From Concept to Proof of Concept info@advinus.com   

Advinus offers a wide range of DMPK services to support lead optimization and preclinical development. Advinus capabilities and track record include:

  • Highly qualified scientists trained in premier universities in India and abroad
  • Performed over 500 PK studies, 5000 in vitro studies; supported over 200 Toxicology studies for regulated bioanalysis and toxicokinetics
  • Bioanalytical team has developed over 120 validated methods for NCEs, supported over 50 complete IND packages

A list of the assays and studies that can be performed is provided below.

Physicochemical Properties

  • Aqueous solubility and stability at different pH condition
  • Stability in simulated gastric and intestinal fluid
  • Octanol water partitioning (Log P and Log D)
  • pKa determination

Permeability 

  • PAMPA
  • Caco-2 cell line
  • MDCKII cell line

P-gp Substrate and Inhibition Potential

  • Caco-2 cell line
  • MDCKII-P-gp transfected cell line

Metabolic Stability

  • Stability in S9, microsomes and hepatocytes to assess potential for intestinal first pass, intrinsic clearance to evaluate in vitro clearance

Plasma Protein Binding

  • Equilibrium dialysis and ultrafiltration techniques
  • Blood/Plasma Partitioning and Stability

Tissue Homogenate Binding

CYP Reaction Phenotyping

  • Using recombinant human CYPs as well as human liver microsomes
  • Aldehyde oxidase reaction phenotyping

Metabolite Identification

  • Using unlabeled and radiolabeled compound coupled with mass spectrometric detection
  • Preliminary metabolite identification
    • In in vitro and in vivo study samples
    • Reactive metabolite trapping and characterization

Drug-Drug Interaction Assays

  • CYP Inhibition using human liver microsomes (IC50, Ki determination)
  • Time dependent CYP inhibition (IC50shift)
  • CYP induction in human hepatocytes
  • P-gp substrate and inhibition assays using Caco2 and MDCKII-P-gp cell lines

Cytotoxicity

  • MTT Assay
  • Species (rodent and non-rodent)
  • Absolute and relative bioavailability assessment
  • Cannulation techniques used: Jugular vein, femoral vein, carotid artery, portal vein and bile duct
  • Dosing techniques: IV, Oral, IM, SC, intranasal instillation, endotracheal intubation, dermal application, intradermal etc.
  • Brain penetration in vivo, supplemented with P-gp assessment in vitro
  • Validated WinNonlin Phoenix software is used for PK data analysis
  • Mass Balance / Excretion balance
  • Tissue distribution
  • Ocular PK study in rabbits
  • Biliary excretion study
  • Metabolite profiling
  • Toxicokinetic data analysis and report preparation to support IND enabling studies
  • Allometric scaling: FIH dose projections and human PK predictions
  • Validated Phoenix WinNonlin® software

Ideally a lead compound should have > 30% oral bioavailability and < 30% liver blood flow clearance and an adequate half-life for once daily dosing. In the absence of this, to improve bioavailability, a suitable formulation needs to be developed. Advinus has the capability to execute the following:

  • Development of solution formulation for IV and PO studies of low solubility lipophilic compounds for conduct of preclinical PK studies using
    • pH adjustment
    • Co-solvents
    • Inclusion complexes (cyclodextrins)
  • Attempts are made to achieve formulation using excipients acceptable for use in repeated dose studies
  • The prepared formulations are assessed for accuracy using HPLC or LC/MS/MS method
  • If necessary, salt forms or pro-drugs can be considered for improving the bioavailability of lead compound along with micronization of compound
  • Formulation method development and validation for preclinical dose formulation sample analysis