Proof-of-concept

We have conducted proof-of-concept studies for a range of small and large pharmaceutical companies. The following case studies demonstrate how simple study design combined with the AMS platform may be applied to your development program. Our customers have saved years and significant expense by using a microtracer and AMS in either a pharmacological-dose or microdose setting.

 


Arpida

CLINICAL INDICATION
Anti-infective AR-709 to treat MRSA in the upper respiratory tract

OBJECTIVE
Obtain early evidence of drug disposition in lungs to determine the optimal clinical route of administration prior to starting full-scale preclinical toxicology studies

SERVICE

  • Helped to design a Phase 0 microdose study using an oral/iv crossover design, followed by an IV microdose with tissue biopsies of the lung to determine amounts of drug getting to the target
  • Full project management of compound 14C labelling, preclinical toxicology and clinical dosing
  • Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS

OUTCOME

  • AR-709 attained concentrations appreciably higher within the lung than in plasma
  • Low oral bioavailability however, precluded oral administration
  • No expensive oral formulation required for clinical study
  • Pursued inhaled formulation with two-year saving in development time

 


Lundbeck

CLINICAL INDICATION
CNS

OBJECTIVE
De-risk late-stage clinical investigations by investigating potential for unexpected human metabolites. Regularly use early microtracer studies to guard against late-stage discovery of human-specific metaolites

SERVICE

  • Helped to design adaptive Phase I studies with oral microtracer to investigate metabolism and mass balance
  • Chromatographic separation of parent and metabolites plus analysis of total and fractionated 14C by AMS

OUTCOME
Lundeck adopted AMS as part of early development strategy

 


Astra Zeneca

CLINICAL INDICATION
Various, including oncology

OBJECTIVE
Various including;

  • Early estimate of formulation resource for development plans
  • Assess backup compound PK to compare to poorly performing leads
  • Assess compound developability with better dose-dependent PK

SERVICE

  • Helped to design a series of concomitant oral/IV dosing study designs to generate absolute bioavailability data and other PK data
  • Chromatographic separation of parent and metabolites plus analysis of total and fractionated 14C by AMS

OUTCOME
Objectives achieved

 


Incyte

CLINICAL INDICATION
Unknown

OBJECTIVE
Determine relative abundance of human metabolites

SERVICE

  • Helped design PI healthy human volunteer investigation to identify major metabolites of Compound “X”. Used a microtrace amount of 14C labeled material co-administered with a pharmacologically relevant dose of ‘cold’ compound during the course of a phase I clinical study
  • Transferred HPLC chromatography method
  • Analysed all samples using HPLC + AMS

OUTCOME

  • Early assessment of major human metabolites compared to traditional drug development. This in turn enabled the determination of safety margins for the major metabolites in nonclinical toxicology studies.
  • Using AMS, the plasma concentration of metabolite M5 (cleavage product of parent compound) was determined to be 13.8% of total 14C (35.1% of parent present), compared to ~1% of parent when based on qualitative LC-MS analysis
  • Concluded that quantitation of metabolites based solely on mass spectral response (in the absence of synthetic standards) can be misleading and should be avoided for the purpose of establishing the relative abundance of metabolites.

 


US biotech company

CLINICAL INDICATION
Acute Myeloid Leukemia (AML)

OBJECTIVE
Determine preclinical concentrations of highly potent parent cytotoxic and metabolites in two preclinical species as part of an antibody-drug conjugate IND submission

SERVICE
Chromatographic method development and analysis using HPLC + AMS for quantitative metabolite profiling.

OUTCOME
IND approved and ADC is now in a phase 1 clinical trial designed to assess its safety and anti-leukemia activity in AML.

 


Organon

CLINICAL INDICATION
Female health (birth control)

OBJECTIVE
Develop fast-follow backup leads for lead with toxicology risk

SERVICE

  • Helped to design a comparative 56-d, three-compound microdose study of highly potent compounds
  • Compare lead compound microdose with pharmacological dose PI study to validate approach
  • Full project management of compound 14C labelling, preclinical toxicology and clinical dosing
  • Measured compounds concentrations out to 56 days

OUTCOME
Original lead compound microdose PK scaled perfectly with pharmacological dose providing confidence in reliability of backup compound microdose information


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