Pharmacokinetics: Volume of Distribution Quiz

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Questions and Answers

What is the primary characteristic of volume of distribution in pharmacokinetics?

It determines the duration of medication in the bloodstream.

It indicates the presence of the drug in the blood plasma. (correct)

It measures the rate of drug metabolism in the liver.

It evaluates the effectiveness of drug absorption.

Which method is commonly used to determine the volume of distribution?

Intravenous injections of the drug. (correct)

Intramuscular injection of the drug.

Clinical observation of drug effects.

Oral administration of the drug.

Which of the following statements is true about MyocetTM and DoxilTM?

Both consist entirely of unbound doxorubicin.

DoxilTM is primarily used for oral administration.

MyocetTM comprises a large amount of unbound doxorubicin. (correct)

DoxilTM has a significant amount of unbound doxorubicin.

What type of injection has the highest percentage of administration in biologics?

Intravenous (IV) Signup and view all the answers

What aspect do SC/IM injections have a higher tolerance for?

Oily liquids Signup and view all the answers

What is one characteristic of intravenous (IV) administration compared to subcutaneous (SC) and intramuscular (IM) injections?

IV administration requires strict sterility requirements. Signup and view all the answers

Which of the following best describes parenteral drug delivery?

It often requires a healthcare professional for administration. Signup and view all the answers

What is a common reason for the high production cost of parenteral preparations?

The requirement for strict sterility measures. Signup and view all the answers

Which type of parenteral preparation is not typically associated with injection methods?

Pills Signup and view all the answers

What is a critical role of excipients in injectable formulations?

To ensure stability and solubility of the drug. Signup and view all the answers

What do Cmax and AUC primarily evaluate in pharmacokinetics?

The extent and rate of absorption Signup and view all the answers

What is the relationship between dissolution rates and absorption rates?

Faster dissolution leads to faster absorption Signup and view all the answers

Which molecules are typically unable to enter the lymphatic system?

Particles and molecules >100 nm Signup and view all the answers

What is a key characteristic of higher molecular weight molecules in relation to lymphatic capillaries?

They cannot diffuse through tissue but may enter lymphatic capillaries. Signup and view all the answers

What is primarily indicated by a high Cmax in a drug's plasma concentration graph?

Fast absorption of the drug Signup and view all the answers

What is the best strategic approach to minimize the formation of Anti-Drug Antibodies (ADAs)?

Avoid ADA during preclinical evaluation of molecules. Signup and view all the answers

Which statement is true regarding poorly soluble drugs?

Smaller particle sizes can enhance dissolution rates. Signup and view all the answers

Which of the following is a disadvantage of injectable medications?

They require a sterile environment to avoid contamination. Signup and view all the answers

Which of the following statements about injections is correct?

Injections are prepared with active substances mixed in Water for injections. Signup and view all the answers

What is a significant challenge faced in developing long-acting injectable formulations?

They are more challenging to develop compared to oral medications. Signup and view all the answers

Study Notes

Course Information

Course code: PR5217
Course name: Injectables 1
Instructor: Associate Professor Matthias G. Wacker, PhD
Department: Department of Pharmacy, Faculty of Science, National University of Singapore
Email: [email protected]
Website: www.pollev.com/mgwacker

Learning Objectives

How do different injection sites affect drug performance?
What are the regulatory requirements for parenteral products?
What excipients are used for different injectables and what are their roles?
How is sterility achieved in drug products (liquid and solid)?

Parenteral Drug Delivery

Invasive treatment, often needed in emergencies.
Rapid onset of action is a key advantage, but this is often balanced by high production costs due to sterility requirements.
Often used for degradable and poorly permeable compounds.

Parenteral Preparations

Sterile solutions, emulsions, or suspensions for injection, infusion, or implantation.
Types include injections, infusions, concentrates, powders, and implants.

Injection Sites

Intravenous (IV) administration has stricter requirements compared to subcutaneous (SC) or intramuscular (IM) injections.
SC/IM injections have higher tolerance to particles, oily liquids, hypotonic and hypertonic solutions & pH variations.

Volume of Distribution

Pharmacokinetic parameter that describes the drug's presence in blood plasma.
IV injections are commonly used to determine distribution volume of drugs.

IV Injection Case Study: Liposomes

Conventional doxorubicin distributes into tissue well with Myocet™, which has a larger amount of unbound doxorubicin.
Doxil™ has minimal unbound doxorubicin.

Influence of Biologics

Parenteral administration accounts for 92% of total administration routes.
Intravenous (IV) injections are the most frequent injection type (47%).

Subcutaneous Tissue

Shows the lymphatic drainage, metabolism, and immune response processes around the injection site.

Pharmacokinetic Profiles

Plasma concentrations reflect absorption extent and rate.
Cmax and AUC (area under the curve) are key parameters to assess absorption.

Dissolution

Poorly soluble drugs exhibit varying dissolution rates depending on particle size.
Faster dissolution often corresponds to faster absorption (as indicated by Cmax and AUC).

Subcutaneous Fluid

Data table showing total protein content, albumin content and others in various mammals(Mouse, Rat,... Human)
Note that there are differences in parameters between species

Tissue Retention Molecular Volume

Images showcasing different time-points of tissue retention of labeled molecules.
A way of quantifying tissue retention of molecules

Lymphatic System

Particles over 100nm typically do not enter the lymphatic system.
Smaller molecules can diffuse through tissue and enter the lymphatic capillaries (around 15-20nm wide).

Immune Responses Anti-Drug Antibodies

Anti-drug antibodies (ADAs) can make pharmacokinetics less predictable.
Preclinical testing usually avoids ADAs to improve predictability.

Injectables Advantages and Disadvantages

Advantages: Rapid onset of action, lower barriers for absorption of proteins/peptides, long-acting formulations possible.
Disadvantages: Invasive treatment, high safety requirements regarding purity, sterility is a challenge, and costly formulation.

Preparations

Categorization of various types of preparations.

Injections

Sterile solutions, emulsions, or suspensions.
Prepared by dissolving, emulsifying, or suspending active substances and excipients in water for injections.
Clear solutions, free of particles, and no phase separation.
Suspension sediments must easily redisperse.

Injections - Multidose and Single Dose Vials

Multidose vials often use preservative (like benzyl alcohol).
Some single-dose vials can be preservative-free.

Excipients Tonicity

Includes sodium chloride, buffer salts (e.g., histidine, citrate, phosphate), small molecules (e.g., dextrose, glucose, mannitol, sorbitol), and 288 mOsmol solution (0.9% NaCl).
Acceptable tonicity range is approximately 225-430 mOsmol, with a typical range of 250-300 mOsmol.

Excipients pH

Buffered pH conditions using phosphate buffer (pKA2 = 7.2), acetate buffer (pKa = 4.76), citrate buffer (pKA1 = 4.76, PKA2 = 6.4), and histidine (pKa = 1.8).
pH adjustment accomplished with sodium hydroxide and hydrochloric acid.

Excipients Stabilization

Stabilizers can improve physical, chemical, and microbiological stability during storage.
Some examples are surfactants (polysorbate, poloxamer), steric stabilizers (dextran, albumin), antioxidants (e.g., ascorbic acid) and preservatives (e.g., metacresol).

Insulin Solution

List of ingredients for insulin solution - Zinc chloride, Glycerol, Metacresol, Sodium hydroxide, Hydrochloric acid, Water for injections.

Infusions

Sterile, aqueous solutions or emulsions with water as the continuous phase, made isotonic and administered in high volumes.
No preservatives typically added, and solutions are particle-free and show no phase separation.
Must be tested for pyrogens.

Concentrates for Injections or Infusions

Sterile solutions intended for later dilution and intended use.
Dilute according to prescribed volume and liquid.

Antibody Concentrate

Example of an antibody concentrate including Polysorbate 80 (stabilizer), sodium chloride (tonicity), tri-sodium citrate dihydrate (pH / buffer), Water for injections (Vehicle).

Powder for Injections or Infusions

Sterile solid substances intended for dissolution or suspension in liquid before use.
Usually produced by freeze-drying including added excipients to facilitate drying.

Implants

Sterile, solid preparations for implantation, releasing active substance over an extended period of time.
The size and shape are suitable for parenteral implantation.
An example mentioned is Implanon (Etonorgestrel 68 mg).

Implants Hot Melt Extrusion

Process used for preparing Implants.

Sterility

Sterility is a key requirement for injectables.

Sterility and Pyrogens

Sterility and absence from pyrogens are required for all injectables.
Key point - sepsis is a serious health problem with high death count
Data about causes of death.

Sterility Assurance Level (SAL)

SAL indicates the probability of one viable microorganism in a certain number of drug products.
Defines an acceptable safety level according to pharmacopeiad standards, including heat sterilization, sterile filtration, aseptic production, radiation sterilization, and chemical sterilization methods.

Sterility Testing

Methods for testing sterility, including incubation media summary, and filtration to determine microorganism counts.

Pyrogens

Traceback to dates when pyrogens were identified and tested, with particular mention of the LAL method in 1980.

Sterilization Methods

Different techniques for ensuring sterility, including moist heat and dry heat for different product types.

Moist Heat Sterilization

Use of saturated steam and pressure.
Suitable for aqueous and thermostable solutions instruments/lab equipment.
Procedures for using autoclaves.

Dry Heat Sterilization

Direct heat input.
Suitable for thermostable powders, water-free ointments, and objects requiring dry air. (like laboratory dishes)

Gamma Radiation

High-energy radiation used for sterilization, with a diagram of the sterilization setup.

Summary

Injectables are a varied group of preparations suited to a diverse range of injection sites, differentiated by their biopharmaceutical traits and classified by pharmacopeia based on their tolerance to pH, concentration parameters.
Excipients adjust tonicity and pH, and prevent physical, chemical, or microbiological degradation (instability).
Key to success for injectables is their sterility achieved through various processes including moist heat, gamma radiation, etc.

Thermodox®

Thermodox® delivers doxorubicin triggered by heat following radiation therapy, selectively targeting areas of solid tumors.
Data suggest that pre-clinical data does not result in consistent clinical improvement.

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Description

Test your knowledge on pharmacokinetics, focusing on volume of distribution and parenteral drug delivery methods. This quiz covers essential aspects like administration techniques and critical roles of excipients in injectable formulations. Challenge yourself with questions to deepen your understanding of drug absorption and distribution.