Infographic: PKI Combo™
PKI Combo™ addresses the goals of both in vivo PK screening and metabolite profiling early, rapidly and economically. The key success of this service is to integrate, previously unrelated, discovery DMPK studies into one lab, using one animal study, one analytical instrument, and one study team.
White Paper: Intraperitoneal Dose Administration: Successful Testing In Dogs Using IP Catheters With Access Ports
Intraperitoneal (IP) dose administration is the preferred method of dosing in the treatment of certain cancers as well as for peritonitis. Unfortunately, replicating IP administration in dogs in order to evaluate drug toxicity has posed multiple, serious challenges, rendering the approach unworkable in the laboratory. It is possible, however, to overcome these challenges by using a modified catheter with an access port to administer the investigational product. Frontage Labs has successfully applied this technique in dosing dogs as part of a study of a chemotherapy drug for ovarian cancer, demonstrating the viability of this method.
Frontage is a full-service CRO that enables biopharmaceutical and generic companies to advance their molecules from preclinical and clinical development, through commercialization. We believe partnership is what turns service into solutions. Our comprehensive laboratory services include analytical testing, product development and CTM manufacturing, DMPK, and bioanalysis Our clinical service portfolio includes early stage clinical services and biometrics.
This wide range of offerings enables us to provide a variety of solutions to your drug development challenges.
Poster: Pre-Existing Antibodies within Immunogenicity Testing
Monoclonal antibodies and next generation molecules such as antibody-drug conjugates (ADC) are being developed and moved into early phase clinical testing. These new molecules bring challenges for measuring immunogenicity within human serum samples.
• Therapeutic monoclonal antibodies could have structural regions which could contain ADA binding domains [Figure 1].
• ADC molecule has a mAb joined to a small drug by a linker region [Figure 2]. This may lead to a highly potent drug which is also a selective binder of a specific tumor antigen; however, the structure may also present a neoepitope to the immune system.
• Development of anti-drug antibody (ADA) assays to both mAb’s and ADC’s very commonly has demonstrated the presence of pre-existing antibodies (PEXA) in a small percentage of drug naïve normal human serum samples. It is currently unclear as to the evolutionary mechanism that has allowed PEXA to develop. Their presence may serve as a regulatory mechanism to suppress the immune system under certain conditions.
• Regardless of how pre-existing antibodies may have developed, measuring an anti-drug antibody (ADA) response in serum samples may present additional challenges with these pre-existing molecules present. Here, we outline a strategy to determine where on the molecule the ADA reactivity is directed against.
Journal: Development And Validation Of LC-MS/MS Methods For The Quantification Of The Novel Anticancer Agent Guadecitabine And Its Active Metabolite Β Decitabine In Human Plasma, Whole Blood And Urine
Guadecitabine (SGI-110), a dinucleotide of β‑decitabine and deoxyguanosine, is currently being evaluated in phase II/III clinical trials for the treatment of hematological malignancies and solid tumors. This article describes the development and validation of bioanalytical assays to quantify guadecitabine and its active metabolite β‑decitabine in human plasma, whole blood and urine using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Since β‑decitabine is rapidly metabolized further by cytidine deaminase, plasma and whole blood samples were kept on ice-water after collection and stabilized with tetrahydrouridine (THU) directly upon sample collection. Sample preparation consisted of protein precipitation for plasma and whole blood and dilution for urine samples and was further optimized for each matrix and analyte separately. Final extracts were injected onto a C6-phenyl column for guadecitabine analysis, or a Nova-Pak Silica column for β‑decitabine analysis. Gradient elution was applied for both analytes using the same eluents for each assay and detection was performed on triple quadrupole mass spectrometers operating in the positive ion mode (Sciex QTRAP 5500 and QTRAP 6500). The assay for guadecitabine was linear over a range of 1.0–200 ng/mL (plasma, whole blood) and 10–2000 ng/mL (urine). For β‑decitabine the assay was linear over a range of 0.5–100 ng/mL (plasma, whole blood) and 5–1000 ng/mL (urine). The presented methods were successfully validated according to the latest FDA and EMA guidelines for bioanalytical method validation and applied in a guadecitabine clinical mass balance trial in patients with advanced cancer.