Drug approval

Xceleron has been supporting drug approvals since its inception in 1998. We have helped to remove simple hADME studies from the critical path by using a microtracer and AMS sensitivity to save time in 14C manufacture and dosimetry determination. More recently, we have employed novel clinical pharmacology designs to save valuable time when regulatory authorities request, for example, last-minute absolute bioavailability data. We are aware of 13 marketed drugs which have benefitted from one or more of these approaches. In 2013, six of the 27 drugs approved by FDA included AMS-generated data in their regulatory submissions. The case studies which follow show some of the ways in which our clients have worked with Xceleron to gain product registration.

 


Genentech, Vismodegib

CLINICAL INDICATION

Advanced basal cell carcinoma (hedgehog signaling pathway inhibitor)

OBJECTIVE

Understand previously observed non-linear PK

SERVICE
  • Helped to design enriched PI IVPK investigation in healthy post-menopausal women
  • Transferred and validated fully quantitative HPLC methodology
  • Analyzed 14C tracer samples using HPLC + AMS
  • Supported a Phase 1 open-label mass balance study in healthy female subjects of non-childbearing potential using AMS to determine routes of excretion, mass balance and extent of metabolism following a single oral dose
OUTCOME
  • Genentech achieved accelerated FDA approval for vismodegib in 2013
  • Provided insight to the complex and multifactorial mechanism for time-dependant PK observed with vismodegib.
  • Specifically identified differential plasma protein binding, solubility-limited absorption and slow metabolic elimination
  • Removed investigation off the critical path by saving Genentech 18 – 24 months of IV formulation design and IV toxicology studies

 


GSK, Dabrafenib

CLINICAL INDICATION

BRAF mutation-positive solid tumor oncology

OBJECTIVE

Satisfy regulator request for absolute bioavailability data for their late stage development compound

SERVICE
  • Transfer and validate analytical methodology
  • Conduct all analyses using HPLC + AMS
OUTCOME
  • Efficiently conduct critical path investigation to meet regulatory need
  • Remove the need for any IV toxicology
  • Reduce cost and time of IV formulation development as the IV dose was only 100 µg and could be developed by the clinical CRO
  • Reduce number of patients by collecting oral and IV PK data in the same individuals concurrently
  • Conduct study in patients without need for wash out between oral and IV doses
  • Gain information on circulating metabolites by measuring total 14C in plasma

 


US biotech company

CLINICAL INDICATION

Secondary Hyperparathyroidism (SHPT) in patients with Kidney Disease

OBJECTIVE

conduct regulatory mass balance and metabolism studies in renally impaired patients to support NDA for drug in Phase III

SERVICE
  • Help design clinical protocols
  • Coordinate with specialist clinical research site
  • Conduct all total radioactivity measurements using AMS in all clinical samples
  • Transfer and validate metabolite profiling methods using HPLC + AMS for quantitative metabolite profiles
OUTCOME
  • Determined rate and routes of radioactivity excretion by measurement of radioactivity related to [14C] in excreta over time.
  • Measure radioactivity concentrations in whole blood, plasma, and excreta over time.
  • Determined biotransformation product profiles in selected matrices
  • Assessed the impact of treatment on drug elimination
  • Reduced the radiation burden to chronically sick patients
  • Allowed patients to be released from clinic after initial excreta collection period with further excreta collections during routine clinical visits used to follow slow excretion over several weeks.

 


Japanese pharmaceutical company

CLINICAL INDICATION

Oncology

OBJECTIVE

Minimize radiation burden to patients during conduct of a regulatory mass balance/metabolism investigation of antineoplastic combination therapy

SERVICE
  • Full project management of 14C re-purification,patient dosing, LC-MS/MS analysis and PK analysis
  • Chromatographic separation plus 14C analysis
OUTCOME

Accelerated the hADME without delay of new 14C manufacture and dosimetry testing

 


Client case study links

Proof-of-concept »  Asset sale »  Asset purchase »


Client case study PDF

Read the full client case study PDF here

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