Before first -in-man studies are initiated it is imperative that the toxicity of a drug candidate is well understood. Protein biomarkers are increasingly being used to determine toxicity of pharmaceuticals at the preclinical stage. MSD is the perfect instrument to measure these biomarkers because:
- Multiplexing is possible
- Improved sensitivity over ELISA methods
- Increased dynamic range over ELISA
- Validated toxicity panels available
- Smaller sample amounts required
Choosing lead compounds have never been easier. MSD toxicity panels are designed to screen large amounts of compounds early in the drug development stage. Dozens of validated toxicity biomarkers available from MSD. The understanding the toxicological affects of a drug candidate is a crucial aspect of lead optimization and drug development and MSD’s validated toxicity panels can sped up the process while being cost effective and providing superior data.
Compounds that are toxic to the kidneys will have a deleterious affect on renal function, the kidney’s ability to filter blood to remove waste products and excess water and salts. Kidney failure could result in an increase in waste products and an increase of fluids within the blood stream requiring dialysis to remove. It is crucial to assess a compounds affect on kidney function before exposing the drug candidate to humans. Traditional biomarkers that detect kidney damage, such as BUN and creatinine often can not detect mild kidney injuries.
MSD provides three products that can help determine the nephrotoxicity of a compound. These include:
Argutus AKI (Acute Kidney Injury) Test
The Argutus AKI test quantitates the following kidney injury biomarkers: Alpha-GST, GST Yb1, and RPA-1. Together, these three biomarkers can be used to determine the extent (and even location) of acute kidney injury.
Kidney Injury Panel 1 (Rat)
The kidney injury panel 1 can measure the amount of albumin, TIM-1, lipocalin-2 and OPN within urine samples. Albumin and TIM-1 are biomarkers recognized by the FDA and EMA. Lipocalin-2 and OPN have been implicated to cause nephrotoxicity by several different groups.
Clusterin is a secreted protein which has been shown to have multiple functions, from clearing debris to apoptosis. Urinary clusterin levels have also been associated with kidney damage and has been accepted by both the FDA and EMA as a nephrotoxicity biomarker.
Reproductive toxicity is a major concern for certain populations. Compounds that are toxic to the reproductive system will affect adult males and females and could even affect the development of offspring. MSD provides a validated steroid hormone panel which quantitates the amounts of estradiol, testosterone, DHEA, and progesterone in serum and plasma samples. This panel is available for human or rat samples.
Inflammation and Growth Factors
An increase concentration of cytokines, growth factors and inflammation biomarkers within the circulatory system have been associated with heart failure and kidney disease. MSD has dozens of cytokines and inflammation biomarkers available. If interested in testing these biomarkers please contact PBL for a complete list of inflammation and growth factors kits that are available.
Muscle injury can be assessed through a variety of biomarkers and MSD provides five qualified panels that can help determine if a drug candidate is myotoxic. The following biomarkers are available either as a singleplex kit or a multiplex panel: skeletal troponin, cTn1, cTnT, FABP3, Myl3, Paravalbumin, TIMP-1, and CK.
Intracellular signaling is be a mechanism in which proteins responsible for many different diseases can be activated or inactivated. For example, for diabetes, insulin is responsible for activating P13 kinase which in turn is responsible for the phosphorylation of Akt which signals downstream proteins ultimately stimulating protein synthesis, glycogen synthesis and fatty acid oxidation. MSD manufacturers an Akt signaling panel for their MSD platform. Other insulin signaling panels are available as well as many singleplex signaling kits.
Toxicity Testing at PBL
Pacific BioLabs specializes toxicology. Our in vivo toxicology department can perform the in vivo aspects of a toxicology study while our analytical group can perform the bioanalysis, including the MSD analysis. Contact PBL today to initiate a toxicology study.