Linear/
Nonlinear PK
Nonlinear PK
What is the term for after drug administration, drug concentrations are linearly related with the amount of dose administered
Linear pharmacokinetics
What model considers the whole organism the whole organism as a single compartment where the drug distributes homogeneously and instantaneously?
One compartment pharmacokinetic model
What kind of PK does not rely on assumptions about body compartments?
Noncompartmental PK also known as model-independent PK
What are the compartments in the two compartment model?
Central and peripheral compartments.
What is the goal of pharmacometrics?
Also known as quantitative pharmacology, it characterizes the different levels of variability that can be observed in the dose-exposure response relationship and disease progression
What metric to look at for assessing drug bioavailability?
Area under the curve, maximum concentration
What are the assumptions of the one compartment pharmacokinetic model?
Apparent Vd is constant. Drug elimination follows first order kinetics
Where is noncompartmental PK used for characterizing PK?
Single study, for example in analyses in dose escalation decisions, and also to obtain summary parameters used in bioequivalence studies (such as total area under the plasma drug concentration versus time profile, AUC 0-∞, or peak plasma concentration Cmax or time to the peak concentration)
How do we describe a two compartment pharmacokinetic model?
Movement from one compartment to another is not instantaneous and follows first-order kinetics.
Depending on the modelled therapeutic scenario, drug absorption will be assumed to be instantaneous (intravenous bolus) or follow zero- or first- order kinetics (constant rate intravenous infusion or extravascular drug administration)
Most common modeling, represent 80% published models
What is the difference between inter-individual variability (between subject variability) versus inter-occasion variability (between occasion variability)?
BSV describes the observed heterogeneity in mechanisms and outcomes among different individuals
BOV describes the observed heterogeneity in mechanisms and outcomes for the same individual among different occasions. An occasion is a time period in which we can assume that the system has the same behavior at the individual level
In linear pharmacokinetics, what is the kinetics that govern the transfer of drug molecules between the different body spaces?
First order
What drug delivery follows a one compartment model?
Bolus intravenous injection
What are the assumptions for non-compartmental analysis in drug elimination?
Linear process and the terminal phase of the concentration-time curve follows a mono-exponential decay.
λz parameter (units 1/time) can be graphically obtained from terminal slope of semilogarithmic plasma concentration-time curve. Ideally, 3-4 half lives should have elapse to achieve a reliable estimate. Once λz is estimated, t1/2 (units time) can be computed
What is the fast disposition (distribution plus elimination) phase or α-phase?
Net flow of molecules from compartment 1 to compartment 2 and from compartment 1 to the exterior of the system
Mixed modes are used in population analysis to quantify typical parameters along with the magnitude of various sources of variability. These models contain fixed effects and random effects. What are they?
Fixed effects are model parameters that explain the variability and do not vary across individuals. Fixed effects include parameters of the mapping function (ie. PK) that describes the population mean outcome and parameters relating an individual characteristic with one system property/element
Random effects are stochastic variables accounting for unexplained variability at the population level: inter-individual variability (IIV) and inter-occcasion variability (IOV)
What is the response between the dose and the pharmacodynamic effect? For example, the equilibrium of concentrations between the drug bound to the action receptors and the drug dissolved in the surrounding fluid
What order absorption is considered when the drug enters the systemic circulation at a constant rate?
Zero order absorption
How do we get Cmax and tmax from the observed concentration time data? How do we get AUC 0- ∞?
Cmax and tmax is directly recorded from the observed concentration-time data. AUC0-∞ is calculated by the linear trapezoidal rule, log-linear trapezoidal rule, or a mixture of these methods
How do we describe a two compartment pharmacokinetic model?
Central and peripheral compartments.
Movement from one compartment to another is not instantaneous and follows first-order kinetics.
Depending on the modelled therapeutic scenario, drug absorption will be assumed to be instantaneous (intravenous bolus) or follow zero- or first- order kinetics (constant rate intravenous infusion or extravascular drug administration)
Most common modeling, represent 80% published models
What are the methods to estimate population parameters?
Naive Average Data: observations from different subjects are initially processed obtaining the average observation for the population at each sampled time
Naive Pooled Data: data from all subjects are considered as arising from one unique individual, and an individual model is fitted to obtain estimates of the structural model and the RUV
Two Stage Method: most widely used. First stage, datasets coming from each subject is independently analyzes, and the individual model of interest is obtained for each subject by nonlinear regression. Individual parameters are obtained for pooling at the second stage, in which summary statistics are obtained as estimators of population parameters
What pharmacokinetics does valproic acid have for chronic epileptic patients?
Linear and nonlinear pharmacokinetics
What methods are utilized to determine the rate constants in the one-compartment model for extravascular administration?
Method of residuals or feathering;
Estimate a valid ka value assuming the validity of an intravenously obtained k known as the Wagner and Nelson method
In a standard noncompartmental model, what is the assumption for drug absorption kinetics? Distribution kinetics? Elimination kinetics?
Drug absorption- no assumption
Distribution- assume to be first order
Elimination- assume to be first order
What is steady state? After steady state, what happens in the terminal phase, slow disposition phase, or β phase?
Steady state (true equilibrium) is when there is no exchange of drug between the compartments
β phase (pseudo equilibrium) where the amount of drug in both compartments evolves in parallel ie. the concentrations in both compartments decrease proportionally
What are nonlinear mixed effects models?
Standard method that allows the estimation of population parameters, residual variability in a single stage, and taking the whole population as the unit of analysis
In NLME models, parameters are structural, statistical, and the covariate models can be simultaneously estimated from the population dataset. The hierarchical structure of variability (RUV, IIV, IOV) is considered in the single step of the analysis
Estimate parameters by the maximum likelihood approach where the maximum likelihood estimation is to nonlinear mixed effects modeling what "least squares" is to linear regression