Sheila Breidinger
Merck & Co.
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Featured researches published by Sheila Breidinger.
Clinical Infectious Diseases | 2008
Marian Iwamoto; Larissa Wenning; Goutam C. Mistry; Amelia S. Petry; Sarah Y. Liou; Kaylan Ghosh; Sheila Breidinger; Neal Azrolan; Maria J. Gutierrez; William E. Bridson; Julie A. Stone; Keith M. Gottesdiener; John A. Wagner
Raltegravir is an HIV integrase inhibitor that is metabolized through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1, and its use is anticipated in combination with atazanavir (a uridine diphosphate glucuronosyltransferase 1A1 inhibitor). Two pharmacokinetic studies of healthy subjects assessed the effect of multiple-dose atazanavir or ritonavir-boosted atazanavir on raltegravir levels in plasma. Atazanavir and atazanavir plus ritonavir modestly increase plasma levels of raltegravir.
Clinical Infectious Diseases | 2009
Marian Iwamoto; Larissa Wenning; Bach-Yen Nguyen; Hedy Teppler; Allison Moreau; Rand R. Rhodes; William D. Hanley; Bo Jin; Charlotte M. Harvey; Sheila Breidinger; Neal Azrolan; H. Frank Farmer; Robin Isaacs; Jeffery A. Chodakewitz; Julie A. Stone; John A. Wagner
Raltegravir, a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has pH-dependent solubility. Raltegravir plasma concentration increases with omeprazole coadministration in healthy subjects; this is likely secondary to an increase in bioavailability attributable to increased gastric pH. Increased gastric pH has been reported in HIV-1-infected individuals, and the effects of omeprazole in this intended population may be diminished. Further investigation is necessary.
Clinical Pharmacology & Therapeutics | 2009
Larissa Wenning; Amelia S. Petry; James Kost; Bo Jin; Sheila Breidinger; I DeLepeleire; Ej Carlini; S Young; Tom Rushmore; F Wagner; Nm Lunde; F Bieberdorf; Howard E. Greenberg; Julie A. Stone; John A. Wagner; Marian Iwamoto
Raltegravir is a human immunodeficiency virus–1 (HIV‐1) integrase strand transfer inhibitor metabolized by glucuronidation via UDP‐glucuronosyltransferase 1A1 (UGT1A1). In this study, 30 subjects with a UGT1A1*28/*28 genotype (associated with decreased activity of UGT1A1) and 27 UGT1A1*1/*1 control subjects (matched by race, age, gender, and body mass index) received a single 400‐mg dose of raltegravir after fasting. No serious adverse experiences were reported, and there were no discontinuations due to adverse experiences. The geometric mean ratio (GMR) (UGT1A1*28/*28 to UGT1A1*1/*1) and 90% confidence interval (CI) were 1.41 (0.96, 2.09) for raltegravir area under the concentration–time curve (AUC0–∞), 1.40 (0.86, 2.28) for maximum plasma concentration (Cmax), and 1.91 (1.43, 2.55) for concentration at the 12‐h time point (C12 h). No clinically important differences in time to maximum concentration (Tmax) or half‐life were observed. Plasma concentrations of raltegravir are modestly higher in individuals with the UGT1A1*28/*28 genotype than in those with the UGT1A1*1/*1 genotype. This increase is not clinically significant, and therefore no dose adjustment of raltegravir is required for individuals with the UGT1A1*28/*28 genotype.
Antimicrobial Agents and Chemotherapy | 2008
Larissa Wenning; Evan J. Friedman; James Kost; Sheila Breidinger; Jon E. Stek; Kenneth C. Lasseter; Keith M. Gottesdiener; Joshua Chen; Hedy Teppler; John A. Wagner; Julie A. Stone; Marian Iwamoto
ABSTRACT Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase inhibitor with potent in vitro activity (95% inhibitory concentration of 31 nM in 50% human serum). This article reports the results of an open-label, sequential, three-period study of healthy subjects. Period 1 involved raltegravir at 400 mg twice daily for 4 days, period 2 involved tenofovir disoproxil fumarate (TDF) at 300 mg once daily for 7 days, and period 3 involved raltegravir at 400 mg twice daily plus TDF at 300 mg once daily for 4 days. Pharmacokinetic profiles were also determined in HIV-1-infected patients dosed with raltegravir monotherapy versus raltegravir in combination with TDF and lamivudine. There was no clinically significant effect of TDF on raltegravir. The raltegravir area under the concentration time curve from 0 to 12 h (AUC0-12) and peak plasma drug concentration (Cmax) were modestly increased in healthy subjects (geometric mean ratios [GMRs], 1.49 and 1.64, respectively). There was no substantial effect of TDF on raltegravir concentration at 12 h postdose (C12) in healthy subjects (GMR [TDF plus raltegravir-raltegravir alone], 1.03; 90% confidence interval [CI], 0.73 to 1.45), while a modest increase (GMR, 1.42; 90% CI, 0.89 to 2.28) was seen in HIV-1-infected patients. Raltegravir had no substantial effect on tenofovir pharmacokinetics: C24, AUC, and Cmax GMRs were 0.87, 0.90, and 0.77, respectively. Coadministration of raltegravir and TDF does not change the pharmacokinetics of either drug to a clinically meaningful degree. Raltegravir and TDF may be coadministered without dose adjustments.
Antimicrobial Agents and Chemotherapy | 2010
David Croteau; Scott Letendre; Brookie M. Best; Ronald J. Ellis; Sheila Breidinger; David B. Clifford; Ann C. Collier; Benjamin B. Gelman; Christina M. Marra; Gilbert Mbeo; Allen McCutchan; Susan Morgello; David M. Simpson; Lauren Way; Florin Vaida; Susan Ueland; Edmund V. Capparelli; Igor Grant
ABSTRACT HIV-associated neurocognitive disorders continue to be common. Antiretrovirals that achieve higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV and improved cognition. The objective of this study was to measure total raltegravir (RAL) concentrations in CSF and to compare them with matched concentrations in plasma and in vitro inhibitory concentrations. Eighteen subjects with HIV-1 infection were enrolled based on the use of RAL-containing regimens and the availability of CSF and matched plasma samples. RAL was measured in 21 CSF and plasma pairs by liquid chromatography-tandem mass spectrometry, and HIV RNA was detected by reverse transcription-PCR (RT-PCR). RAL concentrations were compared to the 50% inhibitory concentration (IC50) for wild-type HIV-1 (3.2 ng/ml). Volunteers were predominantly middle-aged white men with AIDS and without hepatitis C virus (HCV) coinfection. The median concurrent CD4+ cell count was 276/μl, and 28% of CD4+ cell counts were below 200/μl. HIV RNA was detectable in 38% of plasma specimens and 4% of CSF specimens. RAL was present in all CSF specimens, with a median total concentration of 14.5 ng/ml. The median concentration in plasma was 260.9 ng/ml, with a median CSF-to-plasma ratio of 0.058. Concentrations in CSF correlated with those in with plasma (r2, 0.24; P, 0.02) but not with the postdose sampling time (P, >0.50). RAL concentrations in CSF exceeded the IC50 for wild-type HIV in all specimens by a median of 4.5-fold. RAL is present in CSF and reaches sufficiently high concentrations to inhibit wild-type HIV in all individuals. As a component of effective antiretroviral regimens or as the main antiretroviral, RAL likely contributes to the control of HIV replication in the nervous system.
The Journal of Clinical Pharmacology | 2008
Marian Iwamoto; James Kost; G. C. Misty; Larissa Wenning; Sheila Breidinger; T. C. Marbury; Julie A. Stone; Keith M. Gottesdiener; Daniel M. Bloomfield; John A. Wagner
Raltegravir is a novel HIV‐1 integrase inhibitor with potent in vitro activity (IC95 = 31 nM in 50% human serum). A double‐blind, randomized, placebo‐controlled, double‐dummy, 3‐period, single‐dose crossover study was conducted; subjects received single oral doses of 1600 mg raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2‐sided 90% confidence interval for the QTcF interval placebo‐adjusted mean change from baseline of raltegravir was less than 10 ms at every time point. For the raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean Cmax of ∼20 μM raltegravir was attained, ∼4‐fold higher than the Cmax at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2‐, 3‐, and 4‐hour time points. Administration of a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.
The Journal of Clinical Pharmacology | 2011
Diana M. Brainard; Evan J. Friedman; Bo Jin; Sheila Breidinger; Maria D. Tillan; Larissa Wenning; Julie A. Stone; Jeffrey A. Chodakewitz; John A. Wagner; Marian Iwamoto
A the worldwide percentage of individuals infected with human immunodeficiency virus type 1 (HIV-1) has stabilized since 2000, the absolute number of people infected with HIV globally has increased because of an ongoing high level of new infections each year and the life-saving benefits of more widely available antiviral therapy. New antiviral agents have played a critical role in expanding treatment options for patients with extensive treatment experience and high levels of drug experience as well as those undergoing initial therapy. Raltegravir (Isentress; formerly known as MK-0518) is an agent in a new class of antiretroviral drugs, the HIV integrase inhibitors, which block the strand transfer step of the integration process. Raltegravir has potent in vitro activity, blocking HIV replication with a 95% inhibitory concentration (IC95) of 31 nM in 50% normal human serum. In placebo-controlled trials of viremic patients, raltegravir administered twice daily has been shown to be efficacious in reducing HIV viral load to undetectable levels in both treatment-naïve patients and heavily treated, multidrug-resistant patients. The current dose and schedule of raltegravir is 400 mg administered by mouth twice daily without regard to food. Because the nutritional content of different meals when administered with drugs has the potential to significantly influence the pharmacokinetics of drugs, understanding potential food–drug interactions is important. Meals that are high in total calories and fat content are more likely to influence gastrointestinal physiology and may, therefore, result in a greater effect on drug bioavailability. An initial study of raltegravir with food indicated that a high-fat meal may affect the pharmacokinetic profile of raltegravir without affecting overall exposure. This article describes a more detailed analysis of the effects of different meal types (low, moderate, and high fat content) on the plasma pharmacokinetic profile of raltegravir.
Analytical Chemistry | 2012
Li Sun; Hankun Li; Kenneth Willson; Sheila Breidinger; Matthew L. Rizk; Larissa Wenning; E.J. Woolf
HIV-1 integrase strand transfer inhibitors are an important class of compounds targeted for the treatment of HIV-1 infection. Microdosing has emerged as an attractive tool to assist in drug candidate screening for clinical development, but necessitates extremely sensitive bioanalytical assays, typically in the pg/mL concentration range. Currently, accelerator mass spectrometry is the predominant tool for microdosing support, which requires a specialized facility and synthesis of radiolabeled compounds. There have been few studies attempted to comprehensively assess a liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach in the context of microdosing applications. Herein, we describe the development of automated LC-MS/MS methods to quantify five integrase inhibitors in plasma with the limits of quantification at 1 pg/mL for raltegravir and 2 pg/mL for four proprietary compounds. The assays involved double extractions followed by UPLC coupled with negative ion electrospray MS/MS analysis. All methods were fully validated to the rigor of regulated bioanalysis requirements, with intraday precision between 1.20 and 14.1% and accuracy between 93.8 and 107% at the standard curve concentration range. These methods were successfully applied to a human microdose study and demonstrated to be accurate, reproducible, and cost-effective. Results of the study indicate that raltegravir displayed linear pharmacokinetics between a microdose and a pharmacologically active dose.
Antiviral Therapy | 2010
Li Zhu; Joan R. Butterton; Anna Persson; Michele Stonier; Wendy Comisar; Deborah Panebianco; Sheila Breidinger; Jenny Zhang; Richard Bertz
BACKGROUND Atazanavir plus raltegravir 300/400 mg twice daily is being explored as a ritonavir- and nucleoside-sparing treatment strategy. The pharmacokinetics and safety of this combination in healthy individuals were evaluated. METHODS A total of 22 healthy individuals received raltegravir 400 mg on days 1-5, atazanavir 300 mg on days 6-12 and atazanavir plus raltegravir 300/400 mg on days 13-26, twice daily with a light meal. Serial blood samples were collected 12 h after the morning dose on days 5, 12 and 26; safety assessments, clinical laboratory data and serial electrocardiograms (ECGs) at 0, 2 and 6 h were obtained. RESULTS Raltegravir coadministration reduced atazanavir geometric mean maximum plasma concentration (C(max)), area under the plasma concentration-time curve from 0 to 12 h post-dose (AUC(0-12)) and trough plasma concentration (C(min)) by 11%, 17% and 29%, respectively, compared with atazanavir alone. Geometric mean atazanavir C(min) was 817 ng/ml (range 250-1,550) with raltegravir coadministration. Atazanavir increased raltegravir geometric mean C(max), AUC(0-12) and C(min) by 39%, 54% and 48%, respectively. All adverse events were of mild or moderate intensity. Hyperbilirubinaemia and ECG PR increases with atazanavir were similar to those of atazanavir/ritonavir once daily. No corrected QT prolongations were noted. Mean QRS increase from baseline was 11.0 ms (range 2-25) after receiving atazanavir for 7 days; no further QRS increase was noted and no QRS interval was >120 ms with raltegravir coadministration. No ECG changes were observed with raltegravir alone. CONCLUSIONS Coadministration of atazanavir and raltegravir 300/400 mg twice daily decreased atazanavir AUC(0-12) and C(min) relative to atazanavir alone, and increased AUC(0-12) of raltegravir relative to raltegravir alone. Atazanavir and raltegravir alone and coadministered appeared safe and well-tolerated.
Bioanalysis | 2018
Yang Xu; Dina Goykhman; Ming Wang; Tonya Jackson; Iris Xie; Kenneth Willson; Sheila Breidinger; Helengrace Schuck; Jane Harrelson; Eric Woolf
AIM Advances in technology have led to a shift for peptide quantification from traditional ligand-binding assays to LC-MS/MS-based analysis, which presents challenges, in other assay sensitivity, specificity and ruggedness, in addition to lacking of regulatory guidance, especially for the hybrid assay format. Methodology & results: This report communicates a strategy that has been employed in our laboratories for method development and assay validation, and exemplified in a case study of MK-2640, a glucose-responsive insulin, in multiple matrices. Intact MK-2640 was monitored, while immunoaffinity purification and SPE were used to support the rat/dog GLP and clinical studies, respectively. The rationale and considerations behind our approach, as well as the acceptance criteria applied to the assay validation are discussed.