Frontage Laboratories Inc.

Malvern, PA, United States

Frontage Laboratories Inc.

Malvern, PA, United States

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Xue Y.-J.,Celgene | Gao H.,Vertex Pharmaceuticals | Ji Q.C.,Bristol Myers Squibb | Lam Z.,QPS LLC | And 5 more authors.
Bioanalysis | Year: 2012

Distribution of drugs into tissues is an important determinant of the overall PK and PD profile. Thus, bioanalysis of drugs and their metabolites in tissues can play an important role in understanding the pharmacological and toxicological properties of new drug candidates. Unlike liquid matrices, bioanalysis in tissues offers unique challenges such as proper tissue sampling, appropriate tissue sample preparation, efficient extraction of the analytes from the tissue homogenates, and demonstration of stability and recovery of analytes in intact tissues. This article provides a systematic review of tissue sample analysis for small molecules using LC-MS/MS. The authors provide rationale for tissue sample analysis, and discuss strategies for method development, method qualification or validation, and sample analysis. Unique aspects of method development and qualification/validation are highlighted based on authors' direct experiences and literature summary. Analysis using intact tissue samples such as MALDI imaging is also briefly discussed. © 2012 Future Science Ltd.

Huang M.-Q.,Janssen Pharmaceutical | Lin Z.,Frontage Laboratories Inc. | Weng N.,Janssen Pharmaceutical
Bioanalysis | Year: 2013

High-resolution MS (HRMS) in conjunction with LC (LC-HRMS) has become available to many laboratories in the pharmaceutical industry. Due to its enhanced, though sometime perceived, specificity using the high-resolution power and its capability of simultaneous quantitation and structural elucidation using the post-acquisition data mining feature, utilization of LC-HRMS for bioanalysis could lead to potential rapid and reliable method development as well as sample analysis, thus generating both cost and resource savings. Here, we would like to share our perspectives about several current and future applications of LC-HRMS in bioanalysis. We will also discuss the factors influencing the quality of method establishment and potential pitfalls that need to be considered for the utilization of LC-HRMS in the field of regulated bioanalysis. We believe when utilized appropriately, LC-HRMS will play a significant role in the future landscape of quantitative bioanalysis. © 2013 Future Science Ltd.

O'Shannessy D.J.,Morphotek Inc. | Somers E.B.,Morphotek Inc. | Palmer L.M.,Morphotek Inc. | Thiel R.P.,Thiel Statistical Consultants | And 3 more authors.
Journal of Ovarian Research | Year: 2013

Background: Evaluate and compare the utility of serum folate receptor alpha (FRA) and megakaryocyte potentiating factor (MPF) determinations relative to serum CA125, mesothelin (MSLN) and HE4 for the diagnosis of epithelial ovarian cancer (EOC). Methods. Electrochemiluminescent assays were developed for FRA, MSLN and MPF and used to assess the levels of these biomarkers in 258 serum samples from ovarian cancer patients. Commercial assays for CA125 and HE4 were run on a subset of 176 of these samples representing the serous histology. Data was analyzed by histotype, stage and grade of disease. A comparison of the levels of the FRA, MSLN and MPF biomarkers in serum, plasma and urine was also performed in a subset of 57 patients. Results: Serum and plasma levels of FRA, MSLN and MPF were shown to be highly correlated between the two matrices. Correlations between all pairs of markers in 318 serum samples were calculated and demonstrated the highest correlation between HE4 and MPF, and the lowest between FRA and MPF. Serum levels of all markers showed a dependence on both stage and grade of disease. A multi-marker logistic regression model was developed resulting in an AUC=0.91 for diagnosis of serous ovarian cancer, a significant improvement over the AUC for any of the individual markers, including CA125 (AUC=0.84). Conclusions: FRA has significant potential as a biomarker for ovarian cancer, both as a stand-alone marker and in combination with other known markers for EOC. The lack of correlation between the various markers analyzed in the present study suggests that a panel of markers can aid in the detection and/or monitoring of this disease. © 2013 O'Shannessy et al.; licensee BioMed Central Ltd.

Dalvie D.,Pfizer | Xiang C.,Pfizer | Xiang C.,Celgene | Kang P.,Pfizer | And 3 more authors.
Xenobiotica | Year: 2013

1. Aldehyde oxidase (AO) is a cytosolic enzyme that contributes to the Phase I metabolism of xenobiotics in human and preclinical species. 2. Current studies explored in vitro metabolism of zoniporide in various animal species and humans using S9 fractions. The animal species included commonly used pharmacology and toxicology models and domestic animals such as the cat, cow or bull, pig and horse. 3. In addition, gender and strain differences in some species were also explored. 4. All animals except the dog and cat converted zoniporide to 2-oxozoniporide (M1). 5. Michael-Menten kinetic studies were conducted in species that turned over zoniporide to M1. 6. Marked differences in KM, Vmax and Clint were observed in the oxidation of zoniporide. 7. Although the KM and Vmax of zoniporide oxidation in male and female human S9 was similar, some gender difference was observed in animals especially, in Vmax. 8. The domestic animals also showed marked species differences in the AO activity and affinity toward zoniporide. © 2013 Informa UK, Ltd.

Zhang W.,Frontage Laboratories Inc. | Han F.,Frontage Laboratories Inc. | Zhao H.,Frontage Laboratories Inc. | Lin Z.J.,Frontage Laboratories Inc. | And 2 more authors.
Biomedical Chromatography | Year: 2012

Metformin is a well-known oral antihyperglycemic drug used in treatment of type II diabetes. Analysis of metformin in biological fluids is a challenge owing to its high polarity and small molecular size, which lead to poor retention of metformin on reversed-phase liquid chromatographic columns. A high-throughput method was developed and validated for the determination of metformin in rat plasma in support of preclinical toxicology studies, using hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC-MS/MS) and Tecan automated sample preparation. Extracted samples were directly injected onto the unbounded silica column with an aqueous-organic mobile phase. This HILIC-MS/MS method was validated for accuracy, precision, sensitivity, stability, matrix effect, recovery and calibration range. Acceptable intra-run and inter-run assay precision (coefficient of variation≤3.9%) and accuracy (99.0-101.8%) were achieved over a linear range of 50-50,000ng/mL. Metformin is stable in rat plasma for at least 6h at room temperature, 147days at -70°C and through three freeze (-70°C) and thaw cycles. Metformin is also stable in rat whole blood for at least 2h at room temperature and in an ice-water bath. The validated method was successfully used in support of several preclinical studies where metformin is dosed together with an investigational drug substance. The ruggedness of the validated method was demonstrated by the incurred sample reproducibility test. Copyright © 2011 John Wiley & Sons, Ltd.

Zhang W.,Frontage Laboratories Inc. | Han F.,Frontage Laboratories Inc. | Guo P.,Frontage Laboratories Inc. | Zhao H.,Frontage Laboratories Inc. | And 4 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2010

Drug-drug interactions involving cytochrome P450 (CYP450s) are an important factor for evaluation of a new chemical entity (NCE) in drug development. To evaluate the potential inhibitory effects of a NCE on the pharmacokinetics of a cocktail of representative probes of CYP enzymes (midazolam for CYP3A4, tolbutamide for CYP2C9, omeprazole for CYP2C19 and dextromethorphan for CYP2D6) and the safety and tolerability of the NCE in the presence of probe substrates, a high throughput liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of tolbutamide, omeprazole, midazolam and dextromethorphan in human plasma using tolbutamide-d9, midazolam-d4, (±)-omeprazole-d3, and dextromethorphan-d3 as the internal standards (ISs). Human plasma samples of 50 μL were extracted by a simple protein-precipitation procedure and analyzed using a high performance liquid chromatography electrospray tandem mass spectrometer system. Reversed-phase HPLC separation was achieved with a Hypersil GOLD AQ column (50 mm × 4.6 mm, 5 μm). MS/MS detection was set at mass transitions of 271 → 172 m/z for tolbutamide, 346 → 198 m/z for omeprazole, 326 → 291 m/z for midazolam, 272 → 171 m/z for dextromethorphan, 280 → 172 m/z for tolbutamide-d9 (IS), 349 → 198 m/z for (±)-omeprazole-d3 (IS), 330 → 295 m/z for midazolam-d4 (IS), and 275 → 171 m/z for dextromethorphan-d3 (IS) in positive mode. The high throughput LC-MS/MS method was validated for accuracy, precision, sensitivity, stability, recovery, matrix effects, and calibration range. Acceptable intra-run and inter-run assay precision (<10%) and accuracy (<10%) were achieved over a linear range of 50-50,000 ng/mL for tolbutamide, 1-1000 ng/mL for omeprazole, 0.1-100 ng/mL for midazolam and 0.05-50 ng/mL for dextromethorphan in human plasma. Method robustness was demonstrated by the 100% pass rate of 24 incurred sample analysis runs and all of the 50 clinical study samples used for incurred sample reproducibility (ISR) test having met the acceptance criterion (%Diff within 20%). The overall ISR results for all compounds showed that over 95% of the samples had a %Diff of less than 10%. The method is simple, rapid and rugged, and has been applied successfully to sample analysis in support of a drug-drug interaction study. © 2010 Elsevier B.V. All rights reserved.

Modak A.S.,Frontage Laboratories Inc.
Journal of Breath Research | Year: 2011

Over the last decade noninvasive diagnostic phenotype [13C]- breath tests using suitably labeled 13C substrates as well as breath tests using endogenous/exogenous volatile organic compounds in breath have been extensively researched. Despite the potential benefits of these companion diagnostic tests and stand-alone diagnostic tests for patient/disease stratification and market segmentation to personalize medicine, the clinical and commercial development of these diagnostic tests will need to overcome a number of regulatory, financial and scientific hurdles prior to their acceptance into routine clinical practice. © 2011 IOP Publishing Ltd.

Wang Z.,University of Tennessee Health Science Center | Wang Z.,Frontage Laboratories Inc. | Chen J.,University of Tennessee Health Science Center | Wang J.,University of Tennessee Health Science Center | And 7 more authors.
Pharmaceutical Research | Year: 2012

Purpose: To evaluate abilities of 2-aryl-4-benzoyl-imidazoles (ABI) to overcome multidrug resistance (MDR), define their cellular target, and assess in vivo antimelanoma efficacy. Methods: MDR cell lines that overexpressed P-glycoprotein, MDR-associated proteins, and breast cancer resistance protein were used to evaluate ABI ability to overcome MDR. Cell cycle analysis, molecular modeling, and microtubule imaging were used to define ABI cellular target. SHO mice bearing A375 human melanoma xenograft were used to evaluate ABI in vivo antitumor activity. B16-F10/C57BL mouse melanoma lung metastasis model was used to test ABI efficacy to inhibit tumor lung metastasis. Results: ABIs showed similar potency to MDR cells compared to matching parent cells. ABIs were identified to target tubulin on the colchicine binding site. After 31 days of treatment, ABI-288 dosed at 25 mg/kg inhibited melanoma tumor growth by 69%; dacarbazine at 60 mg/kg inhibited growth by 52%. ABI-274 dosed at 25 mg/kg showed better lung metastasis inhibition than dacarbazine at 60 mg/kg. Conclusions: This new class of antimitotic compounds can overcome several clinically important drug resistant mechanisms in vitro and are effective in inhibiting melanoma lung metastasis in vivo, supporting their further development. © 2012 Springer Science+Business Media, LLC.

Lin Z.J.,Frontage Laboratories Inc. | Li W.,Novartis | Weng N.,Johnson and Johnson Pharmaceutical Research and Development LLC
Bioanalysis | Year: 2011

With the globalization of drug development activities, transferring a validated bioanalytical procedure to a different site within a pharmaceutical company, or to one or multiple contract research organizations has been dramatically increased in recent years. Undeniably, bioanalytical method transfer is the needed step prior to routine sample analysis at the receiving laboratory. It is clearly stated in the 2001 US FDA Guidance on Bioanalytical Method Validation that a partial validation is needed for method transfer between laboratories. In the current EMA draft guidelines on method validation, the necessity of a method transfer is also emphasized. However, the above guidelines do not give many details on how and when a method transfer validation should be conducted. There is a need for a step-by-step deliberation on the overall strategies, procedures and even technical details for a successful bioanalytical method transfer. In this article, we review the contemporary information available in the scientific literature on method transfer and illustrate various bioanalytical method transfer scenarios using case studies. A flexible and fit-for-purpose bioanalytical method transfer strategy is proposed. © 2011 Future Science Ltd.

Modak A.S.,Frontage Laboratories Inc.
Journal of Breath Research | Year: 2013

Over the last decade non invasive diagnostic phenotype [ 13C]-breath tests as well as tests using endogenous volatile organic compounds (VOCs) in breath have been researched extensively. However, only three breath tests have been approved by the FDA over the last 15 years. Despite the potential benefits of these companion diagnostic tests (CDx) for evaluation of drug metabolizing enzyme activities and standalone diagnostic tests for disease diagnosis to personalize medicine, the clinical and commercial development of breath tests will need to overcome a number of regulatory, financial and scientific hurdles prior to their acceptance into routine clinical practice. The regulatory agencies (FDA and EMEA) need to adapt and harmonize their approval process for companion diagnostic tests as well as standalone diagnostic breath tests for personalized medicine. The Center for Devices and Radiological Health has deemed any breath test that involves a labeled 13C substrate/drug and a device requires a Pre Market Approval (PMA), which is analogous to an approved New Drug Application. A PMA is in effect, a private license granted to the applicant for marketing a particular medical device. Any breath test with endogenous VOCs along with a device can be approved via the 510(k) application. A number of 13C breath tests with clinical applications have been researched recently and results have been published in reputed journals. Diagnostic companies will need to invest the necessary financial resources to develop and get regulatory approval for diagnostic breath tests capable of identifying responders/non responders for FDA approved drugs with narrow therapeutic indices (personalized medicine) or for evaluating the activity of drug metabolizing P450 polymorphic enzymes or for diagnosing diseases at an early stage or for monitoring the efficacy of medications. The financial success of these diagnostic breath tests will then depend entirely on how the test is marketed to physicians, healthcare organizations, payers (reimbursement), insurance companies and most importantly to patients, the eventual beneficiaries. © 2013 IOP Publishing Ltd.

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