Understanding Absorption Processes, BCS Class, and Their Impact on Pharmacokinetics

Introduction

Pharmacokinetics is the study of how drugs move through the body, including their absorption, distribution, metabolism, and excretion. Among these processes, absorption plays a crucial role in determining the onset, intensity, and duration of a drug’s effects. In this educational blog, we will explore the intricacies of absorption processes, the Biopharmaceutics Classification System (BCS), and how they collectively impact pharmacokinetics.

Absorption: A Gateway to Therapeutic Action

Absorption refers to the movement of a drug from its site of administration into the bloodstream. It is a vital step as it determines the bioavailability of a drug, which is the fraction of the administered dose that reaches systemic circulation unchanged. Understanding the factors that influence absorption is essential for optimizing drug delivery and achieving desired therapeutic outcomes.

Factors Affecting Drug Absorption

1. Route of Administration:
The route by which a drug is administered significantly influences its absorption. Common routes include oral (through the gastrointestinal tract), intravenous (directly into the bloodstream), intramuscular (into the muscle), subcutaneous (under the skin), and topical (applied to the skin). Each route has unique characteristics that impact the rate and extent of absorption.

2. Physicochemical Properties:
The physicochemical properties of a drug, such as molecular weight, solubility, and lipid solubility, play a crucial role in its absorption. Lipophilic (fat-soluble) drugs tend to be absorbed more rapidly than hydrophilic (water-soluble) drugs.

3. Drug Formulation:
The formulation of a drug, including its dosage form and presence of excipients, can affect its absorption. Factors like particle size, pH, and coating can influence drug dissolution and subsequent absorption.

4. Blood Flow:
Blood flow to the site of drug administration determines the rate of absorption. Areas with abundant blood supply, such as the gastrointestinal tract, allow for faster drug absorption compared to areas with limited blood flow.

5. First-Pass Metabolism:
Drugs absorbed through the gastrointestinal tract undergo first-pass metabolism in the liver before reaching systemic circulation. This metabolism can significantly reduce the amount of active drug available, known as the first-pass effect.

Biopharmaceutics Classification System (BCS)

The Biopharmaceutics Classification System (BCS) is a scientific framework that classifies drugs based on their solubility and permeability characteristics. The BCS provides valuable insights into the behavior of drugs in the gastrointestinal tract and their potential for absorption.

The BCS categorizes drugs into four classes (Class I, II, III, and IV) based on their solubility and permeability properties. Let’s explore each class and its implications on drug absorption:

1. Class I:
Class I drugs exhibit high solubility and high permeability. These drugs readily dissolve in the gastrointestinal fluids and easily permeate across the intestinal membranes. They generally exhibit predictable and consistent pharmacokinetics. Examples of Class I drugs include aspirin, acetaminophen, and metoprolol.

2. Class II:
Class II drugs have high permeability but low solubility. Although they can permeate across the intestinal membranes efficiently, their limited solubility can hinder their dissolution in the gastrointestinal fluids. Consequently, the rate and extent of absorption may be variable. Formulation strategies that enhance the solubility of Class II drugs, such as the use of solubilizing agents or particle size reduction techniques, can improve their absorption. Examples of Class II drugs include ketoconazole and ibuprofen.

3. Class III:
Class III drugs have high solubility but low permeability. These drugs readily dissolve

in the gastrointestinal fluids but face challenges in effectively crossing the intestinal membranes. Consequently, their absorption may be limited and variable. Strategies such as prodrug formation or the use of permeation enhancers can be employed to improve their permeability. Examples of Class III drugs include atenolol and cimetidine.

4. Class IV:
Class IV drugs have low solubility and low permeability. These drugs have significant challenges in both dissolution and permeation. They often exhibit poor and inconsistent absorption. Enhancing the solubility and permeability of Class IV drugs is crucial for improving their bioavailability. Examples of Class IV drugs include danazol and griseofulvin.

Impact of Absorption on Pharmacokinetics

1. Onset and Duration of Action:
The rate of drug absorption influences how quickly the drug reaches therapeutic levels in the bloodstream, thereby affecting the onset of action. Additionally, the duration of action depends on the rate at which the drug is absorbed, metabolized, and eliminated from the body.

2. Bioavailability:
The extent of drug absorption determines its bioavailability, which directly affects the dose required to achieve the desired therapeutic effect. High bioavailability indicates efficient absorption, while low bioavailability may necessitate higher doses or alternative routes of administration.

3. Variability in Drug Response:
Variations in drug absorption between individuals can contribute to variability in drug response. Factors such as genetic differences, food intake, disease states, and concomitant drug use can influence drug absorption and lead to variability in pharmacokinetics.

Conclusion

Understanding the absorption processes, including factors affecting drug absorption and the classification of drugs according to the Biopharmaceutics Classification System (BCS), is crucial for optimizing drug therapy. The BCS provides valuable insights into the solubility and permeability characteristics of drugs, guiding formulation strategies for optimal drug delivery. By comprehending these processes, healthcare professionals can make informed decisions regarding dosage, dosing intervals, and route of administration to achieve desired therapeutic outcomes while minimizing the risk of adverse effects.

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Oral Absorption

Following extravascular drug administration, the drug needs to be absorbed into the systemic circulation.

Following absorption from the gastrointestinal (GI) tract, the hepatic portal vein passes the drug through the liver, where it undergoes first pass metabolism. For some drugs a large portion of the dose is metabolized by first pass metabolism before the drug gets the chance to reach the systemic circulation.

Following an oral dose, not all the dose administered necessarily reaches the systemic circulation. The fraction of drug which reaches the systemic circulation is termed it’s oral bioavailability.

Therefore, in order to determine the absolute bioavailability, we compare systemic drug exposure, based on determining the area under a concentration vs time profile from the extravascular route to intravenous.

 

F = bioavailability; AUCpo = area under the concentration-time profile following oral dosing; AUCIV = area under the concentration-time profile following intravenous dosing

 

Many factors affect drug absorption, some of those may be related to the physicochemical properties of the drug itself. How soluble is the drug and will solubility across the different pH range of the GI tract limit available drug for absorption? What part of the GI tract is the drug absorbed? For many drugs, the small intestine is the primary site of absorption due to it’s high surface area and active transporters. Is the drug permeable through membranes and able to be taken up readily? Other factors in a clinical setting could include food or drug interactions. Food can delay gastric emptying, stimulate bile flow, change gastrointestinal (GI) pH, increase splanchnic blood flow, change luminal metabolism of a drug substance, and physically or chemically interact with a dosage form or a drug substance. Does the formulation limit absorption? Are there any concomitant medications could interact with enzymes and transporters or alter pH of the gastric fluid?

There are many questions that need to be answered in order to understand the absorption process in order to assess how various factors may influence PK exposures, safety and efficacy of a particular dosing regimen in clinical drug development and intended patient populations.

If you have a drug development program that you would like to discuss with us, please get in touch.

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Metabolism

Why do we want to understand metabolism?

With the rise in polypharmacy it has become important to understand how concomitantly administered drugs will impact each other’s exposure and thus safety and efficacy. In the context of drug development.

Metabolism Overview

Drugs are metabolized by the body in order to make them easier to be excreted. Typically, metabolizing enzymes increase the polarity of the drug thereby it is more easily removed in urine and feces. For most small molecules, the gut and liver are major sites of drug metabolism. In vitro studies can help us to understand the role that enzymes play in metabolizing the investigational drug, what enzymes are inhibited or induced by the investigational drug and whether the drug is a substrate or inhibitor of transporters.

Do We Need a Clinical Drug Interaction Study?

Understanding whether an investigational drug has a potential to interact with other medication based on in vitro data can inform whether further clinical drug interaction studies are necessary. Here are a few questions that may guide the need for a clinical drug interaction study:

 

Metabolite Drug Interaction Considerations

Some metabolites may also exhibit or comprise a significant exposure in plasma and therefore the drug interaction potential of metabolites may be of clinical concern and need to be evaluated.

Evaluation of drug interaction potential is critical in a drug development program. Scientists at PK consultancy have expertise in providing gap analyses and guiding drug development programs from IND to NDA stages. Contact us if you would like to discuss your development program.

References

  1. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions
  2. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions

 

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pH Dependent Drug Interactions with Acid Reducing Agents

Do I Need to Conduct a Clinical Study?

Well the answer is, that it depends on certain characteristics of your investigational drug.

For immediate release basic drugs that has pH dependent solubility at pH of 1.0-6.8, this can mean that solubility in the stomach can decrease as pH increases. When solubility of the investigational drug is lower than the clinical dose/250mL at pH 6.0-6.8 this can reduce solubility at higher pH levels resulting in a potential gastric pH dependent interaction. In the case these criteria are met, one can also test the dissolution profiles in vitro at various pHs. For investigational drugs which have similar dissolution profiles under different pH conditions, it would seem unlikely that there will be a drug interaction with acid reducing agents. However, if there is a difference in dissolution profiles across the pH range or this is not studied a clinical study would be warranted.

For immediate release acidic drugs less information is know, however, for investigational drugs with low solubility at pH 1.0-2.0 an increase in pH could lead to an increase in solubility and thus increase the exposure. Thus the need for a clinical study depends on the safety profile of the investigational drug.

For modified or slow release drugs, the guidance is less clearcut. In some instances in the case of pH-senistive release mechanisms there may be a potential drug interacation with acid reducing agents. If there is a potential for pH to impact the pharmacokinetics of the investigational drug the sponsor should conduct an in vivo study to evaluate the potential interaction.

Study Design

A single dose of the investigational drug in healthy volunteer study designed in a crossover manner can allow evaluation of a potential interaction with acid reducing agents in general unless there are specific concerns related to use in healthy volunteers or if absorption is altered upon multiple dosing. The maximal clinical dose of the investigational drug should be evaluated along with the maximal dose of acid reducing agent in order to best understand the most extreme drug interaction scenario that could occur in clinical practice.

The choice of acid reducing agent includes proton pump inhibitors (PPIs), H2 blockers and antacids. Proton pump inhibitors take approximatley 4 to 5 days to reach maximal efficacy and due to their mechanism of action the pharmacodynamic effect of increased gastric pH is long lasting and therefore staggering the dose of investigational drug relative to that of the PPI is unlikely to resolve any drug interaction if one does occur. H2 blockers can maximize pH increases for a much shorter duration after dosing and therefore can potentially be administered with the investigational drug by staggering the dosing sufficiently to avoid a drug interaction. And finally antacids have a short duration of action and therefore it is simplest to mitigate any drug interaction by administering the investigational drug 2 hours prior to or post administration of the antacid. An important consideration to note when selecting the acid reducing agent is to ensure that there are no other potential interactions with metabolism of the investigational drugs.

Data Analysis

The pharmacokinetics of the investigational drug and any active metabolite that contributes towards safety and efficacy should be evaluated thoroughly. The pharmacokinetic (PK) blood samples should be collected in a manner that allows the adequate characterization of PK parameters. In particular, maximal observed concentration (Cmax), time of maximal observed concentration (Tmax), area under the concentration versus time curve extrapolated to infinity (AUC0-∞) following single doses, area under the concentration vs time curve over a dosing interval AUCτ and minimum concentration Cmin following multiple doses.

Modeling Approaches

Population based pharmacokinetics can be used to better understand the impact of acid reducing agents on the pharmacokinetics of an investigational drug. However, accurate dosing information of both the investigational drug and acid reducing agent are critical to interpretation of the potential drug interaction. Physiologically based pharmacokinetic modeling is another area of study which is rapidly evolving and could be used to further understanding of potential drug interactions.

Interpretation of Study Results and Clinical Relavence

Findings from one acid reducing agent can be translated within the same class, however, this is not the case between classes. Depending on the particular interacting acid reducing agent the recommendation will vary.

PPI – For PPIs, since the effect is long-lasting, staggering the dose of the investigational drug will not be helpful, therefore administering with a PPI should either be avoided or a lower dose of the PPI could be evaluated further.

H2 blockers – Since H2 blockers exert their effect for less time than PPIs, the recommendation would be either to avoid use of H2 blockers or the sponsor could evaluate staggered dosing in a clinical study.

Antacids – In the case of antacids, the dosing recommendation would be either avoid administration of the investigational drug with antacids or stagger dosing by 2 hours, i.e. administration of the investigational drug either 2 hours prior or post administration of the antacid. If a shorter duration is warranted a further clinical study investigating a reduced duration between administration of the investigational drug and antacid should be conducted.

Our Expertise

Study design and selection of pharmacokinetic concentration timepoints to be taken during a clinical study are critical factors to provide meaningful conclusions on the impact of gastric pH on pharmacokinetic drug interactions. Our team has extensive experience with study design, analysis and reporting of drug interactions on pharmacokinetics. If you have any questions regarding your clinical development program and the need to run a dedicated drug interaction study with acid reducing agents do reach out to us.

References

FDA Guidance – Evaluation of Gastric pH-Dependent Drug Interactions With Acid-Reducing Agents: Study Design, Data Analysis, and Clinical Implications Guidance for Industry, Nov 2020

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Food Effect on Pharmacokinetics

Physiological Impact of Food

Food can impact the absorption of drugs, and alter the bioavailability by impacting the rate and extent of absorption. The physiological impact of meals can result in:

Delayed gastric emptying

Stimulation of bile flow

Changes in gastrointestinal pH

Increased splanchnic blood flow

Changes in luminal metabolism of a drug substance

Physical or chemical interactions with a dosage form or a drug substance

Why Conduct Food Effect Studies?

In some cases, absorption of the investigational drug is facilitated by administration with food. This may lead to enhanced efficacy or increased adverse effects. We need to conduct food effect studies to understand whether the we should advise the patients to take the drug with a meal, under fasted conditions  or regardless of meals in order to optimize efficacy and minimize safety risks.

During early Phase 1 development in single ascending and multiple ascending dose MAD studies, oral drugs are typically administered under fasting conditions as the impact of food is not know, however, this can be a cumbersome requirement for Phase 2 and 3 studies or even Phase 1 multiple dose studies if fasted conditions are not needed. Therefore many sponsor pharmaceutical companies like to conduct a food effect early during their SAD and MAD studies to inform the need for fasted or fed conditions in future studies.

In clinical practice some drugs will need to be crushed or dispersed on soft foods or liquids for administration, this is often the case in those with difficulty swallowing, elderly or young patients. Commonly apple sauce is a vehicle used for administering crushed medications, however other soft foods may also be evaluated as there is a potential physical interaction that can occur with the drug and the soft food media. Additionally drugs that are intended for use in babies may need to be administered in breast milk or formula and the potential interactions with milk may also need to be evaluated.

FDA Food Effect Guidance

Study Design

The FDA guidance for industry specifies that the study have a randomized, balanced, single-dose, two-treatment (i.e., fed versus 10 hours fasted), two-period, crossover design. There should be a sufficient washout period between the treatment groups of a recommended five elimination half-lives. An adequate number of subjects based on the pharmacokinetic variability of the drug should be included in the study in order to sufficiently characterize the effect of food on the PK of the drug. However, 12 subjects should be enrolled in each treatment arm at a minimum.

Food Effect Waivers

For drugs in Biopharmaceutical Classification 1 (BCS class 1) that have high solubility, high permeability and high bioavailability (≥85%),  requirements for a food effect study may be waived by the FDA.

Data Analysis

Similarly to a bioequivalence study, food effect studies are conducted in healthy volunteers and usually in a cross-over manner. Cmax, Tmax and AUCinf parameters are measured under fed conditions and compared to exposure under fasted conditions. A bioequivalence approach can be taken to evaluate the impact of food on pharmacokinetics and should be placed in clinical context.

Our Expertise

Study design and selection of pharmacokinetic concentration timepoints to be taken during a food effect study are critical factors to provide meaningful conclusions on the impact of food on pharmacokinetics. Our team has extensive experience with study design, analysis and reporting of food effect on pharmacokinetics. Reach out to us to discuss your needs

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Pharmacokinetics of Different Administration Routes

Drugs can be administered by many different routes, with the most common being oral administration of drugs either as tablets, capsules or liquids. Other routes of administration include intravenous, subcutaneous, intramuscular, topical, inhalation, buccal, sublingual, intrathecal etc. Despite many routes of administration, we can generally divide them up into intravascular or extravascular.

For drugs administered by the extravascular route, they first need to be absorbed from the site of delivery, whether that be the gastrointestinal tract following oral dosing, absorption through the skin after a topical administration, etc.

In the concentration vs time figure above, following extravascular administration drug is released from it’s formulation and absorbed into the systemic circulation. During the absorption phase, the amount of drug being absorbed is greater than that being eliminated. Therefore concentration increases until the amount of drug being absorbed is equal to that being eliminated. At this point, we have reached the maximal concentration. After this point in time, the rate of drug being eliminated is faster than than absorption and the concentration declines over time. For intravenous doses that are administered as a bolus, meaning that they are administered immediately in a single “push”, the maximal concentration occurs as soon as the drug is administered since the absorption step does not need to occur. In practice we often cannot measure drug concentration in plasma of a subject instantly after the IV bolus is administered but we are able to mathematically calculate what the theoretical concentration at the time of the bolus would be.

The types of concentration vs time profiles that we see following intravenous compared to extravascular dosing are markedly different.

  • Following intravenous dosing bioavailability is 100%, however following extravascular administration can be impacted by the absorption process.
  • Following IV bolus maximal observed concentrations are usually higher than extravascular dosing.
  • For drugs that exhibit very slow absorption, the elimination phase following extravascular administration may likely reflect the rate of absorption rather than the terminal elimination rate. This is refered to as “flip-flop” kinetics and results in different half-lives between IV and extravascular dosing.

Our experts have over 77 years combined expertise in pharmacokinetics, if you have any questions related to a on-going program please contact us.

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Compartmental Models

In a non-compartmental model we assume the person to be like a well-stirred beaker. The entire dose is considered equally distributed through the body. Most drugs do not distribute evenly throughout the body and may preferentially distribute to different organs or tissues.

If we think about what happens when we take a drug, after the drug reaches the systemic circulation, it could undergo first order elimination from the systemic circulation via the kidneys and or liver. A lot of drugs will distribute to tissues, which could also potentially be their site of action.

Drug distribution is usually a dynamic process and concentrations in tissues will distribute back into the systemic circulation with time. Therefore, a compartmental model can represent hypothetical “compartments” that are also well-stirred. The compartments are not necessarily referring to particular organs such as the heart, liver, brain etc., but rather groups of tissues that can account for the distribution of drug.

If in addition to a shallow compartment, some compartments take longer to clear, they could be termed as deep tissue compartments and may result in a model with multiple compartments. Compartments in a compartmental analysis do not represent a particular organ such as liver, heart, brain etc.

One Compartment Model

For a one compartment model, drug is administered or input into the central compartment or CMT1. The drug is evenly distributed within this compartment and eliminated directly from CMT1.

Two Compartment Model

For a two compartment model the drug is also administered or input into the CMT1, from there it can distribute to a second compartment. Drug that enters into CMT2 can also distribute back into CMT1. From CMT1, drug can also be permanently eliminated. During the distribution phase you could observe a steep decline in concentration as in the center figure above.

Three Compartment Model

For a three compartment model you might have a shallow compartment CMT2 and a deep compartment CMT3 from which drug can distribute from CMT1. Distribution of drug to the shallow compartment will show rapid decline in concentration, followed by a shallower distribution into the deep compartment. Once the compartments reach equilibrium, the drug concentration will decline following the elimination rate from CMT1.

Summary

Compartmental modeling allows us to mathematically fit the concentration data. Depending on the purpose of analysis, compartmental modeling can be used to inform further drug development.

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Non-Compartmental Analysis

What is the purpose of non-compartmental analysis?

Non-compartmental analysis of pharmacokinetic data provides basic information on the exposure of drug, typically in plasma. This allows us to compare drug exposure to potential safety and efficacy endpoints of concern. Non-compartmental analysis plays a critical role in guiding drug development from preclinical studies through first in human studies in healthy volunteers, other clinical pharmacology studies and in patient studies all the way to drug approval and post-marketing commitments.

Non-Compartmental Model

In a non-compartmental model we assume the person to be like a well-stirred beaker. The entire dose is considered equally distributed through the body. Although this is not technically true, non-compartmental analysis can be very helpful, especially since we do not need to make any assumptions about the model and all analyses are based on observed data.

What are the assumptions of NCA?

In a non-compartmental model we assume the person to be like a well-stirred beaker. The entire dose is considered equally distributed through the body. Although this is not technically true, non-compartmental analysis can be very helpful, especially since we do not need to make any assumptions about the model and all analyses are based on observed data.

NCA pharmacokinetic parameters

Cmax – maximal observed concentration. Since this is based on observed data, it is important that sufficient blood samples are taken over the time period where we expect Cmax in order to accurately determine this concentration.

Tmax – time of maximal observed concentration

AUC – area under the concentration vs time profile allows us to better understand exposure following single or multiple doses

Half-life – Is the time for concentration to decline to 50% it’s initial value. This is useful to understand how drug concentration can accumulate with multiple dosing or how much time is needed to completely washout of the body.

Volume of Distribution – is a hypothetical volume rather than based in relation to total body weight or volume. It is calculated based on the volume required to account for a given dose.

Systemic Clearance – Represents the volume cleared per unit time.

Summary

In summary NCA is a tool that can facilitate drug development in a timely manner and requires few underlying assumptions. Since NCA uses observed concentration vs time data, it is important to design studies well in order to optimize PK sample collection. NCA can produce a wealth of parameter data, but it is important to keep in mind whether these parameters are supported by the underlying PK data.

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Drug Excretion

Why do we want to understand excretion pathways?

After a drug has entered the body it will be eliminated via a number of routes however, as the FDA renal guidance states, most drugs are cleared by elimination of  unchanged drug by the kidney and/or by metabolism in the liver and/or small intestine. If a drug is eliminated primarily through renal or hepatic excretory mechanisms, impaired function can alter the drug’s pharmacokinetics to an extent that the dosage regimen needs to be changed from that used in patients with normal organ function or may even need to be contraindicated.

Mass Balance studies typically administer the investigational drug that has a radiolabeled isotope such as carbon 14 attached. The radiolabel allows total radioactivity of the investigational drug to be tracked, whether it be as the administered parent drug or metabolites. Excreta including urine and feces are monitored for total radioactivity following administration of the radiolabeled investigational drug. This allows us to track the major routes for elimination of the parent drug and metabolites.

Renal Impairment

After a drug has entered the body it will be eliminated via a number of routes however, as the FDA renal guidance states, most drugs are cleared by elimination of  unchanged drug by the kidney and/or by metabolism in the liver and/or small intestine. If a drug is eliminated primarily through renal excretory mechanisms, impaired renal function usually alters the drug’s pharmacokinetics to an extent that the dosage regimen needs to be changed from that used in patients with normal renal function.

Renal impairment studies are important when the impact of renal impairment is likely to impact the pharmacokinetics of the drug, for example if greater than 30% of the drug or active metabolite are found in the urine.

Renal impairment can inhibit some pathways of hepatic and gut drug metabolism and transport. Therefore, a PK study in patients with renal impairment should be conducted for most drugs intended for chronic use. Some drugs that are not chronically used can also be evaluated in patients with renal impairment for dose adjustment purposes if there are clinical concerns for use in these patients. There is evidence that even biologics with molecular weights less than 69kDa renal impairment can impact renal clearance of cytokines and cytokine modulators.

Hepatic Impairment

The FDA guidance on hepatic impairment states that, “The liver is involved in the clearance of many drugs through a variety of oxidative and conjugative metabolic pathways and/or through biliary excretion of unchanged drug or metabolites. Alterations of these excretory and metabolic activities by hepatic impairment can lead to drug accumulation or, less often, failure to form an active metabolite.”

From this we can gather that it is important to understand the impact of hepatic impairment on exposures of drugs is needed in order to best understand the impact on efficacy and safety for patients and inform whether doses need to be adjusted in patients with hepatic impairment or whether the treatment cannot be administered in patients with hepatic impairment safely and therefore requires a contraindication listed in the drug label.

The primary purpose of the hepatic impairment guidance is to help understand whether dosage adjustments are required in patients with hepatic impairment based on the impact of hepatic impairment on PK and/or PD of a drug and its active metabolites.

Understanding of elimination pathways and any potential impact of organ impairment on pharmacokinetics, efficacy and safety is critical to a drug development program and also key information to enable safe and effective clinical prescribing in patients. Scientists at PK consultancy have expertise in providing gap analyses and guiding drug development programs from IND to NDA stages. Contact us if you would like to discuss your development program.

References

  1. FDA Renal Impairment Guidance
  2. FDA Hepatic Impairment Guidance

 

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Distribution

Following drug absorption from the site of administration, drug will enter the bloodstream. From the blood, drug can distribute to various tissues throughout the body. Many drugs do not distribute evenly throughout the body and may preferentially distribute to different organs or tissues. Drug distribution is usually a dynamic process and concentrations in tissues will distribute back into the systemic circulation with time.

 

Concentration vs Time Profile Following a Single Intravenous Bolus Dose

Shallow vs Deep Compartments We might observe from concentration vs time data that following administration and reaching maximal concentration the concentration declines rapidly for a brief period. This decline can represent a group of tissues and organs in which the drug is readily distributing to. In general, we would call this a shallow compartment as drug will also leave this compartment quickly. Deep compartments take longer to remove drug from the bloodstream but also will empty at a slower rate.

Protein Binding Albumin is an abundant protein that binds with low affinity to many drugs. Drugs which exhibit high protein binding tend to be more confined to the bloodstream as bound drug is unable to distribute to tissues.

Lipophilicity and Transporters Influences the ability to cross membrane barriers such as the blood brain barrier or placenta. In general, drugs with high lipophilicity can passively diffuse across membranes. Distribution of water-soluble drugs to tissues is improved if they are substrates for active transporter.

Molecule size Large biological molecules do not readily distribute outside of the systemic circulation due to their size. Their volume of distribution usually reflects blood volume.

Patient Factors Differences between patients may lead to differing distribution. For instance, a drug which distributes to fat tissues may show much higher volumes of distribution in an obese patient compared to someone with a typical body mass index.

Concept of Volume of Distribution Volume of distribution is a hypothetical volume rather than based in relation to total body weight or volume. It is calculated based on the volume required to account for a given dose. Since we are only able to sample drug concentration directly from the bloodstream, for drugs that are highly distributed to other tissues the concentration will show low concentrations in the blood and therefore to account for the total dose we will note volumes of distribution that are beyond the actual body volume.

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