (probenecid, PBC), organic cation (tetraethylammonium, TEA; cimetidine, CMD) and nucleoside (uridine, URD) transport systems on FTC excretion, and to determine the potential interaction between FTC and trimethoprim (TMP). FTC excretion was studied over a range of doses (80-1600 microg), targeting concentrations encompassing the therapeutic range of FTC (1-20 microg/mL). FTC (2 microg/mL) was also coperfused with PBC (500 microM), TEA (500 microM), CMD (2 mM), URD (500 microM), and TMP (13.7 microM). FTC dose-linearity studies revealed that excretion parameters were not significantly different among dosing groups. Of the transport inhibitors tested, FTC XR decreased more than twofold in the presence of CMD (0.32 +/- 0.099). PBC, TEA, and URD had no observed effect on FTC excretion. TMP coadministration significantly inhibited FTC excretion (XR = 0.43 +/- 0.052). The results suggest that FTC renal transport is likely mediated by a CMD-sensitive organic cation transporter (OCT) in the kidney. TMP may inhibit the renal excretion of FTC when the two compounds are coadministered in vivo.
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http://dx.doi.org/10.1002/jps.21370DOI Listing
December 2008

Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F.

J Immunol 2007 Oct;179(8):5462-73

Department of Molecular and Cell Based Discovery, ZymoGenetics Incroporated, Seattle, WA 98102, USA.

The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity and share many biological properties. Both have been implicated as factors contributing to the progression of inflammatory and autoimmune diseases. Moreover, reagents that neutralize IL-17A significantly ameliorate disease severity in several mouse models of human disease. IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17RA). We report here that the IL-17RA-related molecule, IL-17RC is the receptor for IL-17F. Notably, both IL-17A and IL-17F bind to IL-17RC with high affinity, leading us to suggest that a soluble form of this molecule may serve as an effective therapeutic antagonist of IL-17A and IL-17F. We generated a soluble form of IL-17RC and demonstrate that it effectively blocks binding of both IL-17A and IL-17F, and that it inhibits signaling in response to these cytokines. Collectively, our work indicates that IL-17RC functions as a receptor for both IL-17A and IL-17F and that a soluble version of this protein should be an effective antagonist of IL-17A and IL-17F mediated inflammatory diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849293PMC
http://dx.doi.org/10.4049/jimmunol.179.8.5462DOI Listing
October 2007

Effects of trimethoprim on the clearance of apricitabine, a deoxycytidine analog reverse transcriptase inhibitor, and Lamivudine in the isolated perfused rat kidney.

J Pharmacol Exp Ther 2006 Nov 22;319(2):941-7. Epub 2006 Aug 22.

Division of Pharmaceutical Sciences, Long Island University, 75 DeKalb Avenue, Brooklyn, NY 11201, USA.

Apricitabine (ATC) is a novel deoxycytidine analog reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus infection. Studies were performed to characterize the excretion of ATC and its metabolite, BCH-335 (-1-(2-hydroxymethyl-[1,3]oxathiolan-4-yl)-1H-pyrimidine-2,4-dione), in the isolated perfused rat kidney (IPK). A second objective was to investigate the effect of trimethoprim on ATC excretion because trimethoprim inhibits the excretion of lamivudine, structurally similar to ATC, in the IPK. ATC excretion was nonlinear at doses of 80 to 1600 microg. The excretion ratio (ratio of clearance to glomerular filtration rate, assuming negligible protein binding) was greater than 1.0, indicating net tubular secretion. In contrast, the excretion of BCH-335 was independent of the dose of BCH-335. Concomitant administration of ATC and BCH-335 did not affect the excretion of either compound. Trimethoprim significantly inhibited the excretion of both ATC and BCH-335, with IC(50) values of 0.45 and 0.54 microg/ml, respectively. In the presence of trimethoprim, the excretion ratios for both compounds were less than 1.0, indicating tubular reabsorption. Trimethoprim inhibited the excretion of ATC and lamivudine to similar extents. Following concomitant administration of ATC, lamivudine, and trimethoprim, there was no evidence of an interaction between ATC and lamivudine. These results suggest that ATC undergoes active tubular secretion in the kidney. Because the renal excretion of both ATC and lamivudine is inhibited by trimethoprim to similar extents, in clinical practice exposure to ATC, it would be expected to be increased in the presence of therapeutic concentrations of trimethoprim to a similar extent as has been shown previously for lamivudine.
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http://dx.doi.org/10.1124/jpet.106.108522DOI Listing
November 2006

The isolated perfused rat kidney model: a useful tool for drug discovery and development.

Authors:
David R Taft

Curr Drug Discov Technol 2004 Jan;1(1):97-111

Division of Pharmaceutics and Industrial Pharmacy, Long Island University, 75 DeKalb Avenue, Brooklyn, NY 11201, USA.

Over the past three decades, the Isolated Perfused Rat Kidney (IPK) has been used to study numerous aspects of renal drug disposition. Among the available ex-vivo methods to study renal transport, the IPK allows for elucidation of the overall contributions of renal transport mechanisms on drug excretion. Therefore, IPK studies can provide a bridge between in vitro findings and in vivo disposition. This review paper begins with a detailed overview of IPK methodology (system components, surgical procedure, study design). Various applications of the IPK are then presented. These applications include characterizing renal excretion mechanisms, screening for clinically significant drug interactions, studying renal drug metabolism, and correlating renal drug disposition with drug-induced changes in kidney function. Lastly, the role of IPK studies in drug development is discussed. Demonstrated correlations between IPK data and clinical outcomes make the IPK model a potentially useful tool for drug discovery and evaluation.
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http://dx.doi.org/10.2174/1570163043484824DOI Listing
January 2004