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Aberg J.A.,New York University | Tebas P.,University of Pennsylvania | Overton E.T.,University of Washington | Gupta S.K.,Indiana University | And 5 more authors.
AIDS Research and Human Retroviruses | Year: 2012

We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/ emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4+ cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r,-0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted. © 2012, Mary Ann Liebert, Inc.


Van De Merbel N.C.,Bioanalytical Laboratory | Van De Merbel N.C.,University of Groningen | De Vries R.,Janssen RandD
Bioanalysis | Year: 2013

Apart from the well-known matrix effects that can occur in ESI LC-MS, biological matrices may have other effects influencing the quantitative reliability of bioanalytical methods. In this paper, six case studies are presented that show the effect that aging, that is the change in properties and composition of biological matrices over time, can have on the performance of bioanalytical methods. It is shown that selectivity can be affected due to the formation or disappearance of endogenous compounds. Stability can be influenced because of the decrease (or increase) of enzyme activities and recovery can be impacted if the extractability from binding sites in the matrix is enhanced or decreased. A general discussion on the importance of these matrix effects is provided as well as a perspective on how to properly address them in the method-development and validation stages of regulated bioanalysis. © 2013 Future Science Ltd.


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.


Stuyver L.J.,Janssen Diagnostics Inc. | Verbeke T.,Open Web Analytics | Van Loy T.,Janssen Diagnostics Inc. | Van Gulck E.,Janssen Infectious Disease CREATe | Tritsmans L.,Janssen RandD
Virology Journal | Year: 2013

Background: Human polyomaviruses (HPyV) infections cause mostly unapparent or mild primary infections, followed by lifelong nonpathogenic persistence. HPyV, and specifically JCPyV, are known to co-diverge with their host, implying a slow rate of viral evolution and a large timescale of virus/host co-existence. Recent bio-informatic reports showed a large level of peptide homology between JCPyV and the human proteome. In this study, the antibody response to PyV peptides is evaluated. Methods. The in-silico analysis of the HPyV proteome was followed by peptide microarray serology. A HPyV-peptide microarray containing 4,284 peptides was designed and covered 10 polyomavirus proteomes. Plasma samples from 49 healthy subjects were tested against these peptides. Results: In-silico analysis of all possible HPyV 5-mer amino acid sequences were compared to the human proteome, and 1,609 unique motifs are presented. Assuming a linear epitope being as small as a pentapeptide, on average 9.3% of the polyomavirus proteome is unique and could be recognized by the host as non-self. Small t Ag (stAg) contains a significantly higher percentage of unique pentapeptides. Experimental evidence for the presence of antibodies against HPyV 15-mer peptides in healthy subjects resulted in the following observations: i) antibody responses against stAg were significantly elevated, and against viral protein 2 (VP2) significantly reduced; and ii) there was a significant correlation between the increasing number of embedded unique HPyV penta-peptides and the increase in microarray fluorescent signal. Conclusion: The anti-peptide HPyV-antibodies in healthy subjects are preferably directed against the penta-peptide derived unique fraction of the viral proteome. © 2013 Stuyver et al.; licensee BioMed Central Ltd.


Chapuy C.I.,Brigham and Women's Hospital | Nicholson R.T.,Brigham and Women's Hospital | Aguad M.D.,Brigham and Women's Hospital | Chapuy B.,Dana-Farber Cancer Institute | And 4 more authors.
Transfusion | Year: 2015

BACKGROUND Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. STUDY DESIGN AND METHODS DARA binding to CD38+ or CD38- HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. RESULTS Normal plasma samples spiked with DARA (0.1-10 μg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38- controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. CONCLUSION DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K- units are provided to these patients. © 2015 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.


Patel N.,Cytel, Inc | Bolognese J.,Cytel, Inc | Chuang-Stein C.,Pfizer | Hewitt D.,Merck And Co. | And 2 more authors.
Drug Information Journal | Year: 2012

Traditionally, sample size considerations for phase 2 trials are based on the desired properties of the design and response information from the trials. In this article, we propose to design phase 2 trials based on program-level optimization. We present a framework to evaluate the impact that several phase 2 design features have on the probability of phase 3 success and the expected net present value of the product. These factors include the phase 2 sample size, decision rules to select a dose for phase 3 trials, and the sample size for phase 3 trials. Using neuropathic pain as an example, we use simulations to illustrate the framework and show the benefit of including these factors in the overall decision process. © The Author(s) 2012.


Jian W.,Janssen RandD | Edom R.W.,Janssen RandD | Huang M.Q.,Janssen RandD | Weng N.,Janssen RandD
Bioanalysis | Year: 2014

Significant differences in the pharmacodynamic activity and pharmacokinetic properties could exist for a pair of enantiomeric drugs. In order to evaluate the activity, toxicity, absorption, distribution, metabolism, and excretion properties of the individual enantiomers, and any potential for chiral inversion caused by the biotransformation process, chiral bioanalytical assays are necessary for individual enantiomers and/or their metabolites for in vivo samples. However, development and validation of chiral quantitative assays are highly challenging in comparison to typical nonchiral assays. Therefore, a tiered approach should be used to address specific needs arising in different scenarios of chiral drug development, including development of racemate or fixed-ratio (nonracemic) enantiomers, development of a single enantiomer, racemic switches, and quantitation of enantiomeric metabolites. The choice of a nonchiral quantitative assay, a chiral qualitative assay, or a chiral quantitative assay should be based on the development strategy and on the molecular properties of the drug candidate. © 2014 Future Science Ltd.


Higton D.,Astrazeneca | Young G.,Glaxosmithkline | Timmerman P.,Janssen RandD | Abbott R.,Shire Pharmaceuticals | And 2 more authors.
Bioanalysis | Year: 2012

Accelerator mass spectrometry (AMS) is being used more widely to provide PK data for early decision making or to generate absolute bioavailability data in later phases of development. Presently, there is no clear consensus on the level of the scientific validation required for these assays. The European Bioanalysis Forum (EBF) has conducted two surveys with its members and presented the results at its 4th Open Symposium. With AMS being used for discrete scientific assessment, method establishment of AMS assays should focus on science rather than trying to fit the assay parameters into validation criteria used for Regulated Bioanalysis guidance, and an amount of freedom of execution and interpretation is needed. Hence, the EBF focuses their recommendation on introducing terminology around scientific qualification or validation to be used in relation to AMS. Guidance is given on which parameters should be investigated when a qualified method is required. The recommendations of the EBF for scientific validation are described herein. The scientific validation of AMS assays will be different to that applied for LC-MS/MS assays, and an example is that accuracy and precision limits, as used for ligand-binding assays, would be more appropriate. © 2012 Future Science Ltd.


Ford S.L.,Glaxosmithkline | Gould E.,Glaxosmithkline | Chen S.,Glaxosmithkline | Margolis D.,Glaxosmithkline | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

Dolutegravir (DTG) and GSK1265744 are HIV integrase inhibitors (INIs) in clinical development. The oral formulation of rilpivirine (RPV), a nonnucleoside reverse transcriptase inhibitor (NNRTI), has been approved for treatment-naive HIV infection. Long-acting depot injections of GSK1265744 and RPV are also being developed. This study evaluated the potential for drug interactions between RPV and these INIs. This phase 1, open-label, two-cohort, three-period, single-sequence crossover study evaluated oral coadministration of RPV with DTG or GSK1265744. Healthy subjects received DTG (50 mg every 24 h for 5 days) or GSK1265744 (30 mg every 24 h for 12 days) in period 1 followed by a washout, RPV (25 mg every 24 h for 11 or 12 days) in period 2, immediately followed by RPV (25 mg every 24 h) plus DTG (50 mg every 24 h) for 5 days or GSK1265744 (30 mg every 24 h) for 12 days in period 3. Steady-state pharmacokinetic (PK) parameters were estimated using noncompartmental analysis of data collected on the last day of each period. The combinations of RPV and DTG (n=16) and of RPV and GSK1265744 (n=11) were well tolerated; no grade 3 or 4 adverse events (AEs) or AE-related discontinuations were observed. The 90% confidence intervals for the area under the curve from time zero until the end of the dosage interval [AUC0-τ] and maximum concentration of drug in serum (Cmax) geometric mean ratios were within 0.8 to 1.25. Following administration of DTG+RPV, DTG and RPV Cτ increased by 22% and 21%, respectively. Following administration of GSK1265744+RPV, RPV Cτ decreased 8%. DTG and GSK1265744 can be administered with RPV without dosage adjustment for either agent. These results support coadministration of RPV with DTG or GSK1265744 as either oral or long-acting depot injection regimens. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Rice D.A.K.,Janssen Medical Affairs | Kaniga K.,Janssen RandD | Lee M.,Janssen RandD | Redman R.,Janssen RandD
International Journal of Antimicrobial Agents | Year: 2013

An analysis of subjects with concurrent bacteraemia and either nosocomial pneumonia, complicated intra-abdominal infection or complicated urinary tract infection from six phase 3 clinical trials demonstrated similar cure rates and clearance of bacteraemia in patients treated with doripenem and comparator agents. © 2013 Elsevier B.V. and the International Society of Chemotherapy.

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