Pharmacokinetics Concepts Workshop 9 PDF

WORKSHOP 9 Plasma level Curve Pharmacokinetic Parameters Optimization of dosage regimen 3° MEDICINE Academic year: 2024/25 Professor: Vittoria Carrabs PhD The study of ADME processes of a drug is what will allow us to determine the concentrations that cause the desire...

WORKSHOP 9 Plasma level Curve Pharmacokinetic Parameters Optimization of dosage regimen 3° MEDICINE Academic year: 2024/25 Professor: Vittoria Carrabs PhD The study of ADME processes of a drug is what will allow us to determine the concentrations that cause the desired therapeutic effect without toxicity. CLINICAL PHARMACOKINETICS The ultimate aim of drug therapy is to achieve efficacy without toxicity This involves achieving a plasma concentration (Cp) within the ‘therapeutic window/range’ (range of drug concentration that produces desired response without toxicity) so it means above the minimal effective concentration (MEC), but below the minimal toxic concentration (MTC). Minimum toxic concentration (MTC) The minimum drug concentration needed to just produce a toxic effect. Minimum effective concentration (MEC) The minimum concentration of drug needed to produce the desired pharmacologic effect. https://youtu.be/rnIRykbgtbM?si=YabRfBghB1d8_FwK  PLASMA DRUG LEVEL–TIME CURVE Single dose administration After an IV administration concentrations are always decreasing after the dose. But after extravascular administration the concentrations will increase until Cmax and then the concentrations will start to decrease Drug elimination = drug metabolism + drug excretion  PLASMA DRUG LEVEL–TIME CURVE The plasma drug level–time curve describes the pharmacokinetics of the systemically absorbed drug Cmax I administration Single dose AUC tmax (t0) 1 Minimum effective concentration (MEC): The mínimum concentration of drug needed at the receptors to produce the desired pharmacologic effect. 2 Minimum toxic concentration (MTC): The drug concentration needed to just produce a toxic effect. 3 Onset time: The time required for the drug to reach the MEC. 4 Duration of action: The difference between the onset time and the time for the drug to decline back to the MEC. 5 The time of peak plasma level (tmax ): The time of maximum drug concentration in the plasma and is proportional to the rate of d6 rug absorption. 6 The peak plasma level (Cmax): The maximum drug concentration, usually related to the dose and the rate constants for absorption and elimination of the drug. 7 Area under the curve (AUC): It is related to the amount of drug absorbed systemically. 8 Intensity of the drug´s effect (I): from MEC to Cmax  PLASMA DRUG LEVEL–TIME CURVE After an IV administration, Tmax=0 and concentrations are always decreasing after the dose. But after oral administration, Cmax and Tmax are dependent on the extent, and the rate of drug absorption and the disposition profile of the drug. Single dose administration Bioavailability Bioavailability (F): the rate* and extent* to which the active ingredient is absorbed from a drug product and becomes available at the site of action. * Rate: How rapidly does the drug get from its site of administration, to the general circulation * Extent: How much of the administered dose enters the general circulation IV dose have 100% BIOAVAILABILITY → F = 1 PLASMA DRUG LEVEL–TIME CURVE Single dose administration Drug products may be considered bioequivalent in extent and rate of The most reliable measure of a drug's absorption if their plasma concentration bioavailability is AUC curves are essentially superimposable.  PLASMA DRUG LEVEL–TIME CURVE Bioavailability and Bioequivalence: Two dosage forms are bioequivalent: Two dosage forms are NOT bioequivalent: REMEMBER Half-Life (t1/2): time taken for the serum drug level to fall to 5O% during elimination (the time it takes to decrease the drug plasma concentration by half) For drugs with first order kinetics, takes 4-6 t1/2 for drug ELIMINATION t1/2  Dosage Regimen The most common in therapeutic treatments is not a single dose administration if not: MULTIPLE-DOSAGE regimen CONTINOUS IV INFUSION regimen The “target” of dosage regimen is to achieve and maintain a: Cpss: DRUG CONCENTRATION IN PLASMA STEADY STATE within the therapeutic window during the desired time To achieve OPTIMAL CLINICAL EFFECTIVENESS  Dosage Regimen Plasma levels of a drug will depend on: Route of administration Rate of administration (dose/time) Half-Life (t1/2): MULTIPLE-DOSAGE regimen Half-Life (t1/2): it is used to stablish how often it is necessary to take a dose (dosing interval) Drug is given once every t1/2 The drug concentrations in plasma should become relatively constant and stable when: Amount of Amount of drug drug administered metabolized during each and t½ eliminated  Dosage Regimen MULTIPLE-DOSAGE regimen https://youtu.be/a4Jo E05MHaM?si=XuCZApe8 b4vASBoN Time to attain steady state depends on t1/2 Changes of dosage and regimen affect to the plasmatic concentration achieved at steady state  Dosage regimen Desired Drug Level- Steady State Steady-state concentrations can be achieved either: -by administering a continuous IV infusion -by giving a series of intermittent doses (either as IV bolus injections or orally or any other ROA): multiple-dosage regimen  Dosage regimen Desired Drug Level- Steady State Steady State : the concentration at which the same amount of drug entering the system is eliminated from the system Continuous IV infusion Use of CONTINUOUS INFUSION:  Drugs with a very short t1/2  When there is need for a long-term effect and multiple or frequently repeated doses are too inconvenient  Dosage regimen Desired Drug Level- Steady State Steady State:the concentration at which the same amount of drug entering the system is eliminated from the system MULTIPLE-DOSAGE regimen Drug is given once every t½ It takes 4 to 6 t½ for that drug to reach Cpss regardless of dose administerd Cpss min Cpss max  Dosage regimen The main pharmacokinetic parameters that must be considered in order to get a precise adjustment of the dosage and dosage intervals to the patient : » Clearance (CL) » Bioavailability (F) » Volume of distribution (Vd) » Half-Life (t1/2) REMEMBER Clearance (Cl): volume of plasma from which a drug Volume of distribution (Vd) is the is completely removed by the processes of apparent volume in which a drug is at excretion or metabolism per unit time (L/h, equilibrium in the body: mL/min).  Dosage regimen MULTIPLE-DOSAGE regimen Maintenance Dose (MD): is the dose administered every dosing interval = dosing interval F = Bioavailability Cpss = drug concentration in plasma steady state 0.693 is a mathematical constant that reflects first- order clearance (metabolism and excretion) It comes from the formula for half-life, where the half-life is inversely proportional to the elimination rate constant.  Dosage regimen MULTIPLE-DOSAGE regimen Loading Dose Use a LOADING DOSE: Loading Dose (LD): a higher dose to more more rapidly achieve effective blood levels (Cp). –drugs with a long t1/2 –when there is clinical need to rapidly achieve therapeutic levels LD MD MD LD = 2 x Maintenance Dose (MD) MD MD MD https://youtu.be/ppbKnLQ6_Es?si=JIjDpyP_Ce35pvGn