Studies determining Absorption, Distribution, Metabolism and Excretion (ADME) characteristics of drug candidates in laboratory animals and humans are an integral part of the Drug Metabolism and Pharmacokinetics (DMPK) services provided by QPS. DMPK research studies are employed at the discovery, candidate selection, Investigational New Drug (IND) enabling, and New Drug Application (NDA) stages of a development program.
Our DMPK research team focuses on high scientific excellence and solid technical expertise. With their extensive industrial experience in drug discovery and development, our passionate scientists can assist with study design, data interpretation, study planning, and execution in a timely fashion. We strive to understand each program’s unique merits so that we can effectively design DMPK research studies and interpret results. Our state-of-the-art instruments are completely supported by a dedicated technical laboratory, ensuring that our data maintains high scientific standards.
DMPK Research Studies Help Determine Bioavailability
An essential component of early drug discovery, DMPK research studies evaluate multiple properties of drugs, including bioavailability, or the extent and rate to which the active drug ingredient is absorbed and becomes available at the site of drug action. The relative bioavailability in terms of the rate and extent of drug absorption is considered predictive of clinical outcomes. With development costs surging, it’s increasingly valuable to select models that can more effectively predict human bioavailability at an early stage in development.
ADME Data Package Supports IND Submission
Many New Chemical Entities (NCEs) can be rapidly screened using the discovery Pharmacokinetics (PK) approach, resulting in more efficient identification of candidates with the most desired ADME properties. By identifying potential liability during the candidate selection process, QPS helps to select drug candidates with the best chance of success. In addition to candidate selection processes, QPS supports whole range of studies for drug development including radiolabeled mass balance studies, comprehensive biotransformation, Quantitative Whole-Body Autoradiography (QWBA) studies, and a host of in vitro and DDI assessment studies. Completion of all the preclinical DMPK studies, coupled with clinical PK, will provide an ADME data package that will fully support regulatory IND and NDA submission.
- 7.5 Average Days from Compound Receipt to Final Report
- 8 Mass Spectrometry Machines
- 9 Accreditations and Permits
- 1 Tomtec Quadra 96
QPS offers discovery screening as part of the drug candidate selection process. Discovery screen studies require small amounts of compound and data generated in a timely manner (7 days), enabling feedback to the discovery chemist on structural activity relationships. A typical discovery screen may include the following:
- Utilize rat and/or human liver microsomes or hepatocytes.
- Identify metabolic “hot” spot.
- Estimate half-life and intrinsic clearance.
Plasma protein binding in rodent and/or human
- Utilize ultrafiltration or equilibrium dialysis.
- Estimate the extent of binding to plasma proteins.
in vitro cytochrome P450 (CYP450) inhibition in human liver microsomes
- Utilize isoform selective probe substrates to assess the inhibition potential of lead NCE(s) to inhibit activity of human CYPs.
- Single IV or PO dose allows chemical leads to be rank-ordered for optimization of PK properties.
Preliminary assessment of formulations
- A single oral dose of compound formulated in pharmaceutically acceptable vehicles helps eliminate NCEs that may be difficult to formulate for oral dosage form.
Biotransformation Studies are increasingly important
QPS provides biotransformation studies to determine how a molecule may be altered by the action of enzymes. Among QPS studies to support discovery and development of new drug candidates are the following:
- in vitro metabolic stability in hepatic subcellular fractions to determine intrinsic clearance
- in vitro comparison of metabolite formation in animal and human hepatic preparations, using non-labeled and radio-labeled test articles
- in vivo metabolite profiling, identification and quantification using samples collected from PK, mass balance excretion studies, and human AME studies to satisfy
Metabolites In Safety Testing (MIST) requirement
- in vitro protein covalent binding assessment using animal and/or human liver microsomes or hepatocytes and in vivo assessment using plasma and liver collected from animals treated with radiolabeled test articles
- in vitro reaction phenotyping using both recombinant CYPs or UGTs or other enzyme systems and human liver microsomes and chemical inhibitors using non-labeled and radio-labeled test articles
Drug-Drug Interaction Studies
QPS provides drug interaction studies to determine the potential of a substance to alter cytochrome P450 activity. Studies conducted to assess inhibition and induction potential to support discovery and development of new drug candidates include the following:
- in vitro inhibition characterization in human liver microsomes or hepatocytes to determine reversible or time dependent IC50
- in vitro mechanistic characterization of reversible inhibitory rate constants, KI
- Identify the reversible mechanism of inhibition as competitive, non-competitive or uncompetitive
- in vitro mechanistic characterization of time dependent inhibition, Kinact and KI
- Identify the mechanism of time dependent inhibition as metabolite mediated via covalent modification or due to tight binding effect of substrate
- in vitro characterization of CYP1A2, CYP2B6, and CYP3A4 induction potential in human hepatocytes based on mRNA and/or CYP activity using isoform selective probe substrates
Full ranges of autoradiography capabilities are available:
- Quantitative and qualitative whole body tissue distribution studies
- Predictions of human radioactive dosimetry for clinical radiolabeled mass balance studies
- Qualitative micro-autoradiography (MARG) coupled with quantitative autoradioluminography
QPS performs GLP and non-GLP small- and large-animal tissue distribution studies using whole-body autoradiography to support drug development and new drug applications. An autoradiograph is an image produced by the radiation emitted from a specimen, such as a section of tissue, that has been treated or injected with a radiolabelled isotope or that has absorbed or ingested such an isotope.
Quantitative Whole-Body Autoradiography (QWBA)
QWBA offers unique insights for investigators by answering key questions related to tissue pharmacokinetics and metabolism, pathology, toxicology, drug delivery, and disposition. QWBA studies provide the tissue distribution and pharmacokinetics data required for new drug registration and for predicting human exposure to radioactivity during clinical radiolabeled mass balance studies.
Micro-autoradiography is a useful tool for visualizing the cellular localization of radiolabeled material.
Identify, Optimize, and Select Drug Candidates
To optimize the “drugability” of a small number of drug candidates, a series of ADME studies may be conducted during the candidate selection process to identify the NCE with the best chance of success. Completion of the candidate selection studies will provide the data to support the nomination to development status of the best compound within a list of potential candidates. Depending on the rigor of study designs and appropriateness of the data, most, if not all, of the data package can be included as a part of an IND submission.
A typical data package to support nomination of an NCE from discovery to development status may include the following studies:
Single IV and oral dose in rodent and non-rodent species to determine the pharmacokinetics and oral bioavailability of the drug candidate
- Administer a pharmacologically active dose to establish the systemic exposure required for biological activity.
- Determine Cmax, tmax, AUC, t½, CL, Vd and oral bioavailability.
- Select the candidate with the best pharmacokinetic properties.
Plasma protein binding in rodent, non-rodent, and human
- Use ultrafiltration or equilibrium dialysis.
- Determine the extent of binding to plasma proteins.
- Select the candidate with the desired (highest) free fraction.
in vitro inhibition of CYP in human liver microsomes (determine IC50)
- Utilize isoform selective probe substrates to assess inhibition potential of lead NCE(s) to inhibit activity of human CYPs (reversible and time dependent).
- Rank order of lead NCEs based on potential to inhibit the CYPs.
- Select the candidate with the lowest potential to cause metabolism-based clinical drug-drug interactions and devoid of time-dependent inhibition.
Preliminary in vitro metabolism studies to assess potential active metabolites
- Use human and animal preparations (microsomes, hepatocytes, etc.) to determine major in vitro metabolites.
- Identity structure of major metabolites and determine their biological activity.
Determine efflux activity
(P-glycoprotein and Breast Cancer Resistance Protein) for CNS programs only
- Use MDCK-MDR1 and MDCK-BCRP cell lines to assess asymmetrical transport.
- Minimize efflux activity for greater CNS penetration.
Temporal relationship between biological activity and plasma concentration
- Administer lead compounds to animal efficacy models to establish that biological activity is correlated to plasma levels.
- Minimize the selection of lead compounds with active metabolites.
- Eliminate the nomination of pro-drugs.
Optimization of oral formulation
- Select the candidate with the best combination of biological activity, pharmacokinetic properties and ease of formulation for solid dosage form.
- Determine the systemic exposure of lead compounds as part of single-dose and dose-ranging toxicology studies.
- Determine therapeutic index of the lead compound by calculating the ratio of the concentration at the “no observed adverse effect level (NOAEL)” dose and the concentration after an active pharmacological dose.