Bioanalytical Assays for Clinical Trials

PK Sample Collection Kit and Equipment Rental

Vast Experience in Bioanalytical Assays for Clinical Trials

Automated Barcode Sample Inventory & Data Handling

Clinical Trial Equipment Rental & PK Sample Collection Kit Supporting PK Sample Collection, Handling & -70°C Storage

Provide significant cost savings and logistic support for PK sample collection and storage at clinical sites prior to delivery to bioanalytical sites

Design & provide training of PK sample collection protocol, sample collection kits, and sample LIMS inventory using Thermo-Watson LIMS™ barcode system

Compact Ultra Low -70°C to -80°C Revco™ Freezer

Refrigerated Low Speed Eppendorf™ Centrifuge

PK Blood / Plasma PK Sample Collection Supplies

Additional Clinical Trial Equipment Available Upon Request

In Vitro DMPK & ADME

BRIVAL™ is our in vitro drug metabolism group co-founded and operated by Dr. Albert P Li and Ms. Clara Faan, featuring a full suite of in vitro metabolism studies based on human and animal hepatocytes, microsomes, S9 fractions and recombinant CYP450 and Phase II enzymes.

In Vitro Drug Metabolism Studies

Unknown Metabolite Profile Using Microsomes or Hepatocytes

The use of ¹⁴C-labeled materials can provide time efficient identification of metabolites across species of animals

Laura ™ - Radio-chromatography Data System &
SoFie ™ - Stop-Flow Controller

The combination of SoFie™ controller and Laura™ software allows radiochemical measurement at either the threshold of detection or at any measurement level required by the user.

Parallel Collection of HPLC/DAD, MS Full Scan and Radiochemical Data

β-RAM - RadioHPLC detector (LabLogic Systems Ltd)

The β-RAM flow-through monitor for HPLC peaks combines a proven detection system with the latest computer technology, enabling the sharpest peak-shape resolution and the lowest amounts of radioactivity quantitation

Free Drug Determination by In vitro Equilibrium Dialysis & Ultrafiltration Assays of Protein Binding in Clinical & Preclinical Samples

In Vitro vs In Vivo Studies on Reactive Metabolites

Established in vitro assays and protocols are available to determine the presence and extent of irreversible binding of 14C-radiolabeled drug candidates to human and rat liver microsomes and hepatocytes to characterize the nature of reactive metabolites and Rank-Ordering of Candidates

HLM / RLM + ¹⁴C-Drug Candidate

Reaction for 60 minutes
Exhaustive Extraction of Non-Bound Drug & Metabolites
Collect Protein for ¹⁴C Liquid Scintillation Counting
Measure Protein Concentration

Covalent Binding Rank-Ordering of Candidates

      References:

1. Evans DC, Watt AP, Nicoll-Griffith DA, and Baillie TA (2004) Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 17:3–16


2. Takakusa H, Masumoto H, Yukinaga H, et.al. (2008) Covalent binding and tissue distribution/retention assessment of drugs associated with idiosyncratic drug toxicity. Drug Metab Dispos. Sep;36(9):1770-9. Epub 2008 May 28.


3. Zhou S, Chan E, Duan W, Huang M, and Chen YZ (2005) Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metab Rev 37:41–213.

In Vivo DMPK & ADME

GLP Rodent Facility for ADME, DMPK & Xenograft Efficacy Studies

A Mouse Dried-Blood Spot (DBS) Rapid PK Model Based on Serial-Sampling for Evaluation of Blood PK & Tissue Drug Distribution

Click here to open the pdf file for "LC/MS/MS Assay Method for Quantitation of Drug in Dried Blood Spot (DBS)"

Traditional mouse PK studies usually require a single terminal PK blood draw from each animal to provide a large sample volume at each time point. This single terminal blood draw sparse sampling approach requires a large number of animals.

The dried blood spot (DBS) sampling technique has allowed the sampling of 20 µL whole blood at each serial time point from a mouse over the entire PK profile thereby providing improved PK data quality and reduced number of animals and cost. A parallel rider group of mouse can also be dosed to provide target organ tissue distribution data.

In Vitro / In Vivo SEDDs Formulation Design prior to ADME & DM/PK Studies

[1] Chervinsky D.S., Brecher B.L., Hoelcle M.J. Anticancer Res., 13:93-96 (1993)

Drug Candidate Early In Vitro & In Vivo Screening

• LCMSMS Assay Development and Performance Qualification

• In Vivo Pharmacokinetic Screening

Rapid PK & Drug Tissue Distribution based on Dried-Blood Spot LCMSMS Assay
Rodent Mass Balance Excretion Model

• In Vitro Drug Metabolism Screening

In Vitro CYP Inhibition / Pathway ID
In Vitro Metabolic Stability / Metabolite ID
Protein Binding Cross-Species Comparison

• In Vivo Pharmacology / Toxicology Screening

Patient-Derived Primary Tumor Xenograft Mouse Model
Acute Tox Screening in Rodents

Patient Tumor-Derived Xenograft Models for Drug Development & Personalized Drug Sensitivity Evaluation at Oncograph™

Oncograph™ is founded by a group of world experts in the area of cancer modeling, anti-cancer drug evaluation and personalized cancer therapy. The mission is to develop new generation of preclinical platforms for 1) better predictive of personalized anti-cancer drug sensitivity; 2) accelerating the development of oncology drugs.

At present, the most commonly used preclinical cancer xenograft models are based on use of cultured human cell lines. Such cell line xenograft models, while valuable for basic research, in general do not adequately predict the efficacy of anticancer agents in the clinic and have been highlighted as a key obstacle in the translation of major advances in basic cancer research into meaningful clinical benefits. In addition to tradition cell line models, Oncograft™ utilizes new generation of pre-clinical platform, a unique panel of patient-derived xenograft models, established by the implantation of primary human tumors under the renal capsule of immune-deficient mice. The high vascularity of this subrenal capsule graft site, compared to the subcutaneous and orthotopic sites, allows a more adequate supply of nutrients to the tumor tissue. This grafting methodology permits a high tumor take rates (>95%) for a variety of low and higher grade malignancies, including cancers of the prostate (Lin et al, 2008; Wang et al, 2005a; Wang et al, 2005b), ovary (Lee et al, 2005; Press et al, 2008), kidney (Liou et al, 2004), lung (Cutz et al, 2006; Guan et al, 2009; Dong et al.,2010), pancreas (Watahiki et al, 2006) and others (unpublished data).

Significantly, the cancer tissue xenografts and transplantable tumor lines derived from such xenografts are histologically highly similar to the donor tissues and retain important genetic and epigenetic features as well as responses to treatment with drugs (Cutz et al, 2006; Lee et al, 2005; Press et al, 2008). It is also proved that patient-derived xenografts can be used for personalized cancer therapy (Dong, et al., 2010). The advanced xenografting technology allows us develop next generation of patient-derived cancer models to support new drug candidate development and personalized oncology drug therapy evaluation for patients.

1. Lee CH, Xue H, Sutcliffe M, Gout PW, Huntsman DG, Miller DM, Gilks CB, Wang YZ. Establishment of subrenal capsule xenografts of primary human ovarian tumors in SCID mice: potential models. Gyn. Oncol. 96 (1): 48-55, 2005
2. Press JZ, Kenyon JA, Xue H, Miller MA, de Luca A, Miller DM, Huntsman DG, Gilks CB, McAlpine JN, Wang YZ. Xenografts of primary human gynecological tumors grown under the renal capsule of NOD/SCID mice show genetic stability during serial transplantation and respond to cytotoxic chemotherapy. Gyn. Oncol. 110: 256-264, 2008.
3. Wang YZ, Revelo MP, Sudilovsky D, Chen WG, Goetz L, Xue H, Sadar M, Shappell SB, Cunha GR, Hayward SW. Development and characterization of efficient xenograft models for benign and malignant human prostate tissue. Prostate 64, 149-159, 2005
4. Wang Y, Xue H, Mawji R, Chen WG, Hayward SW, Gilks CB, Sadar MD, Gout PW, Cunha GR, Wang YZ. An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line. Lab. Invest. 85: 1392-1404, 2005 (Cover art and features inside Lab. Invest.)
5. Lin D, Watahiki A, Bayani J, Zhang F, Liu L, Ling V, Sadar M, English J, Fazli L, So A, Gout P, Gleave M, Squire JA, Wang YZ. ASAP1, a Gene at 8q24, is Associated with Prostate Cancer Metastasis. Cancer Research. 68: 4352-4359. 2008.
6. McPherson S, Hussain S, Balanathan P, Hedwards S, Niranjan B, Grant M, Chandrasiri U, Toivanen U, Wang YZ, Taylor R, Risbridger G. Estrogen receptor beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen-independent and TNFa-mediated. PNAS 107(7): 3123-3128, 2010.
7. Cutz J-C, Guan J, Bayani J, Xue H, Sutcliffe M, English J, Flint J, LeRiche J, Yee J, Squire J, Gout PW, Lam S, Wang YZ. Establishment in SCID Mice of Subrenal Capsule Xenografts and Transplantable Tumor Lines from a Variety of Primary Human Lung Cancers: Potential Models for Studying Tumor Progression-Related Changes. Clin. Cancer Research. 12 (13): 4043-4054, 2006.
8. Guan J, Lo M, Dockery P, Mahon S, Karp C, Buckley A, Lam S, Gout PW, Wang YZ. The xc- Cystine Transporter as a Therapeutic Target for Small Cell Lung Cancer: Use of Sulfasalazine. Cancer Chemotherapy and Pharmacology, 64(3): 463-72, 2009.
9. Dong X, Guan J, English J, Flint J, Yee J, Evans K, Murray N, MacAulay C, Ng R, Gout PW, Lam W, Laskin J, Ling V, Lam S, Wang YZ. Patient-derived first generation xenografts of non-small cell lung cancers: Promising tools for predicting drug responses for personalized chemotherapy. Clin. Cancer Research 16:1442-1451, 2010.

Clinical Benefits of Patient-Derived Primary Tumor Xenograft Services at Oncograph™

Patient-Derived Primary Tumor Xenograft Drug Candidate Development at Oncograph™

Study Designs

Common Study Safety and Efficacy Endpoints

API / Clinical Product Quality Control, Dosing Solutions and Materials, Dose Formulation and Stability

To support CMC development, BRI offers a variety of analytical chemistry assays supporting API / clinical product quality control, toxicology and safety study dosing samples / materials assays, dose formulation and IND-enabling stability studies conducted in conformance to cGMP and ICH requirements.

IND-Enabling API / Clinical Product Quality Control Assays

Toxicology and Safety Study Dose Solutions / Materials Assays

Drug Substance and Drug Product Stability Studies

IND-Enabling Clinical Product Development and Manufacturing

Strategic Development of Botanical Drugs

BRI offers years of experience in the development of Botantical Drugs (US FDA Guidance, 2004), Dietary Supplement (DSHEA, US) and Natural Health Products (Canadian), engaging in the laboratory-scale, pilot-scale, and commercial-scale development of botanical extracts (API), formulation and oral absorption enhancement, and out-source manufacturing of clinical and commercial products.

Naturally Exact™ is a patent-pending mathematical QC control system developed and validated at BRI to ensure lot-by-lot consistency of natural botanical extracts against a pre-defined botanical extract (API) composition specifications. This proprietary process utilize post-extraction treatment of extracts from multiple botanical ingredients to arrive at an exact specification regardless of the raw material content.

BRI also regularly provides consultation and preparation of IND, CTA, Dietary Ingredient Notification, GRAS and NHP submissions in collaboration with regulatory consultants.

Cynomologus and Rhesus Monkey Hepatocytes and Blood Products

ALIVE Laboratories™   

BRI is a Canadian commercial distributor of various cynomology and rhesus monkey and other non-human primate hepatocytes, microsome, S9 and blood products (whole blood, plasma, serum) collected using a variety of anticoagulant. Products are usually shipped within a week of receiving order from within Canada.

Please visit www.alivelaboratories.com for a list of products