MedChem scientists generally have two questions about "Discovery ADME":
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1. Will ADME Studies Mislead MedChem Program?
- Yes. Very often. Below are three "negative" cases demonstrating the risks of "just doing ADME". Misleading Case 1: "Generic Protocol" Is Wrong Pharma client spent 4 months to fix the "instability issue" of their compounds as they had been misled by wrong data from an ADME CRO.
Pharma client outsourced “liver microsomal stability” studies to an ADME CRO. The data, 0.1-20% remaining after 30 min, indicated that the client’s compounds were not stable. Client then spent 4 months making new compounds for metabolic stability enhancement while kept getting the same low stability data.
Frustrated and doubtful client sent a few of their “unstable” compounds to a professor to test and found that their compounds were decently stable!
It turned out that the ADME CRO’s assay protocol was wrong: the client’s compounds co-precipitated with microsomal proteins in acetonitrile leading to partial recovery (for the t= 0 min samples, acetonitrile was added to precipitate microsomal protein before adding the test compounds). The ADME CRO claimed the data was correct because the control compounds (no co-precipitation issue) in the same 96-well plate showed correct percentage remaining.
Misleading Case 2: "Default In Vitro System" Does Not Predict In Vivo
Improvement from <10% to 86% remaining in liver microsomes after 30 minutes did not help boost oral availability! Are the in vitro liver microsomal stability data provided by the ADME CRO in the past 6 months all correct?
Pharma client entered a lead optimization program with a metabolic unstable lead compound (<10% remaining after 30 min liver microsomal incubation); The major ADME/PK challenge was to improve the poor oral availability in rat;
Pharma client collaborated with an ADME CRO (providing in vitro liver microsomal stability data) on lead optimization for 6 months and identified a preclinical candidate with optimized potency, selectivity, and showed 86% remaining in rat liver microsomes;
The preclinical candidate was dosed to rat; oral availability showed no improvement!
The ADME CRO used “liver microsomes + NADPH”, the “default in vitro system” of oxidative metabolism while the pharma client’s lead series all contain a “urea center link”, whose rapid hydrolysis is often the dominant metabolic pathway in rat hepatocytes. So the in vitro system the CRO used was not correct (does not predict major hydrolysis pathway). The 6 months MedChem efforts had been misled by the wrong in vitro metabolic stability data.
Misleading Case 3: "Simple Data Analysis" Goes To the Wrong "Soft Spot"
An “NADPH-dependent” amide bond cleavage was identified as the major metabolic pathway for a series of unstable compounds; Is the amide bond the metabolic soft spot?
Collaborate with MetabQuest to Avoid These Misleadings
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2. Can ADME Studies Push the MedChem Program Forward?
- Yes. With the right expertise, MetID together with other ADME studies can accelerate MedChem programs. Below are a few "positive" cases based on our previous studies.
- Seminars based on the above research have been given to MedChem and ADME/PK scientists at major pharma companies in the US and in China. On-site and on-line presentations are available (download the "Sample Seminar Abstract", pdf). - For ADME-MedChem outsourcing consulting and presentation requesting, please download the "Consulting Brochure and Request Form" (doc), fill it, and send to us: [email] info@metabquest.com or [fax] +86 (10) 6275 2632. |