PHAR 7633 Pharmacokinetics and Biopharmaceutics: Recent Episodes
David Bourne
Pharmacokinetic and Biopharmaceutics from the University of Oklahoma College of Pharmacy - PDF files of course material, Audio AND Video tutorials PHAR 7633 - Description and quantitation of factors affecting the absorption, distribution, and metabolism, and excretion of drugs. Development of appropriate dosage regimens and graphical analysis of drug concentration data sets. Bioequivalence and drug product testing. Drug analysis in biological matrix.
For drugs which exhibit non-linear metabolism within their therapeutic range can be difficult to dose. Small changes in dose can result in larger changes in concentration. Using average values for parameters can be a good start but better results can be achieved with therapeutic drug monitoring. Analysis of TDM data can by use of equations or graphical methods. Both types of approaches are described in this tutorial.
Given the requirement that concentrations stay between Cpmax and Cpmin we can calculate a suitable loading dose, maintenance dose and dosing interval.
Three parameters; kel, ke and fe, can estimated from drug in urine data using a semi-log plot of rate of excretion versus time data
Data collected after an IV infusion can be analyzed by plotting the data on semi-log graph paper. The slope will yield a value for kel. The value of V can be determined from Cp(D), the concentration at the end of the infusion.
Three parameters; kel, ke and fe, can estimated from drug in urine data using a semi-log plot of rate of excretion versus time data
After completing the material in this chapter each student should:- * be able to draw the scheme and write the differential equations for a one compartment pharmacokinetic model with elimination of drug and metabolite into urine (parallel pathways of elimination) * to use the appropriate integrated equations for this pharmacokinetic model to calculate amount of drug excreted into urine * be able to plot cumulative amount excreted versus time, A.R.E. versus time and rate of excretion versus time (midpoint) and use these graphs to calculate pharmacokinetci parameters * be able to define, use, and calculate the parameters: * ke (excretion rate constant) * km (metabolism rate constant) * U∞ and M∞ * fe and fm * * renal and non renal clearance * be able to use fe, the fraction excreted, to calculate overall elimination rate constants in patients with impaired renal function
After completing the material in this chapter each student should:- * understand the separate assumptions associated with the one compartment model, rapid IV bolus dosing and linear elimination * understand the properties of first order kinetics, linear models * be able to write the differential equations for a simple pharmacokinetic model * be able to define, use, and calculate the parameters: * kel (elimination rate constant) * V (apparent volume of distribution) * t1/2 (half-life) * AUC (area under the concentration versus time curve) * * Cl (clearance) as they apply to a one compartment linear model * be able to use the integrated equations for a one compartment linear model to perform various dose and dosing regminen calculations
After completing the material in this chapter each student should:- * have an basic understanding of the scope and impact of biopharmaceutics and pharmacokinetics * have a general knowledge of the factors affecting the rate and extent of drug absorption, distribution, metabolism and excretion
After completing the material in this chapter each student should:- * understand exponents and logarithms, algebraically and graphically * be able to use linear (Cartesian) and semi-log graph paper for the representation of data * be able to draw a 'best-fit' straight line through data on linear and semi-log graph paper *understand and able to use spreadsheets * understand differential and integral calculus * be able to write differential equations given a compartmental modeling scheme as a diagram or description * be able calculate the area under the plasma concentration versus time curve (AUC) using the linear trapezoidal rule
With linear disposition pharmacokinetic models (distribution, metabolism and excretion first order) it is possible to add concentration from various doses together to get the total drug concentration. Various types of doses can be included at various times.
With linear disposition pharmacokinetic models (distribution, metabolism and excretion first order) it is possible to add concentration from various doses together to get the total drug concentration. Various types of doses can be included at various times.
Given the requirement that Cpmax and Cpmin are close to but below specified values we can calculate a suitable loading dose, maintenance dose and dosing interval.
Given the requirement that Cpmax and Cpmin are close to but below specified values we can calculate a suitable loading dose, maintenance dose and dosing interval.
The parameter values kel and V can be determined from the 'best-fit' line drawn through the data on semi-log graph paper.
Given the requirement that concentrations stay between Cpmax and Cpmin we can calculate a suitable loading dose, maintenance dose and dosing interval.
The absorption parameters, ka and V/F, can be determined from oral data. For good estimates of these parameters the ratio between ka and kel must be greater than 5. Also the absorption and elimination should be first order
Calculating the Area under the Concentration versus Time curve (AUC) using the trapezoidal rule
After completing the material in this chapter each student should:- * To understand the basics of a Therapeutic Drug Monitoring service * To describe and understand how changes in physiology effect the pharmacokinetics of drugs in the very young and the elderly
After completing the material in this chapter each student should:- * Describe the need and techniques for separation of a drug from the experimental matrix * Describe methods use to quantitate drug concentrations * Understand the Advantages and Disadvantages of some these methods
After completing the material in this chapter each student should:- * To understand the different types of concentration - effect relationships * To understand the mathematical relationships involved with direct reversible pharmacological effect kinetics * To understand the development and use of physiologically based pharmacokinetic (PBPK) models
After completing the material in this chapter each student should:- * Understand the use of computer programs such as Boomer for non-linear regression analysis of pharmacokinetic data * Consider Bayesian analysis of clinical data * Understand the use of computer programs such as NONMEM for non-linear regression analysis of population pharmacokinetic data
After completing the material in this chapter each student should:- * To draw the scheme and write the differential equations for compartmental pharmacokinetic models with non-linear metabolism elimination * To understand the process of parallel pathways as it applies with one or more non-linear pathways *To define and use the parameters Vm and Km * To design and calculate appropriate dosage regimens when non-linear pharmacokinetics apply
After completing the material in this chapter each student should:- * To understand and use the non compartmental approach to parameter estimation
After completing the material in this chapter each student should:- * To draw the scheme and write the differential equations appropriate to a multi-compartment pharmacokinetic model * To recognize and use the integrated equations for these models to calculate parameter values and for dosage regimen calculations * To calculate the parameters of these models using the method of residuals
After completing the material in this chapter each student should:- * To understand and describe the processes by which drugs are distributed throughout the body * To understand the effect of protein binding on drug distribution and methods by which protein binding is measured
After completing the material in this chapter each student should:- * be able to describe the various processes by which a drug may be metabolized including Phase 1 and 2 reactions * be able to describe the role of pharmacogenomics in drug metabolism and drug response * understand the effect of induction of drug metabolism * understand the role of inhibition of metabolism on drug interactions * be able to define the parameters: * hepatic clearance * hepatic/liver blood flow * extraction ratio * free intrinsic clearance * understand the relationship between the parameters hepatic clearance, hepatic blood flow, fraction unbound, and free intrinsic clearance and be able to discuss the venous equilibration model * be able to discuss the differences between flow limited and capacity limit metabolism/drugs
After completing the material in this chapter each student should:- * be able to describe the various routes by which a drug may be excreted from the body * understand the parameter renal clearance and its relationship with the excretion processes in the kidney * understand the influence of renal disease on drug elimination * be able to calculate suitable drug dosage regimen for patients with impaired renal function based on a Cpaverage or a Cpmin/Cpmax approach
After completing the material in this chapter each student should:- * be able to use the integrated equations for multiple oral dose administration to calculate plasma concentration or calculate appropriate multiple dose regimen * be able to define, use, and calculate the parameter: * * average plasma concentration, * be able to use the Cpaverage equation to calculate or adjust an appropriate dosing regimen * be able to use the superposition principle to calculate Cp after non uniform IV or oral dosing regimen
After completing the material in this chapter each student should:- * understand and be able to describe drug accumulation after repeated dose administration * be able to use the integrated equations for drug concentration after multiple IV bolus doses * be able to calculate suitable dosing regimens including loading dose, maintenance dose, and dosing interval * be able to define, use, and calculate the parameters: * dosing interval, τ * accumulation factor, R * maximum plasma concentration, Cpmax * minimum plasma concentration, Cpmin * be able to calculate suitable multiple dose regimen to achieve desired Cpmin and Cpmax values
After completing the material in this chapter each student should:- * be able to describe various dosage forms and the expected bioavailability and pharmacokinetci consequences of each dosage form * be able to describe formulation components which affect the oral absorption of drug products
After completing the material in this chapter each student should:- * be able to describe the physical-chemical factors that affects oral absorption * be able to describe the pH-partition hypothesis as it applies to drug absorption and estimates values of Brodies D value * be able to describe Fick's first law as it applies to drug dissolution
After completing the material in this chapter each student should:- * be able to describe membrane structure and how it might effect drug transport * be able to describe the differences between passive, facilitated and active transport * be able to describe the effect of parameters of Fick's first law on passive drug transport across membranes * be able to describe the relationship between GI physiology and drug absorption including changes in stomach emptying time and the presence of food
After completing the material in this chapter each student should:- * be able to define various terms relating to bioavailability studies * be able to describe some of the past problems with bioavailability * be able to describe a typical bioavailability study * be able to evaluate data derived from a bioavailability study
After completing the material in this chapter each student should:- * be able to calculate ka using * the method of Inspection * the method of Residuals including * * drawing the Cplate line * * estimating the residual values * * drawing the residual line (and possibly rescaling the time axis) * the method of Wagner and Nelson and describe when each method may be most appropriate * be able to calculate F using plasma (AUC) or urine (U∞) data * understand the difference between absolute and relative bioavailability and be able to convert between these values
After completing the material in this chapter each student should:- * be able to draw the scheme and write the differential equations for a one compartment pharmacokinetic model with first order absorption * be able to use the integrated equations for this pharmacokinetic model to calculate parameter values and dosing regminens * be able to define, use, and calculate the parameters: * absorption rate constant, ka * fraction absorbed, bioavaialability, F * time of peak concentration, tpeak * maximum plasma concentration, Cpmax * be able to describe the effect of changing ka and/or F values on plasma concentration versus time curves including * with altered liver function on first-pass metabolism * with improved drug absorption through reformulation * * with different dosage forms such solution, tablets and controlled release tablets
After completing the material in this chapter each student should:- * be able to describe various routes of drug administration including the concentration versus time profile that might expected from thier administration * be able to describe the advantages and disadvantages of various routes of drug administration
After completing the material in this chapter each student should:- * be able to draw the schemes and write the differential equations for a one compartment pharmacokinetic model after IV infusion administration * be able use the integrated equations for drug concentrations during and after an IV infusion administration to calculate parameter values and suitable dosing regimens including IV infusion alone, fast/slow IV infusion or infusion/bolus dosage regimens * be able to calculate kel and V from data collected after a single IV infusion * be able to define, use, and calculate the parameters: * k0 (infusion rate constant) * D (infusion duration)
Introduction to PHAR 7632 at the University of Oklahoma. Pharmacokinetic and Biopharmaceutics. Description and quantitation of factors affecting the absorption, distribution, and metabolism, and excretion of drugs. Development of appropriate dosage regimens and graphical analysis of drug concentration data sets. Bioequivalence and drug product testing. Drug analysis in biological matrix.
Calculating the Area under the Concentration versus Time curve (AUC) using the trapezoidal rule
Data collected after an IV infusion can be analyzed by plotting the data on semi-log graph paper. The slope will yield a value for kel. The value of V can be determined from Cp(D), the concentration at the end of the infusion.
The parameter values kel and V can be determined from the 'best-fit' line drawn through the data on semi-log graph paper.
The absorption parameters, ka and V/F, can be determined from oral data. For good estimates of these parameters the ratio between ka and kel must be greater than 5. Also the absorption and elimination should be first order