Although drug discovery is primarilydesigned to find compounds with desiredefficacy, the choice from among multiplecompounds potentially offering efficacyoften comes down to those with the mostfavorable pharmacokinetics(Welling and Tse, 1995).
Pharmacokinetics is defined as the quantitative analysis of the processes of drug absorption, distribution, and elimination that determine the time course of drug action.
ADME Scheme Absorption, Distribution, Metabolism and Excretion LADME Inclusion of new term Liberation Liberation is the process of release of drug from the formulation
Where is it measured? For in-vitro data In phase I studies for any new drug During therapeutics to adjust dose For toxicity studies and during poisoning
What to measure? Dose Bio-availability Clearance Volume of distribution Half-life Area under curve Steady state concentration
How to measure? Pharmacokinetic models ▪ Non compartmental ▪ Compartmental ▪ Physiological ▪ Bioanalytical methods Equipment used ▪ High pressure liquid chromatography ▪ Gas liquid chromatography ▪ Fluorescence polarizing immunoassay
CTissue indeterminable directly Indirect analysis using Cp vs Time data Several inter-connected compartments mathematical entities Each compartment has pharmaco-kinetically similar tissues In graph, no. of models shown by lines with different slopes Drug administered to & eliminated from central compartment 9
Non-compartmental Models Offers little insight into the rate or processes involved in drug distribution Mainly uses area under curve parameters Compartment Models Catenary and mammalian models Kinetic models to describe and predict the concentration-time curve Simplest PK compartmental model one- compartmental PK model with IV bolus administration and first-order elimination
Body assumed to be one homogenous compartment Instantaneous distribution Elimination starts simultaneously Only one straight line in ln(Cp) vs time graph ke = Slope ln(C0) = y-intercept C0 = exp(y-intercept) 12
Absorption + Elimination during upstroke Terminal straight line portion Elimination) 13
One Central (1) & One Peripheral (2) compartment 14
Slower distribution Ct = A * e-αt + B * e-βt α = Distribution + Elimination β = Elimination 15
One Central (1) + Two peripheral (2, 3) Compartments Compartment 2 & 3 not interconnected 18
Achieved by mathematically transcribing anatomical, physiological, physical, and chemical descriptions of the phenomena involved in the complex ADME processes Used to extrapolate dose, metabolism and excretion of drugs prior to human exposure
For single-dose study of an immediate release product: For at least three elimination half-lives (cover >80% of AUC) • Absorption phase : 3-4 points • Around Tmax : 3-4 points • During elimination : 4 points Intervals not longer than the half-life of the drug Truncated AUC undesirable except in entero-hepatic recycling (elimination half life difficult to calculate) If urine tested, collect it for at least 7 half-lives
Plasma, serum or blood? Collect after steady state of drug is achieved (5-6 t½) Trough or Peak concentration? Immediate sampling in toxicity Other samples (Saliva)19/11/2008 Dept.of Pharmacology Grant Medical College
Most cases: Active drug substance Active / Inactive metabolite maybe measured in cases of: Concentration of drug too low Limitation of analytical method Unstable drug(s) Drug(s) with very short half life Pro-drugs Measurement of individual enantiomers is sometimes recommended for safety / efficacy purposes
Quantity of a drug or other agent administered for therapeutic purposes Calculating drug dosages for humans based on the doses used in animal studies From weight (eg. mg/kg) initial surface area (eg. mg/m2) animal LD50 = Median lethal dose studies NOEL = No Observed Effect Level and human NOAEL = No Observed Adverse Effect Level extrapolati TWA = Time Weighted Average on
Absorption : passage of drug from the site of administration into the blood stream. Bioavailability : is defined as the amount or percentage of drug that is absorbed from a given dosage form and reaches the systemic circulation following non-vascular administration 25
Parameters for assessing bioavailability T max : time to peak plasma concentration depends on rate of absorption C max : peak plasma concentration AUC (area under the curve) (∫C dt): is a P measure of the total amount of the unaltered drug that reaches systemic circulation 26
40 A Cmax 30plasma Tmaxconc.20(μg/ml) AUC 10 B 0 1 2 3 4 Time (hrs) 27
• AUC 0-t • AUC 0-∞For the segment from Cp2 to Cp3: AUC2-3 = Cp2 + Cp3 x (t3 - t2) 2AUC 0-∞ = AUC 0-t + Clast / k
Describes the fraction of an administered dose of unchanged drug that reaches the systemic circulation By definition, when a medication is administered intravenously, its bioavailability is 100%
“The ratio of areas beneath the blood level-time curvesafter oral administration to that following intravenous administration ofthe same dose is a measure of the absorption of the drug administered” Nimodipine AUC Oral : 1.17 % Nasal : 67.4 % www.chinaphar.com
Apparent volume of distribution is thetheoretical volume that would have to beavailable for drug to disperse in if theconcentration everywhere in the body were thesame as that in the plasma or serum, the placewhere drug concentration sampling generallyoccurs.
VD is a theoretical Volume and determines the loading dose Clearance is a constant and determines the maintenance dose CL = kVD CL and VD are independent variables k is a dependent variable
Volume of Distribution, Clearance and Elimination Rate ConstantV Volume 100 L Clearance 10 L/hr
Volume of Distribution, Clearance and Elimination Rate ConstantV V2 Cardiac and Skeletal Muscle Volume 100 L (Vi) Clearance 10 L/hr
V2 Cardiac andSkeletal Muscle V Volume 100 L (Vi) Clearance 10 L/hr Volume of Distribution = Dose_______ Plasma Concentration
V2 Cardiac andSkeletal Muscle V Volume 100 L (Vi) Clearance 10 L/hr Clearance =Volume of blood cleared of drug per unit time
V2 Cardiac and Skeletal Muscle V Volume 100 L (Vi) Clearance 10 L/hrClearance = 10 L/hrVolume of Distribution = 100 LWhat is the Elimination Rate Constant (k) ?
CL = kV k = 10 Lhr -1 = 0.1 hr -1 100 L10 % of the “Volume” is cleared (of drug) per hourk = Fraction of drug in the body removed per hour
CL = kVIf V increases then k must decrease asCL is constant
An abstract concept Gives information on HOW the drug is distributed in the body Used to calculate a loading dose
What Is the is the loading dose required for drug A if; Target concentration is 10 mg/L VD is 0.75 L/kg Patients weight is 75 kg
Dose = Target Concentration x VD VD = 0.75 L/kg x 75 kg = 56.25 L Target Conc. = 10 mg/L Dose = 10 mg/L x 56.25 L = 565 mg This would probably be rounded to 560 or even 500 mg.
Ability of organs of elimination (e.g. kidney, liver to “clear” drug from the bloodstream Volume of fluid which is completely cleared of drug per unit time Units are in L/hr or L/hr/kg Pharmacokinetic term used in determination of maintenance doses
Major Factors Drug delivery α Q Extraction Ratio (ER) = (Cin – Cout) / Cin 46
Total Body Clearance ClTotal = ClHepatic + ClRenal + ClOthers ClTotal = aVd * Ke ClTotal = Dose / AUC 47
Maintenance Dose = CL x CpSSav CpSSav is the target average steady state drug concentration The units of CL are in L/hr or L/hr/kg Maintenance dose will be in mg/hr so for total daily dose will need multiplying by 24
What maintenance dose is required for drug A if; Target average SS concentration is 10 mg/L CL of drug A is 0.015 L/kg/hr Patient weighs 75 kg
Maintenance Dose = CL x CpSSav CL = 0.015 L/hr/kg x 75 = 1.125 L/hr Dose = 1.125 L/hr x 10 mg/L = 11.25 mg/hr So will need 11.25 x 24 mg per day = 270 mg
Half-life is the time taken for the drug concentration to fall to half its original value The elimination rate constant (k) is the fraction of drug in the body which is removed per unit time.
Biological half-life Time it takes for the blood plasma concentration of a substance to halve ("plasma half-life") its steady-state First-order elimination Proportional to the initial concentration of the drug A0 and inversely proportional to the zero-order rate constant k0 Logarithmic process Fall in plasma concentration: Ct is concentration after time t C0 is the initial concentration (t=0) k is the elimination rate constant
The relationship between the elimination rate constant and half-life is given by the following equation: Half-life is determined by clearance (CL) and volume of distribution (VD) In clinical practice, this means that it takes 4 to 5 times the half- life for a drugs serum concentration to reach steady state after regular dosing is started, stopped, or the dose changed.
Drug ConcentrationC1 Exponential decay dC/dt C = -k.CC2 Time
Log Concn. C0C0/2 t1/2 t1/2 t1/2 Time Time to eliminate ~ 4 t1/2
Steady-state occurs after a drug has been given for approximately five elimination half-lives. At steady-state the rate of drug administration equals the rate of elimination and plasma concentration - time curves found after each dose should be approximately superimposable.
Accumulation to Steady State 100 mg given every half-life 194 … 200 187.5 175 150 100 97 … 100 87.5 94 75 50
Rate in = Rate Out Reached in 4 – 5 half-lives (linear kinetics) Important when interpreting drug concentrations in TDM or assessing clinical response
Develops ADMET modeling and simulation software GastroPlusTM predicts the absorption, pharmacokinetics, for drugs administered orally. ADMET Predictor TM Estimate kinetics based on chemical structure ClassPharmerTM Estimate screening data analysis DDDPlusTM simulates the in vitro disintegration and dissolution of solid dosage forms
Metabolism Human liver microsomes Human intestinal microsomes Human kidney microsomes Human hepatocytes Recombinant CYP and UGT enzymes PK profiles Prediction of volume of distribution based on lipophilicity, ionisation, protein binding and tissue composition Drug – drug interactions Competitive enzyme inhibition (including auto-inhibition) Enzyme-induction (including auto-induction)
Continuous line of heterogeneous human epithelial colorectal adenocarcinoma cells When cultured under specific conditions the cells become differentiated and polarized such that their phenotype, resembles the enterocytes lining the small intestine Used as a model to estimate absorption of drugs at pre- clinical stage of development Other cell cultures with expression of transporters and enzymes are used in calculation of PK parameters E.g.: P-glycoprotein (ABCB1) and BCRP (ABCG2)
HPLCColorimeterSpectrophotometerSpectrophotofluorimeterGLCFlame photometry 19/11/2008 Dept.of Pharmacology Grant Medical College
High ER (Liver, Blood, Lungs) indicates high PRE-SYSTEMIC ELIMINATION (Lidocaine in liver) Maximal clearance = Blood flow 69