Oligonucleotide Drug DMPK Service

Currently, scientists are focusing on oligonucleotide therapy, which employs chemically synthesized nucleotide-like small molecule drugs with potential specificity similar to therapeutic antibodies. At the same time, drug metabolism and pharmacokinetics (DMPK) properties must be evaluated, such as bioavailability, half-life, clearance and metabolic profile. A sub-optimal DMPK profile is a crucial reason for the discontinuation of drug leads, as well as unwanted side effects. Creative Biolabs can help biopharmaceutical companies to minimize the attrition rate of drug candidates in the drug discovery pipeline via our sophisticated technologies and professional scientists.

Oligonucleotide Drug

In the past 30 years, oligonucleotides (ONs) have been studied for clinical development, beginning with siRNAs, and followed by antisense oligonucleotides (ASOs) and aptamers. Most ON therapies act through antisense mechanisms and are directed against various RNA species, as exemplified by gapmers, steric block ONs, antagomirs, small interfering RNAs (siRNAs), micro-RNA mimics, and splice switching ONs.

Figure 1. Seven mechanisms for oligonucleotide drugs.

Mechanisms of Oligonucleotide Drug

Oligonucleotide diversity leads to unique mechanisms of action with diverse toxicology profiles/concerns. There are listed seven mechanisms for oligonucleotide drugs that have been used in the clinic (Figure 1).

1. Binding to Toll-like receptors (TLRs) in the endosome.
2. Small interfering RNA (siRNA).
3. Micro-RNA (miR) mimic.
4. Antagomir, sterically blocking endogenous miR.
5. Gapmer antisense oligonucleotide, inducing RNase H degradation (steric block ONs also exist).
6. Aptamer, binding alters protein surface.
7. Splice switching ON (SSO).

Why Does Drug Discovery Need DMPK?

Within the pharmaceutical industry, the optimization of DMPK properties at the early stage in drug discovery is paramount. The DMPK properties of a compound determine the amount of drug that will reach its target and the time it stays in the target area. Researchers can optimize DMPK and make them maximize exposure at the desired target site for efficacy and minimize the potential toxicity of a drug.

Oligonucleotide Drug DMPK Service

Given the wide array of oligonucleotide-based compounds and the advances made in chemical modifications and drug delivery, the appropriate assay platform should be selected for pharmacokinetic (PK) profiling and drug metabolism.

• Enzyme-linked immunosorbent assays (ELISA)
  

  There are several assay formats that can be followed for PK analysis, among which chromatographic and enzyme-linked immunosorbent assays (ELISA) are typically favored.

• Liquid chromatography assays
  

  Liquid chromatography assays such as UPLC-UV, LC-FL, LC-MS/MS and LC-HRAM typically are highly selective, can distinguish between full-length oligonucleotides and their metabolites, and have a wide dynamic range, but in general, require complex sample preparation and have a lower sample throughput.

Creative Biolabs will continue to adapt and advance technologies and techniques in parallel to ensure success. Our advanced technologies and highly experienced staffs are committed to advancing your program with our oligonucleotide drug DMPK service. If you want to know more detailed information, please feel free to contact us.

References

1. Lundin, K. E.; et al. (2015). Oligonucleotide therapies: the past and the present. Human gene therapy. 26(8): 475-485.