Discovery & Pre-Clinical DMPK
Aryastha provides a comprehensive range of services encompassing in vitro ADME, toxicity (in vitro ADMET), and in vivo pharmacokinetics (PK), offering rapid evaluations of test articles DMPK properties and toxicity. Our team specializes in crafting robust DMPK packages tailored for submissions to regulatory agencies like FDA, MHRA and GLP.
In vitro ADMET
Our team performs efficient screening assays covering the entire in vitro ADMET spectrum, including solubility, drug absorption and transport, metabolic stability, drug-drug interactions, and in vitro toxicity.
Physiochemical Properties
- Solubility (kinetic and thermodynamic)
- Solubility determination in biorelevant fluids (SGF and SIF)
- pKa
- List ItempKa Partition coefficient (LogD)
- Protein binding/tissue binding (plasma, blood, brain, kidney, skin, lung, liver microsomes, and hepatocytes)
- Blood partitioning
- Chemical stability
In Vitro Toxicity
- Liver toxicity package (general and mechanistic toxicity evaluation)
- Cardiotoxicity
- Genotoxicity
Drug - Drug Interaction
- Substrate evaluation & isoform ID (CYP, UGT, AO, FMO, CES, MAO, and XO)
- Enzyme inhibition (CYP, UGT, and non-CYP enzymes)
- CYP induction (human hepatocytes; HepaRG cells)
Metabolic Stability and Metabolite(s) Identification (met-ID)
- Metabolic stability in the liver, intestine, lung, and colon using subcellular fractions
- Long-term hepatocyte culture for low-clearance compounds
- Plasma/blood stability
- Metabolite identification and profiling
- GSH trapping
- Reactivity of Acyl Glucuronides (Ags)
Drug Absorption and Transport
- Permeability evaluation (PAMPA, Caco-2, MDCK-MDR1)
- Transporter investigation on substrate and inhibition
- ATPase assays
Distribution
- Protein binding/tissue binding (plasma, blood, microsomes, brain, kidney, skin, lung etc)
- Tissue distribution
Pharmacokinetics (PK)
Aryastha offers PK, toxicokinetics (TK), and formulation analysis services to support drug discovery and preclinical development. All in-life work of PK/TK studies is conducted in AAALAC accredited animal facilities and follows CPCSEA (equivalent to IACUC) approved study protocols.
- Formulation screening
- Cassette and single compound PK in mouse, rat, rabbit, mini pig, guinea pig, dog, monkey
- Unique dosing routes: infusion, intratracheal, intracolon, etc.
- Portal vein and bile duct cannulation
- Quantitative analysis of samples with various biological matrices
- Microdialysis for compound unbound concentration measurement
- Evaluating intestinal permeability, metabolism, and transporter's interaction
PK / PD
PK/PD studies play a vital role in confirming the exposure of the test article in systemic circulation and tissues, particularly target organs. These studies also facilitate understanding the correlation between test article exposure and its pharmacodynamic (PD) effect, utilizing healthy and diseased animal models.
The quantification of biomarkers is expertly conducted by our In vitro biology and ex vivo pharmacology teams, encompassing the assessment of
- System circulation exposure
- Tissue exposure
- Biomarker analysis
Regulatory DMPK
Aryastha offers comprehensive IND filing DMPK packages meticulously designed to meet the regulatory requirements set forth by FDA, OECD, Indian GLP and MHRA. Our In vitro ADME filing package studies encompass regulatory considerations such as
- Protein binding and blood partitioning
- Metabolism and metabolite identification
- Permeability and transportation assessments
- Evaluations of drug-drug interactions
Our in vitro PK filing package studies encompass
- Single and repeated-dosing PK studies on both rodent and non-rodent
- Comprehensive assessments of mass balance and tissue distribution
- In vivo metabolite identification and analysis
In Vitro Pharmacology
Our in vitro pharmacology team delivers comprehensive in vitro and ex vitro pharmacology services across key therapeutic domains, including oncology/immuno-oncology, metabolic disorders, and inflammatory diseases.
Animal Disease Models
Our in vivo pharmacology team possesses expertise in establishing and validating disease models for efficacy screening and conducting in vivo pharmacology profiling, PK/PD, and MOA studies. Complemented by our internal PK/Bioanalytical, ex vivo pharmacology, and in vitro biology teams.
Oncology Models
- Extensive cancer cell lines and tumor bank
- CDX models and PDX models with access to human tumor samples through a local hospitals
- Syngeneic models with immune profiles, SOC data, and orthotopic imaging models encompassing hundreds of human and murine cancer cell lines
Metabolic Models
- Metabolic models, obesity, diabetes, NAFLD & NASH
- Cardiovascular diseases (MCAO, SHR, cardiac ischemia/reperfusion, hyperlipidemia)
- Organ damage diseases models (CKD)
- Respiratory disease models (lung inflammation and fibrosis) Oncology Models
Inflammation and pain models
- Acute and chronic pain models
- Immune disease models and non-immune inflammatory models
- Arthritis, visceral pain, surgery pain, neuropathic pain models, and PD/PK models
Ex vivo Pharmacology & Biomarkers
Ex vitro analysis confirms the In vitro effects of test articles and establishes the correlation between efficacy, target engagement and biomarkers. All samples utilized in ex vitro analysis are derived from animals involved in the study, encompassing blood, plasma, cerebrospinal fluid (CSF), various body fluids, tissue extractions, urine, and feces.
- Our gene and protein analysis platforms - RT-PCR, ELISPOT, Auto MACS Pro, Alpha LISA, Western Blot, and MSD
- FACS analysis on cells, blood, and tissue samples
- Histology, histochemistry, and immunohistochemistry
- Clinical blood biochemistry, hematology, bone marrow smear, and staining
- Analysis of body fluids, urine, and feces extractions
PK / PD
PK/PD studies play a pivotal role in validating the exposure of the test article and biomarker levels within the systemic circulation and tissues, with a particular focus on target organs.
This aids in comprehending the correlation between the test article’s exposure and its pharmacodynamic (PD) effect, utilizing both healthy and diseased animal models. These studies encompass various aspects,
- Determination of the maximum tolerated dose
- Range finding for dosages
- Assessment of compound exposure in blood and tissues
- Analysis of biomarker levels in blood and tissues
Aryastha's accelerated late-stage lead optimization
Aryastha’s accelerated late-stage lead optimization service delivers crucial data to facilitate rapid and informed decisions in selecting and advancing the most suitable lead candidate(s) before embarking on IND-enabling toxicology studies. This efficient solution ensures the provision of essential data within a matter of weeks. Our services encompass the following
In vitro Tissue Distribution
Comparative target-distribution insights across a range of closely related compounds. This helps confirm whether the test compound(s) effectively reach the intended tissues or potentially accumulate in vulnerable tissues.
In vitro Metabolism
Rapid turnaround time
Quantitative comparison of metabolites formed in hepatocytes from human and non-clinical species (mouse, rat, dog, minipig, monkey, and human). This information is instrumental in choosing the most appropriate toxicology species based on metabolic relevance
Identifying potential human-specific metabolites early and providing insights into metabolite safety concerns
Structural identification of metabolites (Met-ID) through High-Resolution Mass Spectrometry (HRMS)
