The below information will guide you through the working relationship between AIT Bioscience and PreClinOmics (PCO) to show how we can manage a 3-way study relationship, with a case study to detail it all.
Capabilities of Each Firm:
AIT Bioscience is a bioanalytical contract research organization (CRO) specializing in the development and validation of bioanalytical methods supporting clinical, pharmacokinetic, and toxicokinetic studies for new and established drugs and biomarkers. AIT Bioscience was the first CRO to go completely paperless; it uses electronic records to record all data related to a study, whether it is electronic SOPs, study documents, or raw data and observations. This radical design allows study execution and report and data review to be completed within 10 business days after the date of last sample receipt.
PreClinOmics is an in vivo, drug discovery CRO located in Indianapolis. It offers extensive pharmacology and ADME services in both common and highly specialized rodent models. PreClinOmics is AALAC accredited and PHS inspected.
Synergies in a Joint Study:
- PCO provides the in-life study expertise to help the sponsor select the animal model, write the protocol, and obtain IACUC approval. PreClinOmics offers a wide array of in vivo preclinical discovery services including screening, efficacy, ADME, PK/PD and safety studies in both normal and disease rodent models. PCO technicians are skilled in all modalities of dosing, sample and tissue collection. Collected samples and tissues can also be processed according to the needs of the analysis desired. PCO also provides consulting and study design services.
- AIT is very familiar with preclinical study designs and is fully compliant with the GLP regulations (21 CFR Part 58). All of its systems are fully validated if full GLP compliance is required.
- PCO and AIT have mutual confidentiality agreements in place.
- PCO and AIT are located within walking distance of each other; ad-hoc study meetings are easy to arrange.
- AIT can begin LC-MS/MS methods development as soon as the sponsor commits to the study, so that the method is ready in advance of dosing. PCO and AIT staff work closely to ensure the method matches the in-life study design.
- Samples can be transferred from PCO to AIT within minutes of collection at any time during the workday- no overnight shipping required.
Working with PCO and AIT:
- Sponsor establishes confidential disclosure agreements with PCO and AIT.
- Site tours of both companies can be done on the same day (or within the hour!).
- Sponsor, PCO, and AIT can review study objectives and outline study plans in a single on-site meeting.
- AIT and PCO provide draft protocols to sponsor for approval.
- Sponsor approves bids, signs protocols, and sends compounds.
- AIT develops working LC-MS/MS method per protocol and shares performance data with sponsor and PCO.
- AIT provides sample collection kits to PCO according to in-life protocol.
- In-life study is executed at PCO and samples are collected according to protocol.
- Samples are transferred to AIT for analysis.
- Sample concentration data and method performance summary tables are provided to PCO for PK analysis.
- AIT sample analysis report submitted to sponsor for review.
- PCO in-life/PK report submitted to sponsor to review.
- Sponsor invoiced by AIT and PCO.
- Final reports submitted to sponsor after reviewers’ comments are received.
Case Study: Losartan
Losartan is an angiotensin II receptor antagonist marketed by Merck under the trade name Cozaar. The primary metabolite is the 5-carboxylic acid (EXP3174), which is produced from first pass metabolism by cytochrome P450 isoenzymes CYP2C9 and CYP3A4. The metabolite is actually more potent than losartan, and both compounds are typically followed in a PK study.
PCO Study Goal:
Evaluate the effect of a CYP2C9 inhibitor (phenylbutazone) on plasma levels of losartan and its active metabolite.
- Twelve Wistar rats were divided into 2 dosing groups.
- The first group received 10 mg/kg doses once daily for 15 days; PK samples were taken on the 15th day.
- The second group received a combination dose of 10 mg/kg losartan and 50 mg/kg phenylbutazone for 15 days once daily; PK samples were taken on the 15th day.
- The expected plasma concentrations were not expected to exceed 1000 ng/mL.
- Cmax for losartan is approximately 1.5 hours and 3-4 hours for the EXP3174 metabolite.
- Based on an elimination half-life of approximately 2 hours, samples were planned to cover the first 12 hours after dose.
AIT Bioscience Method:
To conserve sample, AIT developed a method in K2EDTA rat plasma that covered 1-1000 ng/mL using a 20 µL sample size. The method used deuterated internal standards for both analytes and liquid-liquid extraction. Extracts were analyzed on a UPLC-MS/MS system using gradient elution and electrospray ionization (Waters Acquity and Thermo Vantage systems).
Calibration curves and a 3 ng/mL low QC sample response are shown below:
PCO Data Analysis