Clinical Pharmacokinetics

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Clinical pharmacokinetics Basic principles and its applications:

Clinical pharmacokinetics Basic principles and its applications SM Habibur Rahman Department of Pharmaceutics PSG College of Pharmacy

Clinical Pharmacokinetics:

Clinical Pharmacokinetics The science of the rate of movement of drugs within biological systems, as affected by the absorption, distribution, metabolism, and elimination of medications

Why Study Pharmacokinetics (PK) and Pharmacodynamics (PD)?:

Why Study Pharmacokinetics (PK) and Pharmacodynamics (PD)? Individualize patient drug therapy Monitor medications with a narrow therapeutic index Decrease the risk of adverse effects while maximizing pharmacologic response of medications Evaluate PK/PD as a diagnostic tool for underlying disease states

Organization of Workshop:

Organization of Workshop PK basic principles ADME factors Half life, Elimination Rate and AUC Models Hands on Experience

Slide 5:

Clinical (Human) Testing Preclinical testing In vitro PK/PD Animal PK/PD PK-guided Dose escalation Safety Assessment Dose response trials Efficacy Dosage selection Patient variables Population PK/PD characteristics in large efficacy trials PK/PD in Special populations Post-marketing surveillance Toxicity Animal testing Phase I Phase II Phase III


Significance Once the target enzyme or receptor is identified, medicinal chemists use a variety of empirical and semiempirical structure-activity relationships to modify the chemical structure of a compound to maximize its in vitro activity. However, good in vitro activity cannot be extrapolated to good in vivo activity unless a drug has good bioavailability and a desirable duration of action. Key role- Pharmacokinetics and drug metabolism -has led many drug companies to PK and drug properties as part of their screening processes in the selection of drug candidates.


Absorption Able to get medications into the patient’s body Drug characteristics that affect absorption: Molecular weight, ionization, solubility, & formulation Factors affecting drug absorption related to patients : Route of administration, gastric pH, contents of GI tract

Physicochemical properties:

Physicochemical properties


Transport Bickel (1994) have shown initial uptake of drugs into adipose tissue is related to their lipophilicity, the degree of adipose tissue storage does not correlate with their lipophilicity. Factors such as drug binding to plasma and tissue proteins also play a significant role in drug storage in adipose tissues.

Pgp transport:

Pgp transport P-glycoprotein, located on the apical surface of the endothelial cells of the brain capillaries toward the vascular lumen (Tew et al., 1993; Pardridge, 1991), is believed to be responsible for the poor BBB penetration of some highly lipophilic drugs. The poor BBB penetration of drugs may be related to the efflux function of p-glycoprotein.


Distribution Membrane permeability cross membranes to site of action Plasma protein binding bound drugs do not cross membranes malnutrition = albumin =  free drug Lipophilicity of drug lipophilic drugs accumulate in adipose tissue Volume of distribution


Metabolism Drugs and toxins are seen as foreign to patients bodies Drugs can undergo metabolism in the lungs, blood, and liver Body works to convert drugs to less active forms and increase water solubility to enhance elimination


Metabolism Liver - primary route of drug metabolism Liver may be used to convert pro-drugs (inactive) to an active state Types of reactions Phase I (Cytochrome P450 system) Phase II


Elimination Pulmonary = expired in the air Bile = excreted in feces enterohepatic circulation Renal glomerular filtration tubular reabsorption tubular secretion

Pharmacokinetic principles:

Pharmacokinetic principles Steady State: the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant serum drug level Drugs with short half-life reach steady state rapidly; drugs with long half-life take days to weeks to reach steady state

Steady State Pharmacokinetics:

Half-life = time required for serum plasma concentrations to decrease by one-half (50%) 4-5 half-lives to reach steady state Steady State Pharmacokinetics

Loading Doses:

Loading doses allow rapid achievement of therapeutic serum levels Same loading dose used regardless of metabolism/elimination dysfunction Loading Doses

Linear Pharmacokinetics:

Linear = rate of elimination is proportional to amount of drug present Dosage increases result in proportional increase in plasma drug levels Linear Pharmacokinetics

Nonlinear Pharmacokinetics:

Nonlinear = rate of elimination is constant regardless of amount of drug present Dosage increases saturate binding sites and result in non- proportional increase/decrease in drug levels Nonlinear Pharmacokinetics

Michaelis-Menten Kinetics:

Follows linear kinetics until enzymes become saturated Enzymes responsible for metabolism /elimination become saturated resulting in non-proportional increase in drug levels Michaelis-Menten Kinetics

Special Patient Populations:

Renal Disease: same hepatic metabolism, same/increased volume of distribution and prolonged elimination   dosing interval Hepatic Disease: same renal elimination, same/increased volume of distribution, slower rate of enzyme metabolism   dosage,  dosing interval Cystic Fibrosis Patients: increased metabolism/ elimination, and larger volume of distribution   dosage,  dosage interval Special Patient Populations

Pharmacologist role:

Pharmacologist role

Clinical Pharmacokinetics:

Clinical Pharmacokinetics Application of pharmacokinetic methods in drug therapy Optimized dosing strategies based on Patient disease state Patient specific consideration Influence of disease on drug disposition Not adequately studied Age, Gender, genetic & ethnic factors Pharmacokinetic difference Population approach TDM

Pharmacokinetics in drug development :

Pharmacokinetics in drug development Stage of development Initial PK studies in Humans (decision Phase) emphasis on safety and tolerance Number of subjects limited but intensive Descriptive evaluation of pharmacokinetics Look for first evidence of concentration-effect relationships Goal: First-Time Knowledge About PK of the Drug

Pharmacokinetics in drug development:

Pharmacokinetics in drug development Later PK Studies in Humans (Registration Phase) Emphases on Expansion and Depth of Knowledge Use number of subjects necessary to be definitive Define concentration-effect relationships Expand studies to wider population (gender, age, ethnic origin) Link data to target population (population PK) Goal: Broaden Understanding, Special Populations Therapeutic drug monitoring (Commercialization Phase)

Key Pharmacokinetic Descriptive Variables:

Key Pharmacokinetic Descriptive Variables Half-Life, T½ Clearance, CL Volume of Distribution, V Primary Pharmacokinetic Measurements – Concentration (mass per volume), Cp – Rate constants (time-1), ka ke k12 λ β – Amount of Drug (mass), A Ae Dose – Area Under the Curve (integration of time and mass per volume), AUC CL = V X 0.693 / T½

Why estimate pharmacokinetics:

Why estimate pharmacokinetics " Need to know" versus "Nice to know“ FDA and other regulatory hurdles Absolute Bioavailability - Dosage form design - Bioavailability problems (F=5% or 95%) - Intersubject Variability (absorption vs DME) Estimate Rate Processes – Distinguish rate process from rate constant

Why estimate pharmacokinetics:

Why estimate pharmacokinetics Characterize drug exposure – time duration – degree of exposure • Predict dosage requirements – how much, how often Assess changes in dosage requirement – special populations – drug interactions

Why estimate pharmacokinetics:

Why estimate pharmacokinetics • Pharmacokinetic – Pharmacodymamic Relationships – Concentration effect relationships – Use PK to provide concentration when PD measurement is performed – Establish safety margins and efficacy characteristics • Efficient and safe drug utilization

Interrelationship Key Pharmacokinetic factors:

Interrelationship Key Pharmacokinetic factors

Dynamic relationship Drug, Drug Product & pharmacologic effect:

Dynamic relationship Drug, Drug Product & pharmacologic effect Drug in systemic circulation Drug in Tissue Excretion and metabolism Pharmacologic or clinical effect Drug release and dissolution Biopharmaceutics & Pharmacokinetics

Biopharmaceutical factors – Dosage form:

Biopharmaceutical factors – Dosage form Protection of activity of drug within the drug product Release of drug Rate of dissolution Systemic absorption

Slide 33:

Effector tissue drug receptor binding Adipose Tissue Storage Peripheral tissues metabolism Lung Kidney Liver Drug Metabolism Bile Drug - Plasma Protein Complex DRUG DRUG Oral Ingestion BLOOD Volatile drug in expired air Drugs and metabolites in urine Drugs and metabolites in stools Intestinal reabsorption INTESTINE Drug Disposition- drug interaction in body

Hard drugs:

Hard drugs Nonmetabolizable drugs. Not only does it solve the problem of toxicity due to reactive intermediates or active metabolites, but the pharmacokinetics also are simplified because the drugs are excreted primarily through either the bile or kidney. Eg. ACE inhibitors and bisphosphonates

Soft drugs:

Soft drugs A soft drug is pharmacologically active as such, and it undergoes a predictable and controllable metabolism to nontoxic and inactive metabolites. The main concept of soft drug design is to avoid oxidative metabolism as much as possible and to use hydrolytic enzymes to achieve predictable and controllable drug metabolism. Eg. Atracurium

Drug Disposition:

Drug Disposition BCS – system BDDS Metabolism Solubility Permeability

BCS & its Application:

BCS & its Application The Biopharmaceutical Classification System (BCS) is based on solubility tests, correlating for drugs with their bioavailability in human body. It is widely used in design and development of innovation drugs New dosage forms (permeability amplifiers) In clinical pharmacology (drug-drug, drug-food interaction) Regulation agencies of several countries as the scientific approach, for testing of waiver on bioavailability.


PHARMACOKINETIC CHARACTERISTICS OF BIOAVAILABILITY Bioavailability is based on the physiological process of absorption, which include three stages Transfer a substance through apical plasma membrane inside cells Intracellular transport of substances followed by their possible metabolism Transfer of the transported and transformed substance from cells into blood or lymph

Characteristics of absorption & bioavailability processes:

Absorption Bioavailability Strictly corresponds to API dose Corresponds to an API dose and clearance value In some cases corresponds to a therapeutic effect Strictly corresponds to therapeutic effect Depends on permeability of corresponding bio membranes (enterocytes) Depends on both API entrance to blood circulation and elimination from it Characteristics of absorption & bioavailability processes

Slide 40:

BCS class The effect of food on bioavailability parameters Action mechanism I Reduction of rate but not duration Decrease of GIT evacuation 2 (Bases) Reduction of rate but not duration Decrease of solubility due to the increase of gastric pH 2 (Acids) Increase of the rate and possibly duration Increase of solubility due to the increase of gastric pH 3 The effect is not observed The effect of food on API absorption

Slide 41:

The ratio of solubility/permeability parameters in BCS classes

Measurement of Drug Concentration:

Measurement of Drug Concentration Milk ▪ Saliva Plasma ▪ Urine Sampling of biological specimens Invasive Method Sampling Blood, Spinal Fluid, synovial fluid, Tissue biopsy Non invasive Method Sampling urine, saliva, feces, expired air

Pharmacokinetic Model:

Pharmacokinetic Model Quantity study of various kinetic process of drug disposition in the body Biological nature of drug distribution and disposition is complex and drug events often happen simultaneously

Steps in modeling:

Steps in modeling Model development Model characterization, i.e. methods to describe how consistent the model is with biology; strengths and limitations of available model and data, such as sensitivity analyses, Model documentation, Model evaluation, i.e. independent review

Basic pharmacokinetic model:

Basic pharmacokinetic model Various mathematical model can devised to simulate the rate process of drug ADE development of equations useful in describing drug concentration in the body as a function of time Predictive capability of model lies in the proper selection & development of mathematical function (s) that parameterize the essential factors governing the kinetic process

Variables in model:

Variables in model Key parameters in a process is commonly estimated by fitting the model to the experimental data Pharmacokinetic function relates an independent variable (time) to a dependent variable (response) Types of model Empirical or Physiological Empirical models are practical but not very useful in explaining the mechanism of the actual process of ADME in the body is not possible

Pictorial and Graphical Understanding of the Shapes of Concentration Time Profiles Mathematical Models that describe and track these time profiles :

Pictorial and Graphical Understanding of the Shapes of Concentration Time Profiles Mathematical Models that describe and track these time profiles Pharmacokinetics

Concentration profile depends - On:

Concentration profile depends - On Route of Administration – Intravenous (bolus, infusion) – Extravascular (oral, IM, SQ) – Specialized Disposition of the drug (ADME) – distribution – metabolism – elimination

Pharmacokinetic Variability:

Pharmacokinetic Variability

Compartment models:

Compartment models

Compartment Models:

Compartment Models Well stirred model Based on assumption using linear differential equation Provides simple way of grouping all the tissues into one or more compartments Types Mammilary Model and catenary model

IV Bolus One Compartment:

IV Bolus One Compartment

IV Bolus Two Compartment:

IV Bolus Two Compartment

Oral One Compartment:

Oral One Compartment

Oral One Compartment:

Oral One Compartment

Compartmental Model:

Compartmental Model

Oral Two Compartment:

Oral Two Compartment

Oral Two Compartment:

Oral Two Compartment

One compartment open model IV Injection:

One compartment open model IV Injection Central compartment Ke Central compartment K Ka One compartment open model with first order absorption compartment model

Two compartment open model IV Injection:

Two compartment open model IV Injection Two compartment open model with first order absorption Multi compartment model Central compartment K12 Tissue compartment K21 k Central compartment K12 Tissue compartment K21 k Central compartment K12 Tissue compartment K21 k ka

Functions of Drawing Models:

Functions of Drawing Models To write differential equations to describe drug concentration changes in each compartment Visual representation of rate process Shows how many pharmacokinetic constants are necessary to describe the process adequately

Deficiencies of compartmental analysis:

Deficiencies of compartmental analysis Lack of meaningful physiological basis for derived parameters Lack of rigorous criteria to determine No of compartments necessary to describe disposition. Lack of ability to elucidate organ specific elimination Inability to relate derived parameters to quantifiable physiological parameters Inability to predict impact of pathophysiology Inability to provide insight into mechanism of drug-drug and drug-nutrient interactions Highly sensitive to sampling frequency

Physiological compartment Model:

Physiological compartment Model Blood flow or perfusion model Describes the data with the consideration that blood flow is responsible for distributing drug to various part of body Uptake of drug into organs is determined by the binding of drug in these tissues Tissue volume describes the drug concentration


PBPK Experimentally difficult In spite of this limitation the PBPK model does describe much better insight into hoe physiologic factor may change drug distribution from one animal species to another No data fitting is required Drug concentration is predicted by organ tissue size, blood flow & tissue – blood ratio (partition) The above facts may vary due to Pathophysiologic condition

Physiologic pharmacokinetic model (Flow Model):

Physiologic pharmacokinetic model (Flow Model) From: Rowland M, Tozer TN. Clinical Pharmacokinetics – Concepts and Applications , 3 rd edition, Williams and Wilkins, 1995, p. 12.

Models in Toxicokinetics:

Models in Toxicokinetics There is no single method or model that can extrapolate the toxicity from animals to humans (Boxenbaum et al., 1988), the species differences in toxicity often can be explained by pharmacokinetic or pharmacodynamic effects of drugs.

Slide 67:

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