PK PD analysis study examines a drug’s effect compared to its exposure in the body after dosing. PK PD assays estimate the safety and efficacy of therapeutics after suitable bioanalysis. Pharmacokinetics modeling and simulation help further understand what the body does to a drug, modeling the processes of absorption, distribution, metabolism, and elimination (ADME). Typically, PK PD modeling includes area under the concentration vs. time curve (AUC), maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T½), clearance or apparent clearance (CL or CL/F), and distribution volume or apparent distribution volume (Vz or Vz/F). NorthEast BioLab supports your single or multiple ascending dose PK PD studies to assess steady-state pharmacokinetics and dose proportionality (linear or non-linear pharmacokinetics). We maintain fully validated software such as Phoenix WinNonlin plus PK Submit for FDA SEND and SDTM domain generation in addition to Watson LIMS, Sciex Analyst, and Spectramax for bioanalysis. Our veteran experts put together high-quality PK PD models to support your regulatory submission needs. We deliver GLP and ICH compliant eCTD format submissions and generate Pharmacokinetic Concentration (PC) and Pharmacokinetic Parameter (PP) CDISC SDTM and SEND domains for your clinical (NDA and BLA) studies and preclinical (IND) submissions, respectively.
PK PD analysis study links drug exposure to therapeutic effect measures so drug developers can better understand the relationships between exposure, efficacy, and toxicity. Thus, PK PD assay and data analysis results are essential to any ECTD submission. Pharmacokinetics (PK) parameters are typically calculated by non-compartmental analysis (NCA) following the determination of test article concentrations in samples from clinical or preclinical studies. Generally, area under the curve (AUC) and maximum concentration (Cmax, or C0 for an IV dose) are accepted as the most critical PK parameters when discussing exposure and activity or toxicity. AUC in pharmacokinetics represents the total exposure of the test article over the tested time course. AUC can be extrapolated to infinity for well-designed studies. We derive absolute or relative bioavailability (F%) from the AUCs of multiple dose groups or administration routes. Scientists can readily obtain the Volume of distribution (Vz) and Clearance (CL) from a single IV dose. We can calculate specific PK parameters such as Volume of distribution at steady-state (Vss) and mean residence time (MRT) related to steady-state pharmacokinetics from a single dose using pharmacokinetic equations using statistical moment analysis. Thus, pharmacokinetic parameters help ascertain dose levels for PK PD modeling of drug exposure and efficacy in preclinical models of human disease, evaluate the impact of dose proportionality (linear or non-linear pharmacokinetics) on efficacy, toxicity, and therapeutic index, assess appropriate dosing intervals, and estimate clearance time in the case of serious adverse events or dose-limiting toxicities.
Our projects with NorthEast BioLab include method development, stability studies, cross-validation of other labs, support for investigator-sponsored studies, and Clinical Phase I – IV studies. They have considerably exceeded our expectations time and again.
NorthEast BioLab provided critical insight into data analysis, and are compliant with industry best practices and regulatory standards. We would certainly recommend them and look forward to working together in the future.
NorthEast Biolab truly goes that extra mile to make the collaboration successful, and I will continue to enjoy very productive interactions with them in the future. The integrity of the staff is as refreshing as their willingness to provide ingenious scientific input and high-quality data.
Our latest study together was a pivotal bioequivalence study, where samples from a cross-over study with about 100 volunteers needed swift analysis. This study, same as all other bioanalytical studies with NorthEast BioLab, was completed with very high quality and reporting standard and incredible responsiveness.
NorthEast Biolab is by far the most responsive and thorough bioanalysis service provider. They work closely with the client to provide the most efficient and cost-effective approach to get the job done.
We have worked with NorthEast Biolab on several programs and have found them to be professional, collaborative, and responsive. As a small company, our vendors are key members of our project teams. The scientists at NorthEast Biolab are technical experts, who produce high-quality data, on-time, and on-budget.
PK PD modeling is performed using non-compartmental analyses (NCA) or compartmental analysis. NCA allows for a model-independent interpretation of pharmacokinetic data using pre-defined equations. For individual studies in preclinical discovery through clinical development, non-compartmental analyses are often employed to characterize the pharmacokinetic data, offering the advantages of consistency of data for interpretation across multiple studies without any assumptions about compartment numbers or behaviors. Alternatively, compartmental analysis involves selecting a discrete number of bodily compartments that are connected and homogenously mixed. Here, the rates of drug flow in and out of each compartment are quantifiable. Physiologically based pharmacokinetic (PBPK) models are the most complex compartmental analyses, where all relevant organs and bodily systems represent compartments in the kinetic model. Typically, compartmental studies are utilized in population PK analyses with specific objectives to compare patient demographics and aid in decisions regarding dosing levels and frequencies to reach appropriate steady-state concentrations of drug in the body for suitable efficacy and minimal toxicity in differing population covariates. In all cases, well-designed PK PD studies are essential to obtain relevant data analysis to properly determine reliable kinetic parameters for correlation to efficacy and toxicity. Preclinical PK PD analysis helps select dose levels and regimens for pharmacology efficacy testing, and PK PD modeling helps scale preclinical results for preliminary predictions of clinical pharmacokinetics.
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…
NorthEast BioLab provides pharmacokinetic/pharmacodynamic (PK PD) study services from early drug discovery through clinical eCTD FDA submission and beyond. We offer end-to-end PK PD analysis services: in vitro ADME studies, bioanalytical method development, validation, and analysis of formulation and biological samples for test articles and metabolites. Additionally, we conduct non-compartmental analysis for pharmacokinetics of small molecules, proteins, peptides, antibodies (mab), etc. during preclinical and clinical studies in healthy subjects, models of preclinical disease, or clinical patients. We can help you interpret exposure and efficacy results to help you gain a clear understanding of your drug’s PK PD relationship. We perform compound screening, optimization, and characterization during drug discovery to improve DMPK properties and refine your screening cascade to lead compounds. We provide bioanalysis and toxicokinetic or pharmacokinetic evaluations using GLP/GCLP validated equipment, software, and methods during preclinical and clinical development. Our scientists are happy to assist you with project and protocol design, study prosecution, and data interpretation guidance at all project stages. We offer detailed audited study reports for sample bioanalysis and pharmacokinetics or toxicokinetics for drug discovery, development, and eCTD submissions. Additionally, we can put together Pharmacokinetic Concentration (PC) and Pharmacokinetic Parameter (PP) domains for your results in CDISC SDTM or SEND format for compliance with requirements for electronic submissions to the FDA and other global regulatory agencies. We maintain the latest and fully validated software packages for your PK data management and calculations, including Certara Phoenix WinNonlin, Watson LIMS, Sciex Analyst, Spectramax, etc.
At NorthEast BioLab, our dedicated team of scientists has the necessary experience and expertise to assist with planning and executing your PK PD analysis, modeling, and reporting. Our assistance during lead optimization and characterization would help you get PK analysis right as a critical component of your drug discovery and development process. We compute AUC and Cmax pharmacokinetics to determine your drug compound’s systemic exposure, toxicity, and efficacy. We can evaluate PK from samples in your preclinical efficacy models from systemic circulation or tissues to help establish your dosing regimens and understand PK PD relationships. This PK PD modeling helps scientists and medics decide the correct drug dosage for early clinical trials. Hence, it is crucial to perform reliable, efficient PK PD studies and analysis to aid compound optimization in drug discovery. Similarly, we must carry out the GLP toxicology studies utilizing a fully validated and reliable bioanalytical and PK method to prepare for regulatory eCTD submissions. We offer formal and audited bioanalysis and pharmacokinetics reports and present your pharmacokinetic concentration and non-compartmental PK parameter results in compliant CDISC SEND or SDTM formats.
In linear pharmacokinetics, systemic concentration over time data fits a one-compartment model. Typically, the concentration data may be matched to a single or multi-compartment PK model to help interpret pharmacokinetic equations and make therapeutic decisions. Most pharmacokinetics of drugs are performed without specifying the applicable mathematical model (non-compartmental analysis). One primary characteristic of linear models is that the change in concentration over time is constant. Thus, the compound’s half-life is constant and area under curve (AUC) pharmacokinetics increases linearly with dosage regardless of the body’s drug level. Therefore, doubling the dose will result in doubling the AUC, or administering half the dose twice per day will result in the same AUC as administering the total dose once per day. Contrastingly, non-linear pharmacokinetic models result from saturable behavior in the absorption, distribution, metabolism, or excretion of the compound. Here, saturable metabolism or excretion results in higher than dose-proportional increases in AUC pharmacokinetics with dosage, and saturable absorption results in lower than dose-proportional increases in AUC pharmacokinetics with dosage. In either case, the validity of PK parameters depends on the data’s quality entered into the model. Thus, dosing and sample collection must be precisely timed, and analytical methods must be sensitive and specific. Pharmacokinetics of drugs must be weighted appropriately to avoid bias due to the increased probability of errors at drug concentrations near the assay’s detection limit. Results obtained using a specific pharmacokinetic model should be compared to those using noncompartmental methods.
Area under curve (AUC) is calculated for the concentration vs. time curve by totaling trapezoidal areas between each measured time point. We can use various mathematical rules for these calculations based on linear or logarithmic transformations. One simple AUC pharmacokinetics calculation uses the linear trapezoidal rule with the equation Atrap = ((c1 + c2) / 2) / (t2 – t1). Here, Atrap is the trapezoidal area, and c1 and c2 are the measured concentrations at time points t1 and t2. AUC is the integration or summation of all such areas throughout the measured time points. We can extrapolate AUC in pharmacokinetics to infinity by adding the final triangle area created by the terminal extrapolation of the elimination phase to the time axis. Our scientists calculate and interpret your drug’s AUC figures to understand total exposure following any pharmacokinetic modeling.
Systemic Clearance (CL or CLs)in pharmacokinetics represents the rate at which a drug gets removed from the bloodstream. Clearance is determined from non-compartmental analysis following IV dosing. It represents total additive clearance from all potential clearing organs (e.g., liver, kidneys, etc.). We measure clearance values in units of volume/time and think of it as a proportionality constant between drug concentration and elimination rate. The non-compartmental pharmacokinetic equation for clearance is CL = Dose/AUC.
Tmax in pharmacokinetics represents the time after dosing when a compound reaches its maximum concentration in the bloodstream following extravascular dosing. Usually, the lower rates of absorption result in extended Tmax values.
Cmax in pharmacokinetics is the maximum observed concentration during a PK study. There is no mathematical calculation for the determination of Cmax. Therefore, we must design PK studies appropriately to capture Cmax and Tmax accurately.
Following repeated drug administrations, the systemic concentrations in the body reach an equilibrium where the rate of drug intake equals the rate of excretion. This equilibrium is described as steady-state. Typically, it takes administrations over approximately five half-lives of the drug to reach steady-state independent of dose level and dosing interval. We can calculate steady-state concentration (Css) by dividing the total exposure over the dosing interval (AUClast) by the interval time (Tlast).
Steady state is attained with repeated dosing and increasing drug concentrations in the body until saturation. At this point, the amount of drug administered is equivalent to the amount of drug leaving the body between each dose (rate in = rate out). Here, drug concentrations rise and fall according to a repeating wave pattern as long as the same dose level gets administered with the same time interval between doses. This repeated dosing interval is often abbreviated using the Greek letter tau (τ) in pharmacokinetics. Generally, drug accumulation and attainment of steady state are possible using any route of administration for dosing.
T1/2 in pharmacokinetics, i.e., elimination half-life, represents the time it takes to clear half of the compound’s concentration from systemic circulation during the log-linear elimination phase. Even as elimination half-life can be calculated for any dose route, it is best represented for a compound following an IV dose given the absorption component is bypassed with direct systemic administration. IV bolus curves for most drugs are biphasic, including a steep early phase representative of compound distribution to tissues, metabolism, and excretion. Once tissue distribution is equilibrated, the second phase of the curve represents metabolism and excretion. Points in this log-linear elimination phase are selected and used to determine the curve slope (m). The elimination rate constant (λz, k, or kel) is calculated from the slope as λz = 2.303 x m. Then, we calculate elimination half-life (t½) as 0.693 / λz. For reliability, the half-life calculation should be performed with a minimum of three terminal points in the λz range and have a determination coefficient (R2) of at least 0.85.
Cp in pharmacokinetics is a common abbreviation used to indicate blood plasma concentration. Usually, the first step following sample bioanalysis for performing PK calculations is to plot the measured blood plasma or serum concentrations versus time.
In a standard non-compartmental model, the elimination rate constant can be represented by several abbreviations including λz, k, kel, β, λn, λlast), and represents the log-linear elimination phase following compound absorption and distribution to tissues. For a mathematical pharmacokinetic model, compound flow through each compartment can be characterized by rates in and out, typically expressed as kin, kout, ka, kb, k1, k2, etc.. Here, an increasing number of constants are needed for an increased number of compartments used in the modeling. These constants vary depending upon the complexity of the mathematical model used.
Volume of Distribution in pharmacokinetics is typically abbreviated Vd, Vz, or Varea. Vd in pharmacokinetics reflects the reversible uptake of drugs by tissues from the blood. It is thought of as a fictitious volume that a drug occupies in the body as a uniform sack relative to the drug concentration in blood. Large Volumes of Distribution indicates more significant levels of the drug, reaching tissues relative to measured plasma concentrations and can show the compound’s potential for achieving the desired target. We calculate Vd in pharmacokinetics by dividing the measured Clearance (CL) with the elimination rate constant (λz). Volumes of distribution can be calculated following IV doses. Similarly, the apparent Volume of Distribution (Vd/F) may be determined for extravascular doses and includes a bioavailability correction factor to account for the compound’s absorption. Volume of distribution at steady-state (Vss) is another useful PK parameter for predicting tissue distribution and is calculated as mean residence time (MRT) times clearance (CL) following IV dosing.
