Pharmacokinetics and ADME Principles

Pharmacokinetics: The Principles of ADME

Introduction to Pharmacokinetics (PK) and ADME

Pharmacokinetics (PK) studies the movement of drugs within the body, focusing on Absorption, Distribution, Metabolism, and Excretion (ADME). Understanding these processes is crucial for determining appropriate dosages and treatment regimens.

• Absorption: How the drug enters the body. Factors such as the route of administration, drug formulation, and physiological conditions at the absorption site influence this process.

• Distribution: Where the drug goes within the body. This involves the movement of the drug from the bloodstream to various tissues and organs. Distribution can be affected by factors like blood flow, tissue binding, and the drug's physicochemical properties.

• Metabolism: How the drug is broken down, primarily in the liver. Metabolism, often mediated by enzymes like cytochrome P450s, converts the drug into metabolites that can be more easily excreted. The liver is the primary site for drug metabolism, but it can also occur in other organs and tissues.

• Excretion: How the drug leaves the body. The kidneys are the primary organs for drug excretion, eliminating drugs and their metabolites in the urine. Other routes of excretion include the bile (via the liver), feces, sweat, and exhaled air.

Transporters play a crucial role in these processes, facilitating the movement of drugs across cell membranes. These transporters can be influx transporters, which promote drug uptake into cells, or efflux transporters, which pump drugs out of cells.

Thomas Dorlo's Background

Thomas Dorlo's research focuses on clinical pharmacology, PK, and PKPD in global health, specifically neglected tropical diseases such as malaria, leishmaniasis, mycetoma, and cryptococcal meningitis. His work involves optimizing treatment in special populations like pediatrics and pregnant women, who may have altered PK profiles due to physiological changes.

Pharmacokinetics (PK) vs. Pharmacodynamics (PD)

Pharmacokinetics (PK) describes what the body does to the drug. This involves ADME processes, determining the drug's concentration in different body compartments over time.

Pharmacodynamics (PD) describes what the drug does to the body. This involves the drug's mechanism of action and its effects on target tissues and organs.

The relationship between dose, plasma concentration, and effect (including side effects) is central to PK/PD. Understanding this relationship is essential for optimizing drug therapy, ensuring that the drug reaches its target site at an effective concentration without causing undue toxicity.

Basic Processes of Pharmacokinetics

Drug Administration Routes:

• Oral Administration:

  • Drug is ingested and travels to the stomach, then the small intestine, where absorption primarily occurs. The presence of food, gastric emptying rate, and intestinal motility can affect drug absorption.

  • Can also be absorbed in the large intestine, although to a lesser extent compared to the small intestine.

  • Unabsorbed drug is excreted in feces. Factors such as the drug's solubility, stability in the GI tract, and interactions with gut bacteria can influence the amount of drug excreted in the feces.

• Intravenous (IV) Administration:

  • Drug is directly introduced into the bloodstream, bypassing absorption. This results in rapid and complete bioavailability, making it a preferred route for drugs requiring precise control over plasma concentrations.

ADME Processes:

• Absorption: Drug moves from the administration site into the bloodstream. The rate and extent of absorption depend on factors such as the drug's physicochemical properties, the route of administration, and physiological conditions at the absorption site.

• Distribution: Drug distributes from the bloodstream to various tissues. Distribution can be affected by factors like blood flow, tissue binding, and the drug's physicochemical properties. Some drugs may accumulate in specific tissues, leading to higher concentrations in those tissues compared to the plasma.

• Metabolism: Drug is metabolized primarily in the liver. The liver contains a variety of enzymes, such as cytochrome P450s, that catalyze the metabolism of drugs. Metabolism can result in the formation of active or inactive metabolites, which can have different pharmacological effects compared to the parent drug.

• Excretion: Drug and its metabolites are excreted via the kidneys into the urine. The kidneys filter drugs and metabolites from the blood, eliminating them in the urine. Factors such as kidney function, urine pH, and drug interactions can affect the rate and extent of renal excretion.

Basic PK Model

• Intravascular Administration: Directly into the circulation (typically IV).

  • Bolus Injection: Rapid, almost instantaneous administration (time ≈ 0). This results in a sharp peak in plasma concentration, followed by a gradual decline as the drug is distributed and eliminated.

  • Infusion: Administration over a longer period. This provides a more sustained plasma concentration compared to bolus injection, which can be advantageous for drugs with short half-lives.

• Extravascular Administration: Not directly into the circulation (e.g., oral). The drug must first be absorbed into the bloodstream before it can be distributed to its target site.

• Important parameters: ${C<em>{max}}$ (maximum concentration) and ${t</em>{max}}$ (time to maximum concentration).

Example: Caffeine Dose Titration

Caffeine dose titration illustrates PK/PD principles. The concentration of caffeine in the body changes over time after consumption. Understanding the PK of caffeine is essential for optimizing its effects, such as increasing alertness and reducing fatigue.

Importance of ADME and PK

Having an active compound is insufficient. A drug must:

1. Reach its effect site in the body at an active concentration to target the pathogen, receptors, or enzymes. The concentration of the drug at its target site must be high enough to exert its desired pharmacological effect.

2. Disappear from the effect site when its action is no longer needed. Prolonged exposure to a drug can lead to adverse effects, so it's important for the drug to be eliminated from the body once its therapeutic effect has been achieved.

Key Questions Addressed by ADME/PK:

• How much drug is needed? Determining the appropriate dose is crucial for achieving the desired therapeutic effect without causing undue toxicity. PK/PD modeling can help predict the dose required to achieve a target plasma concentration or effect.

• How often should the drug be administered? The frequency of drug administration depends on the drug's half-life and the desired duration of effect. Drugs with short half-lives may need to be administered more frequently to maintain therapeutic concentrations, while drugs with long half-lives can be administered less frequently.

• Is the same dosage regimen suitable for all patients? Factors such as age, weight, sex, genetics, and disease state can affect a patient's PK profile. Therefore, dosage adjustments may be necessary to ensure that the drug is safe and effective for all patients.

ADME in Drug Development

Poor ADME properties are a major cause of drug development failure. Optimizing ADME properties is essential for developing drugs that are safe, effective, and convenient to administer. Predicting the Human Efficacious Dose (HED) is crucial. This involves using preclinical data, such as animal studies, to estimate the dose that will be effective in humans. PK/PD modeling can also be used to predict the HED.

PK Processes and Parameters

Movement of the Drug:

• Absorption: From outside the body into the circulation. This process can be affected by factors such as the drug's physicochemical properties, the route of administration, and physiological conditions at the absorption site.

• Distribution: Within the body. This involves the movement of the drug from the bloodstream to various tissues and organs. Distribution can be affected by factors like blood flow, tissue binding, and the drug's physicochemical properties.

• Elimination: From the circulation out of the body. This involves both metabolism and excretion, which remove the drug from the body and prevent it from accumulating to toxic levels.

Parameters:

• Bioavailability (F): The fraction of the administered dose that reaches the systemic circulation. Bioavailability is affected by factors such as absorption, first-pass metabolism, and drug formulation.

• Volume of Distribution (Vd): The apparent volume in which the drug is distributed. Vd is a measure of how widely a drug distributes throughout the body. Drugs with high Vd tend to distribute extensively into tissues, while drugs with low Vd tend to remain in the bloodstream.

• Clearance (CL): The volume of plasma cleared of the drug per unit time. Clearance is a measure of how efficiently the body eliminates a drug. Clearance is affected by factors such as liver and kidney function, drug interactions, and genetics.

Elimination

Importance:

Elimination is a crucial property of a drug. It determines how long the drug will remain in the body and how frequently it needs to be administered.

Definition:

Irreversible loss of drug from the site of measurement. This includes both metabolism and excretion, which remove the drug from the body and prevent it from exerting its effects indefinitely.

Mechanisms/Pathways:

• Excretion:

  • Renal (in the urine). The kidneys filter drugs and metabolites from the blood, eliminating them in the urine. Factors such as kidney function, urine pH, and drug interactions can affect the rate and extent of renal excretion.

  • Biliary (in the bile). Some drugs and metabolites are excreted into the bile, which is produced by the liver and stored in the gallbladder. The bile is then released into the small intestine, where the drugs and metabolites can be eliminated in the feces.

  • Pulmonary (in exhaled air). Some volatile drugs and metabolites can be excreted in exhaled air. This is a minor route of excretion for most drugs.

• Metabolism:

  • Occurs in several organs, requiring subsequent excretion. The liver is the primary site for drug metabolism, but it can also occur in other organs and tissues. Metabolism converts drugs into metabolites that can be more easily excreted.

Physicochemical Properties and Elimination

• Hydrophilic (polar) drugs: Primarily excreted unchanged in the urine. Examples include benzylpenicillin and tobramycin. These drugs are readily soluble in water and can be easily filtered by the kidneys.

• Lipophilic (non-polar) drugs: Need to be metabolized into more hydrophilic compounds before excretion. Example: Nevirapine (NVP). These drugs are not readily soluble in water and need to be converted into more polar metabolites before they can be excreted in the urine.

Multiple Elimination Mechanisms:

Many drugs are eliminated through several mechanisms. For example, Linezolid is eliminated through both renal excretion (~40%) and metabolism in the liver. This means that both kidney and liver function can affect the elimination of linezolid.

Parameter: Clearance (CL)

The volume of plasma (or blood) cleared of drug per unit time (e.g., per minute).

$CL = \frac{Dose}{AUC}$

Determination of Clearance

Clearance is determined by administering the drug intravenously and measuring the plasma concentration over time. This allows for the calculation of the area under the concentration-time curve (AUC), which is needed to determine clearance.

• Concentration changes with time. The plasma concentration of a drug changes over time as it is distributed, metabolized, and excreted.

• CL is constant. Clearance is a constant value that reflects the efficiency of drug elimination.

• Rate of elimination = CL × Concentration (changes with time). The rate of drug elimination is proportional to the plasma concentration.

• $AUC$ = Area Under the Concentration-time curve

• $C<br>ar{max}$ = Maximum plasma concentration

• $t<em>{max}$ = Time of ${C</em>{max}}$

Types of Clearance

• Total Clearance = ${CL<em>R + CL</em>H}$

  • ${CL_R}$ = Renal clearance.

  • ${CL_H}$ = Hepatic clearance.

Renal Clearance:

Collect urine to determine the fraction of the drug excreted in the urine. This involves measuring the amount of drug in the urine over a specific time period and dividing it by the AUC to determine renal clearance.

Excretion: The Kidney

Nephron Processes:

• Glomerulus: Filtration. The glomerulus filters blood, allowing small molecules like drugs and metabolites to pass into the renal tubules.

• Proximal Tubule: Secretion and reabsorption. The proximal tubule secretes drugs and metabolites from the blood into the renal tubules and reabsorbs water and other essential substances back into the blood.

• Entire Tubule: Reabsorption. The entire renal tubule is involved in the reabsorption of water and other essential substances back into the blood. This process can be affected by factors such as urine pH and drug interactions.

$CL_R = Filtration + Secretion - Reabsorption$

Estimating Kidney Function

• Cockcroft-Gault Formula:

${Creatinine\ Clearance\ (CrCL)} \approx \frac{(140 - Age) \times Weight}{Serum\ Creatinine\ (\mu M)} \times X$

Where X = 1.04 (women) or 1.23 (men).

• Valid for adults 20-100 years old.

• Estimates Glomerular Filtration Rate (GFR). GFR is a measure of how well the kidneys are filtering blood.

• Normal GFR in young adults: 120-125 mL/min. GFR declines with age and can be affected by factors such as disease and drug interactions.

Impaired Kidney Function

Example: Ceftazidime Clearance

${CL<br>ar{tot} = 1.07 \times CrCL + 6.02}$

• ${CL_R}$ represents renal clearance.

• ${CL_H}$ represents hepatic clearance.

For patients with creatinine clearance ≤ 50 mL/min, the dose should be reduced to compensate for slower excretion. This is because patients with impaired kidney function have a reduced ability to eliminate drugs renally, which can lead to drug accumulation and toxicity.

Hepatic Clearance (CLH)

Liver Enzyme Activity

• CYP3A4 is the most common drug-metabolizing enzyme. It is responsible for the metabolism of a large number of drugs.

• Significant variation exists between patients (28-fold in the liver, >20-fold in the small intestine). This variation can be due to factors such as genetics, age, disease, and drug interactions.

Drug-Metabolizing Enzymes with Polymorphism:

• >1% of the population has a variant, resulting in a missing or dysfunctional gene coding for the enzyme.

  • CYP2C9

  • CYP2C19

  • CYP2D6

Polymorphism in N-acetyltransferase (NAT)

Isoniazid (INH) is metabolized by NAT to Acetyl-INH.

• A high ratio indicates a fast metabolizer. Fast metabolizers may require higher doses of isoniazid to achieve therapeutic concentrations.

• Isoniazid is used to treat Tuberculosis. The metabolism of isoniazid is important because it can affect the drug's efficacy and toxicity.

Drug-Drug Interactions

Induction

Rifampicin induces CYP3A4, increasing the metabolism of drugs like Lopinavir. This can lead to decreased plasma concentrations of lopinavir and reduced efficacy.

Inhibits CYP3A4: Ritonavir (against HIV).

Induces CYP3A4: Rifampicin (against Tuberculosis).

Metabolized by CYP3A4, low F: Lopinavir (against HIV).

Inhibition

Ketoconazole is a strong inhibitor of CYP3A4, which can enhance the efficacy and side effects of drugs metabolized by CYP3A4. This is because inhibition of CYP3A4 can lead to increased plasma concentrations of these drugs.

• Example: Ketoconazole increases the AUC of midazolam 16-fold. This can lead to increased sedation and respiratory depression.

Distribution

Definition

"The process of reversible transfer of drug to and from the site of measurement."

Drug molecules are distributed between the circulation (plasma) and the tissues until equilibrium is attained. This process is influenced by factors such as blood flow, tissue binding, and the drug's physicochemical properties.

Parameter: Volume of Distribution (V or Vd)

Volume of plasma in which the drug appears to be distributed (or "diluted") in the body. Vd is a measure of how widely a drug distributes throughout the body.

$V = \frac{A<em>b}{C</em>{pl}}$

Where:

• ${A_b}$ = Amount of drug in the body

• ${C<br>ar{pl}}$ = Plasma concentration of drug (Conc)

A low ${C<br>ar{pl}}$ can indicate a high V, meaning a large fraction of the drug is in the tissues. This suggests that the drug is widely distributed throughout the body and is not primarily confined to the bloodstream.

Factors Affecting Distribution

• Passive transport: Driven by concentration gradient. Drugs move from areas of high concentration to areas of low concentration.

• Active transport: Requires a biological carrier/transporter. This process can be saturated, meaning that there is a maximum rate at which drugs can be transported.

• Lipophilic drugs distribute to body fat. Lipophilic drugs tend to accumulate in body fat due to their high affinity for lipids.

• Hydrophilic drugs distribute to body water. Hydrophilic drugs tend to remain in body water due to their high affinity for water.

• Drugs with high affinity to proteins distribute as dictated by protein location. Plasma proteins, such as albumin, can bind to drugs and affect their distribution throughout the body.

Distribution within the Blood

• Freely dissolved (unbound) in the plasma water

  • Unbound concentration = ${C_u}$

• Bound to proteins in the plasma

  • Bound concentration = ${C_b}$

Unbound (free) fraction (fu) in plasma:

$f<em>u = \frac{C</em>u}{C<em>u + C</em>b}$

Free (unbound) drug molecules can pass membranes, bind to receptors, and be eliminated. Only the unbound fraction of a drug can exert its pharmacological effects.

Half-Life (${t</h5><p>ar{1/2}}$)

The time taken for the concentration to reduce to half of its initial value. It remains constant for a drug following first-order kinetics. Half-life is an important parameter that determines how frequently a drug needs to be administered to maintain therapeutic concentrations.