Aragen provides comprehensive and cost-effective drug metabolism and pharmacokinetics (DMPK) studies to evaluate and optimize the drug-like properties of new chemical entities (NCEs). We incorporate customized approaches and advanced technologies such as high-throughput screening to provide decision enabling, high quality data with rapid turnaround time. The extensive experience and problem solving capabilities of our team, along with our large capacity for bioanalysis, ensures flexible solutions and continuous support. Locally present breeding partners, enable us to provide highest quality PK data from our AAALAC accredited vivarium. Our project management team ensures the journey from compound procurement to sharing results, is seamless for clients.
DMPK studies at Aragen span all stages of drug discovery, including exploratory, hit-to-lead, lead optimization and candidate selection, as well as preclinical IND enabling studies.
Through our range of ADME assays, we help identify and mitigate limitations against absorption, distribution, metabolism and excretion related issues very early in drug discovery projects. In addition to small molecules, we conduct comprehensive druggability studies with other modalities such as proteolysis targeting chimeras (PROTACs), molecular glues, nucleotides, nucleosides, peptides and proteins. With a focus on quality and efficiency, our ADME scientists working closely with our synthetic organic chemists, accelerate the design and testing cycles of drug discovery programs.
The compound requirement for in vitro studies is typically 5 mg (to conduct all assays) with a turnaround time of 5-7 working days.
Rodent pharmacokinetics (in life) vivarium studies are conducted in-house on different strains of mice and rats, in accordance with the following certifications, compliances and quality systems:
Ninety SOPs have been established for the regular functioning of the vivarium and for the various studies being conducted.
|Study Type||TAT (Days)||Compound Requirement (mg)|
|Mouse PK: serial sampling||5||10|
|Mouse PK: parallel sampling||5||20|
|Rat Blood Brain Barrier||5||15|
|Mouse Blood Brain Barrier||5||15|
|Cassette dosing||5||25 in rats|
Metabolic profiling or metabolite identification is very important in early drug discovery to help understand the fate of a compound towards a pharmacologically active or toxic metabolite. The FDA recommends the metabolic profiling of any compound whose preclinical toxicity needs to be evaluated. Metabolite profiling helps identify disproportionate metabolites that are solely present in human or at higher concentrations in human than in any preclinical animal species. Such metabolites are considered for further safety assessment. Metabolite profiling also helps in optimizing fast metabolising compounds by proposing soft spots and then blocking the labile soft spots, thereby increasing the metabolic stability of a compound. At Aragen, we use different analytical (XB500-TOF, tandem mass spectrophotometry) and software (Lightsight, MetaboLynx) tools to evaluate the metabolite profile of a compound.
Soft Spot Elucidation
Based on stability red flags or compound clearance, we conduct soft spot elucidations by understanding the fragmentation pattern of compounds and metabolites. Our medicinal chemists use this information in the synthesis/optimization of a series of metabolically stable compounds.
Metabolite & Structure/Pathway Identification
Metabolite identification is conducted on in vivo and in vitro samples. In vitro matrices for metabolite ID include microsomes, S9 fractions, hepatocytes and expressed CYP enzymes across multiple species such as mice, rats, dogs, monkeys and humans. This enables the selection of the best toxicological species to predict human metabolism. The metabolic pathways involved are also elucidated to understand drug-drug interactions.
We conduct comparison studies in diseased and control preclinical species to measure differences in sugars, nucleosides, organic acids, ketones, aldehydes, amines, amino acids, small peptides, lipids, steroids, terpenes, alkaloids, drugs (xenobiotics) etc.
Investigational new drug (IND) studies are an essential prerequisite to conducting clinical trials that administer an investigational drug to humans. Aragen experts can provide customized IND enabling study packages to help sponsors in initiating their IND enabling program. The reports of our study packages complement the IND pharm-tox packages our customers submit to regulatory agencies for approval to initiate Phase I clinical trials. Our studies are aligned with clinical routes of administration, dose schedule and duration of treatment, all designed to identify PK/PD responses, target organs, dose responses, exposure multiples and safety margins.
Typical IND enabling ADME packages contain data from the following studies:
All assay samples must undergo quantitative (PK) and qualitative (ADME) analyses to measure compound presence. As an integral part of drug discovery and development, bioanalysis plays an important role in the progression of any drug discovery project. Additionally, it provides the measurement of exogeneous and endogenous metabolites and biomarkers to guide drug design. Aragen’s state-of-the-art infrastructure supports all hit to IND activities, and we continually expand and update our bioanalysis capacities to maintain high data quality and aggressive turnaround time.
BCS based in vitro biowaiver studies replace clinical BA/BE studies to classify the equivalence of two pharmaceutical products for regulatory approval. Aragen offers the rapid and cost effective establishment of bioequivalence using USFDA/EMEA approved methods. Initially applied for scale-up and post approval changes (SUPAC) of generic products, the studies were later extended to the approval of orally administered BCS class I (high solubility and high permeability) and class III (high solubility and low permeability) IR formulations. These studies involve characterizing the comparative dissolution of test and innovator formulations, solubility, gastrointestinal (GI) stability, and Caco-2 permeability of the active pharmaceutical ingredient (API). Our client studies have been successfully reviewed and audited by USFDA.
Steps in the Design and Conduction of BCS based In Vitro Biowaiver Studies
Conventional clinical BA/BE studies do not allow the characterization of bioequivalence for locally acting drugs. Aragen offers USFDA approved in vitro binding studies for the rapid and cost effective establishment of bioequivalence of complex generics for bile acid and phosphate binding drugs, and sucralfate. Bioequivalence is established by comparing the rate and extent of binding between test and reference formulations.
Steps in the Design and Conduction of In Vitro Binding Studies
Bioequivalence between the test and reference formulations is determined based on the capacity constant (K2)