The Grizzly, October 9, 1981

False Alarms Plague Campus • Task Force Attempts to Answer Concerns in the Evening School • Breaking of Tradition, Speeding Up of Progress • Sadat is Dead: What Happens Now? • Letters to the Editor • Books Sought by Ursinus Friends • Pi Nu Epsilon Banquet • Sid Quinn, Barbara Blatt • Transplanted Texan: A Funny Thing Happened to Me at the Forum • Making Love is Fact of Life • Kinky Culture at the Spectrum • LeKites Elected Class of \u2785 President • Second Semi-annual Photo Exhibit Presented Tomorrow • Oktoberfest Comes to Ritter • Business Law Dropped from Day School Curriculum By Request of the Econ Department • 20 hrs. Limitation Causes Uproar • USGA Notes • Cross Country Leaves \u27Em Talking • Hockey Suffers First Loss of Season • Dickinson Latest Victim to Ursinus Defense • Soccer Shuts Out Hopkinshttps://digitalcommons.ursinus.edu/grizzlynews/1063/thumbnail.jp

The Grizzly, October 2, 1981

Homecoming Celebration Takes on New Meaning • Previously Idle Appeals Procedure Finally Tested • Faculty Member\u27s Dismissal Creates Unrest • President Calls School Start \u27One of the Best Ever\u27 • Comment: I Thought This Was College • Parent Involvement Sought in Planning for the Future • Platforms for Freshman Class Elections • Greaseband Sings its Heart Out to Fortunate Few • Concert Causes Funds Loss • Transplanted Texan: Our Most Illustrious Non-Graduate • Rolling Stones Rock \u27n Roll Circus Levels JFK • Ursinus News Briefs: Postage hike finally granted; \u27Dealing with Stress\u27 offered by evening school • Campus Craziness: Sorority Pledging Begins • Red Cross Bloodmobile at HH • Women Receive Special Attention for Founder\u27s Day • Parents Day: Oct. 10 • Volleyball Holding Even • Soccer Registers First Win • Bears Surrender Lead to Tie Moravian at 10 • Hockey Pulls Out Win in Last Seconds • X-Country Makes it Look Easy . . . Againhttps://digitalcommons.ursinus.edu/grizzlynews/1062/thumbnail.jp

The Grizzly, September 25, 1981

Greaseband Tonight • Campus Welcome • Fridge Fee Unfrozen • Deutsch und Deutschland Heute: German Professor Co-authors Text • Public Speaking Exemption Exam • Books Sought by Ursinus Friends • Red Cross Bloodmobile at Helfferich Hall • Career Planning and Placement Office • Dessert Held in Union • Fast Food Service Losing Convenience • ProTheatre: Canterbury Tales Presented • Transplanted Texan: Nobody Expects the Moral Majority • School Bands Looking for Musicians • WRUC: Back on the Air? • First Coffeehouse Sparkles With Talent • Late Mail for Off-Campus Houses • [Reprinted Articles About the Greaseband] • Bear\u27s Booters Kick Off Season • Business as Usual for Cross-Country • Bears Drop 10-3 Decision to Western Maryland • Davis Leads Hockey Over Widenerhttps://digitalcommons.ursinus.edu/grizzlynews/1061/thumbnail.jp

Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma

A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib,cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for theapplication in daily clinical routine has been developed and validated according to the US Food and Drug Administration andEuropean Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples withacetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5μm(2.1×50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A andmethanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stableisotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min perrun. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2–500 ng/mLfor afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6–1500 ng/mL for cabozantinib, dabrafenib, nilotinib,and osimertinib (coefficients of correlation≥0.99). Validation assays for accuracy and precision, matrix effect, recovery,carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughputand was successfully applied to monitor concentrations of kinase inhibitors in patients

Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial

Purpose Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects. Methods 262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed. Results Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6-99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05). Conclusion Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity

Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells

Background Cancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI) Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo. Methods Cytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays. The 50% effective cytotoxic concentrations (EC50) were calculated and compared to the blood levels in our patients and published data. Results The in vitro EC50 of the different drugs in the BxPC-3 pancreatic cancer cells were: Efavirenz 31.5$\mu$mol/l (= 9944ng/ml), Nevirapine 239$\mu$mol/l (= 63786ng/ml), Etravirine 89.0$\mu$mol/l (= 38740ng/ml), Lersivirine 543$\mu$mol/l (= 168523ng/ml), Delavirdine 171$\mu$mol/l (= 78072ng/ml), Rilpivirine 24.4$\mu$mol/l (= 8941ng/ml). As Efavirenz and Rilpivirine had the highest cytotoxic potential and Nevirapine is frequently used in HIV-1 positive patients, the results of these three drugs were further studied in Panc-1 pancreatic cancer cells and confirmed with colony formation assays. 205 patient blood levels of Efavirenz, 127 of Rilpivirine and 31 of Nevirapine were analyzed. The mean blood level of Efavirenz was 3587ng/ml (range 162-15363ng/ml), of Rilpivirine 144ng/ml (range 0-572ng/ml) and of Nevirapine 4955ng/ml (range 1856-8697ng/ml). Blood levels from our patients and from published data had comparable Efavirenz levels to the in vitro toxic EC50 in about 1 to 5% of all patients. Conclusion All studied NNRTIs were toxic against cancer cells. A low percentage of patients taking Efavirenz reached in vitro cytotoxic blood levels. It can be speculated that in HIV-1 positive patients having high Efavirenz blood levels pancreatic cancer incidence might be reduced. Efavirenz might be a new option in the treatment of cancer

A Physiologically-Based Pharmacokinetic Model of Ruxolitinib and Posaconazole to Predict CYP3A4-Mediated Drug&ndash;Drug Interaction Frequently Observed in Graft versus Host Disease Patients

Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug&ndash;drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim&reg; Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (Cmax) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes

Monitoring of Dabrafenib and Trametinib in Serum and Self-Sampled Capillary Blood in Patients with BRAFV600-Mutant Melanoma

Patients treated with dabrafenib and trametinib for BRAFV600-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters

Chemical structures of the studied non-nucleoside reverse transcriptase inhibitors.

<p>Chemical structures of the studied non-nucleoside reverse transcriptase inhibitors.</p

Apoptosis and necrosis induction in cancer cells by non-nucleoside reverse transcriptase inhibitors.

<p>The fraction of apoptotic and necrotic cells after treatment with different NNRTIs in different concentrations was measured by Annexin-V-APC/7AAD staining and flow cytometry. An example of the gating in the FACS plots is shown for untreated (a) and with a toxic concentration of EFV treated cells (b). A curve was fitted through the data points of the total fraction of dead cells and the EC50 was calculated for each drug. The pancreatic cancer cell line BxPC-3 was treated for 72h with (c) EFV, (d) NVP, (e) RPV, (f) ETR, (g) LSV and (h) DLV. The pancreatic cancer cell line Panc-1 was treated for 72h with (j) EFV, (k) NVP and (l) RPV.</p