A pharmacokinetic study provides the basis for determining drug exposures in the body over time. PK parameters are used in the evaluation of the absorption, distribution, metabolism, and excretion (ADME) processes of drugs.
Absorption, the first topic of PK studies, is the initial process by which drugs enter the blood circulation following dosing. Drug substances in PK lab testing can be administered to the body through several routes such as oral, nasal, dermal, or parenteral. Absorption at the gastrointestinal tract, one of the most common drug absorption sites, is affected by several factors including physicochemical parameters of the drug, gastrointestinal motility, drug concentration, and ionization state at the site of absorption.
Distribution is a reversible drug transfer within the body from one location to another. The distribution of a drug can be influenced by several factors such as lipid-solubility, concentration in plasma and various tissues, and protein binding of drugs in plasma and tissues. PK studies assess whether compounds can distribute throughout the body readily or are confined to the bloodstream once absorbed.
Metabolism, an essential topic of PK analysis, is the process by which a drug is converted to another chemical entity (metabolite). Metabolism happens primarily in the liver and is classified into two broad categories: Oxidative metabolism includes hydrolysis, oxidation, and reduction reactions driven mainly by the cytochrome P450s, monooxygenase systems, and alcohol dehydrogenases. The typical chemical reactions involved in oxidative metabolism include aromatic hydroxylation, aliphatic hydroxylation, oxidative N dealkylation, oxidative O-dealkylation, S-oxidation, reduction, methylation, and hydrolysis. Most often, these reactions increase compound polarity to make a drug more soluble, facilitating elimination through the kidneys. In conjugative metabolism, conjugation occurs by glucuronidation, sulfation, amino acid conjugation, acetylation, or glutathione conjugation to aid elimination. Enzymes involved in conjugation include UDP glucoronyl transferases, aryl sulfatases, N-acetyl transferases, and glutathione S-transferases. Conjugation can serve to inactivate a compound or make it more readily eliminated by urinary or biliary excretion. Several factors influence a drug’s rate of metabolism, including the route of administration, dose, genetics, disease state, and metabolic activity.
Eliminating the drug and other toxic substances from the body, the last topic of the PK study, is known as the process of excretion. Most drugs in the body are eliminated through the urine. Excretion also depends on the solubility of the drug in water. More soluble drugs are excreted faster in the urine. If the excretion is incomplete, the accumulation of compounds in the body can lead to adverse events. Pharmacokinetics study testing should incorporate sufficient sampling times during compound elimination for appropriate assessments of parameters such as elimination half-life and clearance.
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PK analysis is performed throughout the drug research and development process, starting from early discovery to the last Phase of drug development. The primary purpose of preclinical pharmacokinetic studies is to evaluate the characteristics of potential drugs to predict exposures and determine dose levels and frequencies for testing new chemical entities in preclinical disease efficacy models. PK studies in multiple species can be used to predict human pharmacokinetics and estimate the dose required for clinical efficacy and potential manufacturing costs for the intended drug product after achieving therapeutic proof-of-concept and honing structure-activity-relationships (SAR) to determine lead molecules. Pharmacokinetic (PK) Assays during the preclinical phase help determine bioavailability, the volume of distribution, half-life, and clearance. These PK studies help evaluate if the drug has adequate success potential or needs to be modified to improve its pharmacokinetic parameters. Pharmacokinetic (PK) study results from the preclinical stage help design IND enabling Tox studies in animals, and drugs can be advanced farther into clinical development based on these preclinical results. PK bioanalysis meeting the requirements for first in human (FIH) dosing initially undergo single ascending dose (SAD) clinical trials to assess the safety and clinical pharmacokinetics, followed by later multiple ascending dose (MAD) clinical trials to assess steady-state exposures and to correlate with drug pharmacology.
Pharmacokinetics (PK) is the analysis and description of the disposition of a drug in the body, encompassing development of the mathematical description of all dispositional processes in the body, defined as ADME – absorption, distribution, metabolism, and elimination…
We offer a wide range of Pharmacokinetic (PK) Assays beginning from the early discovery phase when a potential drug compound is administered to rodents for understanding ADME properties. Once a compound is found suitable for further development, we also provide Pharmacokinetic (PK) testing services for dose range finding studies followed by IND enabling Toxicology (Tox) studies in rodent and non-rodent animals. PK studies in animals are critical for safely advancing the drug into clinical development. We provide pharmacokinetics services during clinical trials by developing and validating bioanalytical methods in the human biological matrices post the FDA approval of your IND application.
Once your PK bioanalysis is completed, we can complete your Pharmacokinetics (PK) study by calculating relevant parameters for your compound. Additionally, we are glad to assist you with protocol and study design, study execution, and interpretation of your PK data, and/or provide guidance on compound selection, dose levels, collection intervals for preclinical efficacy testing. We maintain fully validated Phoenix WinNonlin software at our facility for non-compartmental analyses (NCA) and PK modeling. Our team can generate formally audited bioanalytical reports for all your regulated studies from early discovery through clinical development.
Pharmacokinetics studies for ADME and toxicokinetic analysis demand both in-depth expertise and nimble execution. NorthEast BioLab is the right partner to assist you in bringing new, effective drugs to the market given the critical and detail-orientated nature of these PK studies in pharmaceutical drug development.
Our team of veteran scientists can help discern your top drug compound based on our 20+ years of experience in method development, validation, transfer for PK bioanalysis and related assay. Together, we can develop robust bioanalytical methods to support your PK studies for the analysis of drugs and metabolites in biological fluids followed by the calculation of PK parameters by non-compartmental analysis (NCA). We promise a high quality and take full responsibility for all your projects, including compliance with various regulations mandated by authorities and agencies such as FDA and ICH.
You can de-risk your drug portfolio right away by leveraging our FDA audited Pharmacokinetics (PK) Study Assay, Testing, And Sample Analysis Services offered to premier biotech/pharma since the early 2000s. We regularly conduct SAD MAD Pharmacokinetics (PK) Studies to determine drug behavior in the body and facilitate critical decision-making on dosage and safety. Our scientists generate and model your GLP PK bioanalysis data using fully validated assay and WinNonlin software. Speak to our Scientists to get started on your first PK Assay with us.
We perform PK studies in clinical trials to examine the absorption, distribution, metabolism, and excretion of a drug. These studies are useful for determining the appropriate dose range for safety and efficacy in subsequent trials. Pharmacokinetic (PK) testing involves a quantitative analysis of the time course of a drug in the body. PK testing in clinical trials often assesses single ascending doses (SAD studies) to investigate dosage proportionality and multiple ascending doses (MAD studies) to correlate the PK effect changes with repeated dosage. SAD and MAD PK studies in clinical trials provide information regarding metabolic alterations and the achievement of steady-state exposures during chronic therapies. Other clinical PK studies include bioavailability and bioequivalence studies, assessment of drug-drug interaction (DDI) potential, and drug penetration studies depending on the therapeutic target.
In early drug discovery, we often perform PK testing to determine whether new chemical entities (NCEs) have adequate exposures for in-vivo efficacy models in mice. Even before dosing in the animals, we typically perform in-vitro pharmacokinetic services to filter out compounds with high metabolic rates or weak absorption potential. During preclinical development, pharmacokinetic testing in additional species is generally performed in one rodent and one non-rodent species to prepare for toxicology and toxicokinetics studies. Additional PK services include allometry or other scaling models to predict clinical PK from the preclinical data ahead of the clinical trials. Early clinical PK studies are often performed at sub efficacious dosage with slow dose escalation to maintain safety and determine the clinical PK parameters while ramping towards therapeutic doses. For reformulations or generics of approved compounds, we perform PK testing to demonstrate bioequivalence. During all drug development phases, PK lab test results may be used to assess dose proportionality, steady-state exposure levels, bioavailability, and the general ADME properties of the test compounds in the various test species.
Pharmacokinetic (PK) study design follows some basic general principals even as it varies based on the chemical structures of the tested compounds and the intended therapeutic targets. Initially, we dissolve the test compound in an appropriate dosing vehicle. Then, the test species is dosed with the vehicle and blood samples are collected over a pre-specified period for drug concentration analysis. Afterward, we plot the blood draw time vs. concentration curves and calculate the PK parameters such as the area under the curve, maximum concentration, clearance, distribution volume, elimination half-life, etc. We select the species and strains for pharmacokinetics studies in animals to meet our objective towards proving compound efficacy and safety with the ultimate goal of reaching the clinic and marketplace. During drug discovery, PK studies in mice and rats are often performed in tandem with pharmacodynamic studies to achieve in-vivo proof of concept against a disease target. Late phase discovery and development PK studies are performed in multiple species to support preclinical toxicology and regulatory submissions.
Pharmacokinetic analysis provides direct information about the fate of a test compound in the body. Pharmacokinetics research focuses on the relationship between the dosing regimen and the body’s exposure to the drug. Typically, we generate PK data through non-compartmental analysis. Non-compartmental PK parameters include area under the curve (AUC), maximum exposure (Cmax), clearance (CL or CL/F), distribution volume (Vd or Vd/F), elimination half-life (t½), etc. These parameters provide crucial information about any drug’s absorption and elimination rates, as well as the potential to distribute to tissues throughout the body. Pharmacokinetics in drug development from multiple species can be used to predict dosing levels and regimens for efficacy in animal models of disease, for predictions of doses required for preclinical toxicology studies, and to scale predicted clinical PK parameters and estimate initial clinical doses.
Pharmacokinetic assays provide a quantitative description of what a body does to a drug. The four major components of the pharmacokinetics process are absorption, distribution, metabolism, and excretion commonly referred to as ADME. Absorption is the process of getting the drug from the site of delivery into the systemic circulation. For example, orally administered compounds must be soluble in the gut environment, then permeate the gastrointestinal tract and pass through the portal vein and the liver (known as the first pass) before reaching central circulation. Distribution describes the drug’s ability to enter and leave central circulation to reach tissues and organs throughout the body. Metabolism and excretion are the processes of eliminating drugs and xenobiotics from the body via metabolic processes or direct biliary or renal excretion of unchanged drug.
Pharmacodynamics describes what the drug does to the body, and pharmacokinetics describes what the body does to the drug. Pharmacokinetics (PK) and pharmacodynamics (PD) are both components of in-vivo pharmacology. Pharmacokinetics evaluates absorption, distribution, metabolism, and excretion of drugs by the determination of systemic exposure over time. Pharmacodynamics studies the relationship between drug concentration at the site of action (receptor) and the observed pharmacological response. PK describes drug exposure, and PD describes drug effects. PK PD analysis provides the relationship between the drug’s in-vivo exposure and efficacy. PK PD studies in multiple species during drug discovery and development are often useful for predictions of initial dosing levels and regimens for safety and efficacy in the clinic.
In-vivo PK drug assessments are critical in drug discovery, development, and clinical testing. Non-compartmental pharmacokinetic (PK) drug parameters vary depending on study design, but typically include volume of distribution (Vd) and total plasma clearance (CL) following IV doses, time to maximum concentration (Tmax), maximum observed concentration (Cmax), area under plasma concentration vs. time curve (AUC), elimination half-life (t1/2) for all dose routes, and bioavailability (F%) where extravascular and IV routes have been tested. As appropriate, our team of experienced scientists at NorthEast BioLab can aid you in study and protocol design, study monitoring, sample bioanalysis, pharmacokinetics parameter calculation using validated Phoenix WinNonlin software, and result interpretation during all project phases.
