Unit 5 Flashcards
What is the summary of drug development?
- Discovery
- Screening
- Design - Laboratory testing (pre-clinical)
- Safety
- Quality
- Efficacy - Clinical trials
- Confirmation - Marketing authorisation (MA)
- Post authorisation surveillance
Increase in cost
Decrease in number of candidates
What is the importance of dose selection?
“Need to provide rapid access to the patient outweighs the need to optimise dose (breakthrough treatments for cancer)”
Temptation to speed up return on investment
Risky and short-sighted strategy as poor dose selection is one of the main reasons for FDA denial of MA approval
- Soaring cost of drug development
- Increased risk for patient and prescribers
What are the three main parts of dosage design?
SAFETY:
- Target animal, consumer, handler, environment
QUALITY:
- Strength, purity, stability, sterility, long shelf-life
- Cost
EFFICACY:
- Optimal or sufficient?
- Without compromising future use (emergence of resistances)
What do you want to achieve in dosage design in Veterinary medicine?
ADMINISTRATION:
- Systemic effect (Oral, S/C, I/V…)
- Local effect (Topical: Gut, mammary gland, eye, airways)
EFFECT:
- Prophylaxis (Prevention)
- Cure
TARGET:
- Individual
- Population (herd, flock)
What are the 3 parts of dosage design regarding PK/PD?
- Dose response (D-R) characterisation: Why do we need PK?
- PK/PD integration for the average scenario
- PK/PD modelling and stimulation for tailored population medicine approach
What is dose titration?
Where the optimal effective concentration at the site of action is not known (e.g. anthelminthic drugs) dose titration studies must be carried out
These are normally carried out in three phases:
- Dose finding study
- Dose titration study
- Dose confirmation study
What is Dose finding study?
Administration over a wide range of doses to a small number of target or model animals
What is Dose titration study?
Four groups of sufficient number to which 0, 0.5, 1 and 2 times the anticipated recommended dose are administered (each group uniformly infected, for example)
What is Dose confirmation study?
Two studies in infected animals*
Using the recommended dose
- Experimental disease model or field study
What are some advantages and disadvantages of traditional dose titration studies: Parallel design
Advantages:
- Easy to perform
- Statistical pairwise comparison between a finite number of doses
Disadvantages:
- Major disadvantage: CAN NOT interpolate between or extrapolate out of doses tested
Is dose the best predictor for effect?
Variability in bioavailability (formulation, individual intake) and in clearance (age, disease) –> Product or animal related
Where the target plasma concentration is known and pharmacokinetics have been determined in the target species, dosage can be calculated.
What is PK-PD integration?
Link between concentration, effect and time.
What are some examples of antimicrobial drugs?
Studies with clinical endpoints
Vs
Studies with microbiological endpoints (minimum inhibitory concentration: MIC)
Dose-response studies (no knowledge of target tissue concentration)
Vs
PK-PD studies (the target tissue concentration is measured)
What happens to antimicrobials if efficacy is measured by clinical response?
Antimicrobials with poor bactericidal activity appear more efficacious than they really are
Antimicrobials with excellent bactericidal activity appear less efficacious than they really are.
What are the microbiological endpoints of antimicrobial design?
Spectrum of activity (gram +, gram -)
Minimum inhibitory concentration (MIC) in relevant target population
Bacteriostatic vs bactericidal
Mode of killing (time, concentration or co-dependency)
What are surrogate markers to predict efficacy?
T% > MIC (I.e. time dependent)
Cmax/MIC ratio (i.e. concentration dependent)
AUC24h/MIC ratio (i.e. co-dependent)
What is Cmax?
Maximum plasma concentration
What is AUC?
Area under plasma concentration time curve
What is the relationship between Time above MIC and Efficacy for Cefotaxime against Klebsiella pneumoniae in a murine pneumonia model?
Neutrapaenic mice infected by Klebsiella aerosol
Cefotaxime (=ß-lactam) given 14hrs later
24 different dosage regimen (dose and frequency)
Correlation between surrogate and bactericidal effect
What is the Monte Carlo simulation for population approach?
“One dose fits all” possibly leads to over-exposure of some individuals, under exposure of others
Monte-Carlo method: Random sampling procedure
Statistical tool to calculate probability of adequate exposure (and cure) of a percentage of the population knowing
- Variability in MIC: Distribution 1
- Variability in individual clearances: Distribution 2
- Variability in bioavailability + food intake: Distribution 3
- Variability in target of PK/PD index: Tailor to bug/drug association
What do we know about PK/PD target refinement: Static in vitro bacterial kill curves?
Specific to bacteria/drug/host
Choice of inoculum size and matrix (serum vs artificial media)
Incubate with multiples of MIC concentrations for 24hrs
Plot bacterial count versus AUC/MIC ratio
What is the formula for the computation of the dose using Monte Carlo simulation?
Dose = clearance x 90 x MIC / F%
What is a drug?
A chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which when administered to a living organism, produces a biological effect
What is pharmacology?
The study of the effects of drugs on the function of living systems
What is clinical pharmacology?
A translational discipline in terms of the basic tools of human pharmacology (e.g. receptor pharmacology) and applied pharmacology (e.g. pharmacokinetics) and how they are used in drug discovery and development and in solving practical therapeutic problems in individuals and populations
What is ADME in clinical pharmacokinetics?
Absorption
Distribution
Metabolism
Elimination
What do we know about (broncho-)pneumonia in dogs?
Aspiration
Infectious
Foreign body
Nosocomial/Hospital acquired
Secondary to immunodeficiency/congenital defects
Treatment options for bacterial (infectious/ aspiration) bronchopneumonia
- Empirical antibiotic therapy
- Targeted-antibiotic therapy
- Supportive therapies
–> Pain relief/anti-inflammatory medications
–> Inhaled therapies
—-> Nebulisation
—-> Mucolytics (can also be given orally)
What is empirical antibiotic selection?
What bacteria are likely to be present? Which antibiotics have a spectrum of activity that match?
Which antibiotics reach therapeutic levels in the target tissue (the lungs)?
Existence/production of a suitable formulation….
What are the common causative agents of infectious bronchopneumonia and aspiration pneumonia?
Infectious pneumonia:
- Many viral!
- Bacteria: Mycoplasma spp. (stains as gram -Ve [lacks cell wall]), Bortadella bronchiseptical (gram -ve)
Aspiration pneumonia:
- Secondary causative bacteria
- Usually mixed!!
- E.coli (gram -ve), pasteurella spp. (gram +ve), Staphylococcus spp. (gram +ve), Klebsiella spp. (gram -ve), Enterococcus spp. (gram +ve)
What is targeted-antibiotic therapy? Enrofloxacin and marbofloxcacin
Enrofloxacin and marbofloxcacin:
- Fluroquinolones
- Typical target organisms: broad (gram -ve and +ve spp.)
- Oral and injectable formulations readily available
- Arthropathy/cartilage lesions in immature animals (humans, foals, dogs)..
What is targeted-antibiotic therapy? Gentamycin
Gentamycin
- Aminoglycoside
- Typical target organisms: Many gram -ve, some grams +ve spp.
- Commonly used topically for bacterial skin/ear infections, available as injectable
–> Low oral availability (polarised, water-soluble compounds, poor intestinal membrane permeability)
- Nephrotoxicity possible
What is targeted-antibiotic therapy? Co-amoxiclav
Amoxicillin-clavulanate (beta-lactam) IV
- Broad spectrum
- IV rather than orally due to inappetence and regurgitation
Minimal improvement; return of BALF culture and sensitivity
What is pharmacovigilance?
Activities relating to the detection, assessment, understanding and prevention of adverse reactions or other medicine-related problems
Veterinary pharmacovigilance = any concerns over the safety of veterinary medicines used for treatment, prevention or diagnosis of disease in animals.
What is veterinary medicine directorate (VMD)?
RESPONSIBILITIES:
- Monitoring and acting on reports of adverse events from veterinary medicines
- Testing for residues of veterinary medicines or illegal substances in animals and animal products
- Assessing applications for and authorising companies to sell Veterinary medicines
- Controlling how veterinary medicines are made and distributed
- Advising government ministers on developing Veterinary medicines policy and putting it into action
- Making, updating and enforcing the veterinary medicines regulation
What is the definition of a drug interaction?
A change in the action of one drug resulting from:
- Administration of other drugs
- Concurrent food intake
- Also drug-herb interaction
What may a drug interaction be?
Clinically insignificant (most common situation), but can also:
- Produce a favourable effect
–> A planned additive or synergistic effect or reduced toxicity - Lead to an adverse outcome
–> I.e. toxicity or therapeutic failure
What is toxicity likelihood?
Toxicity is most likely to occur when drugs have a low therapeutic index.
What is therapeutic index?
The ratio of the toxic dose (TD50)/therapeutic dose (ED50)
It is used as a measure of the relative safety of the drug
How may Drug-Drug interaction alter drug effect?
Additive effect: 1 + 1 = 2
Synergistic effect: 1 + 1 > 2
Potentiation effect: 1 + 0 = 2
Antagonism: 1 + 1 = 0
What are some general points for drug interactions?
Drug interactions may explain poor efficacy or toxic effects
Knowledge of drug Pharmacokinetics and Pharmacodynamics should enable planned, desirable, effects to be achieved with combinations of drugs and unwanted effects to be avoided
Avoid unnecessary use of more than one drug (poly-pharmacy)
Use drugs that have a low therapeutic index with caution
What are pharmacodynamic interactions?
Drugs that act on a common (or a different) target molecule
Drugs with actions on the same (or different) body system
What are examples of enhanced effect of pharmacodynamic interactions between two drugs that work on the same body system?
The cardiovascular system:
- Beta blockers and calcium channel blockers
To increase hypotensive effects
The lungs:
- ß2 agonists (salbutamol), and glucocorticoids
A combination of direct and indirect bronchodilation, which is used in the treatment of inflammatory airway disease
What are examples of enhanced effect of pharmacodynamic interactions between two drugs that work on different body systems?
- Drugs that act on different target sites to produce the same effect can also be used in combination to reduce toxicity for the patient
e.g. combinations of anti-cancer drugs
What are examples of antagonistic effect of pharmacodynamic interactions?
Same target molecule:
E.g. Naloxone, an opioid receptor antagonist, which reverses the sedative effect and respiratory depression of morphine
—> A desirable effect
Administration of a beta blocker to a patient with respiratory disease taking a beta 2 receptor agonist
–> An undesirable effect
What are some drug specific toxicity and antidotes?
OPIOIDS (morphine):
- Toxicity; Sedation, bradycardia, respiratory depression
- Antidote; Naloxone, diprenorphine
ALPHA-2 AGONISTS (Medetomidine, xylazine):
- Toxicity; Sedation, low heart rate
- Antidote; Atipamezole, Yohimbine
BENZODIAZEPINES (Diazepam):
- Toxicity; Sedation
- Antidote; Flumazenil
What are examples of antagonistic effect of pharmacodynamic interactions?
Same body system:
- E.g. the kidney and anti-hypertension
- NSAIDs and ACE inhibitors - reduced hypotensive action of ACE inhibitors (opposite effects on renal excretion of sodium)
—> An unwanted effect
Different body system:
- E.g. Drugs acting on the heart and kidney
- Furosemide (a potassium losing diuretic) increases the toxicity of class III anti-dysrhythmics (K+ channel blockers)
—> An unwanted effect
What are some interactions with bacteria as the target for drug action?
Can lead to enhanced OR decreased effects.
E.g. Combinations of antibacterial drugs used to:
- Increase spectrum of activity
Antimicrobials when used in combination can also be less effective:
- E.g. Combining drugs with bacteriostatic and bactericidal properties (in theory)
Enhanced toxicity can also occur when antimicrobials are used in combination with other drugs:
- E.g. Aminoglycosides (gentmycin) and NSAIDs:
- Increased risk of renal toxicity
What are drug interactions prior to drug administration?
e.g. when mixed in a syringe
Examples of how you might be be able to recognise an incompatibility:
- Change in colour
- Increase in turbidity
- Formation of precipitates
Sometimes you won’t see it
Some drugs may react with the environment (e.g. during storage or on administration) how?
Problems during storage:
- Out of date drugs lose potency
–> If stored correctly, 90% of drug activity should remain as active at the end of the shelf life
- Effect of storage temperature
- Some drugs break down to toxic products during storage.
Problems during dosing:
- Drugs given by infusion: Some drugs adhere to plastic and/or glass
–> Benzodiazepines (diazepam) binds to plastic when infused
–> Light sensitive drugs may decompose
What are pharmacokinetic interactions?
One drug affects the rate or extent of:
- Absorption
- Distribution
- Metabolism
- Elimination
…Of another drug
What is an example of how drug absorption can be affected?
A reduction in absorption due to altered pH
- E.g. Antacids or H2 blockers will increase gastric pH and reduce the absorption of weakly acidic drugs
Adsorbents (like sucralfate) will decrease drug absorption
How can food affect drug absorption?
The rate and extent of absorption can be affected
Some drugs better on an empty stomach
- E.g. Ampicillin, tetracyclines, robenacoxib
Some drugs are absorbed better with food
- E.g. griseofulvin (ringworm treatment), metronidazole
How can drug distribution be affected?
Unlikely to produce a clinically significant effect unless:
- Displaced drug is injected quickly
E.g. Propofol or barbiturates for induction of general anaesthesia (highly protein bound drugs)
A highly plasma protein bound drug with a low therapeutic index is involved
What do we know about hepatic metabolism of drugs?
The cytochrome P450-dependent microsomal enzymes (phase I reactions: Oxidation, reduction, hydrolysis)
- Have varying specificities
- Metabolise many drugs with different structures
The enzymes can be induced or inhibited by drugs
- E.g. phenobarbitone and phenytoin enhance the microsomal activity (cytochrome induction)
- Cimetidine and chloramphenicol reduce microsomal enzyme activity (cytochrome inhibition)
What do we know about renal excretion of drugs?
Drugs may compete for active secretory processes e.g. penicillins and probenecid (anti-gout drug): Competition for organic ion transporter (OAT) (Used during WW2)
The pH of tubular fluid, which can be altered by administration of acidifying or alkalinising agents - can affect drug excretion
- Excretion of weak acids is favoured in alkaline urine
- Excretion of weak bases is favoured in acid urine
NB. Urine pH may affect the solubility of drugs causing them to precipitate.
What is the definition of drug delivery?
The appropriate administration of drugs through various routes in the body for the purpose of improving health
It is highly interdisciplinary
It has recently evolved to take into consideration:
- Drug physics-chemical properties and solubility
- Drug biological interaction with the body
- Desired pharmacological effect (site, duration, intensity)
- Patient comfort and well-being
What are the typical drug formulations human vs veterinary medicine?
HUMAN:
- Large scale
- Cost effective
- Oral administration
- Nasal or pulmonary
Tech transfers with Small animal/Sport
SMALL ANIMAL/SPORT:
- Similar to humans
- Individual bass
- More expensive and targeted formulations
Animal studies before licensing drugs for humans
FOOD PRODUCING ANIMALS:
- Individual or group treatment
- Cost conscious
- One shot (Convenience/ safety)
- Antibacterial drugs, antiparasitics, vaccines
What are the advantages and traditional delivery system/devices of Intravenous (IV) administration?
ADVANTAGES:
- Drug 100% bioavailable
- Rapid response
- Predictable control of blood concentration
- Only possible route for some drugs (critical antibiotics, chemotherapy)
TRADITIONAL DELIVERY SYSTEM/DEVICES:
- Injection - bolus
- IV bag - infusion
What are the disadvantages of IV administration?
- Invasive: Intravenous catheterisation
- Difficult to administer:
–> Hospital setting
–> Trained personnel - Sterility
–> Formulation
–> Catheter handing to prevent catheter infection - Difficult to keep the IV route patent (Dwell time)
What are some devices for prolonged IV access?
PICC - Peripherally inserted central catheter - line:
- Inserted aseptically from a peripheral vessel
- Tip of the catheter in vena cava
- Duration up to 3 months
Implantable vascular access port:
- Surgical implantation
- Chamber with silicone membrane
- Longer term access (life)
What is Plasma concentration-time profiles after IV administration?
Simple IV bolus
Continuous rate infusion (CRI): Steady state after 5 Half lives
Loading dose and CRI (target control infusion)
What are the assumptions in a single compartment model?
Body: One compartment characterised by a volume of distribution - Vd
Vd = amount of drug in the body (A) / Plasma drug concentration (C)
Drug is confined to the single space and equally distributed through the body
What do we know about a One-compartment model with absorption?
Absorption occurs from site of administration
Absorption can be fast or slow
Slow absorption may represent drug entry through GI tract or leakage into circulation after subcutaneous injection
Drugs require multiple doses to maintain drug concentration within the therapeutic window
Absorption –> C, Vd –> Elimination clearance
What is bioavailability as a measure of absorption?
Bioavailability (F) is:
The fraction of the administered dose that reaches the systemic circulation in an active form
Expressed as a percentage of the total administered
Bioavailability = AUC non-vascular / AUC IV x 100%
What is Oral administration of drugs?
Traditional oral delivery systems
Tablets (compressed powder and coating)
- Immediate release
- Modified release (extended release, gastro-resistant, delayed release)
- Hard capsules (filled with powder)
- Soft gelatine capsules (reduced variability)
- Suspensions
What are the advantages of Oral administration?
Patient:
- Convenience
- Non-invasive
- Higher compliance
Manufacture:
- Well established process, widely available
- No need for sterility
What are the disadvantages of Oral administration?
- Unconscious patients cannot take dose
- Problem drugs:
–> Low solubility
–> Low permeability - First pass mechanism
–> Gut
–> Liver - Irregular absorption, food interactions
What do we know about absorption of drugs from the gastro-intestinal tract?
Dissolution in lumen
Mainly passive transfer through enterocytes (small intestine), sometimes active transporters
Portal circulation empties into the liver
Entero-hepatic loop
What is the first pass effect (oral route)
Gut lumen
- Some drugs may go straight to faeces (poor solubility
Gut wall
- Some drugs metabolised in the gut
- Degradation by enzymes or bacterial flora
Liver
- Some may go to hepatic metabolism
- Hepatic metabolism
- Cellular efflux pumps
Some travels to site of measurement
What is the biopharmaceutics classification system (BCS class)?
Class I;
Well absorbed, absorption rate usually > excretion rate
Class II;
Bioavailability is limited by solvation rate (predicted by in vitro studies)
Class III;
Limited by permeation rate (requires work on formulation)
Class IV;
Usually poor bioavailability and high variability of absorption
From class I –> IV: Chance of non-oral dosage required
What drug administrations bypass the first pass effect?
- Intravenous
- Sublingual route
- Rectal route
- Directly to vena cava without transiting the liver
- Higher bioavailability
What are the advantages and traditional delivery system/devices of Buccal/sublingual administration?
ADVANTAGES:
- Bypass first pass metabolism
- Rapid absorption
- Low enzymatic activity
TRADITIONAL DELIVERY SYSTEM/DEVICES:
- Tablets
- Chewing gum
What are the disadvantages of Buccal/sublingual administration?
- Small doses
- Probability of swallowing - loss of effect
- Discomfort during dissolution
What is an example of a buccal drug in industry?
Oral-lyn
- Liquid formulation of human insulin administered to buccal mucosa by aerosolisation
- Drug carried in lipid micelles
What are dosing considerations of long-acting oral formulations?
Can you dose a cow?
Panacur bolus TM (MSD animal health), intra-ruminal
Fenbendazone (antiparasitic), up to 140 days coverage
What are the advantages and traditional delivery system/devices of Rectal administration?
ADVANTAGES:
- Bypass first pass metabolism
- Useful for unconscious patients
TRADITIONAL DELIVERY SYSTEMS/DEVICES:
- Suppository
- Enema
What are the disadvantages and an example of rectal administration?
- Degradation by bacterial flora
- Uncomfortable
Diazepam in seizing dogs (no IV yet)
What are the advantages and typical delivery system of Parenteral injection administration (non-enteral)?
ADVANTAGES:
- For drugs with poor oral bioavailability
- No first-pass effect
- Catheter not needed
TYPICAL DELIVERY SYSTEM:
- Single vial or
- Multiple use, preservative, airtight vial
- Excipients (for adjusting pH, stability and solubility)
What are the disadvantages of parenteral injection administration (non-enteral)?
Sterile formulation needed
What are the advantages and disadvantages of Subcutaneous and intramuscular injection administration?
ADVANTAGES:
- Patient self-administration
- Slow, complete absorption
- No first-pass effect
DISADVANTAGES:
- Invasive
- Irritation, inflammation
- Max volume - 1ml (SC) - 4ml (IM)
- May require some training (IM)
What do we know about long-acting injectable formulations?
Treatment requires drug exposure for several days (antibiotic for example)
Convenience of long-acting formulations: Single visit to the farm
Injection can last up to 120h (Tulathromycin draxxin)
What are the advantages and requirements of Topical/transdermal administration?
ADVANTAGES:
- Local effect (topical) or systemic absorption
- Ease of administration (cream, gel, patches)
REQUIREMENTS:
- Low dosage <10mg a day
- MW<500, logP: 1-4
- Suitable formulation
What are the disadvantages of topical/transdermal administration?
- Stratum corneum barrier
- Low absorption for some drugs
- Slow onset
What do we know about Patch and transdermal technology?
Sustained release or controlled release technology
Human medicine:
- Nicotine
- Oestrogens
- Scopolamine (nausea)
- Rivastigmine (Alzheimer’s disease)
Zero order delivery is important (nicotine patch, immediate bioavailability would be lethal)
Variability in skin structure between species
What are enhancement strategies for transdermal delivery?
Penetration enhancers (modify stratum corneum)
- Alcohols, DMSO, terpenes
Energy-driven release methods (electric current or ultrasounds)
Microneedles, different types (bypass stratum corneum)
What are the advantages of respiratory administration (inhalers)?
ADVANTAGES:
- Drugs for local or systemic effect
- Portability
- Bypass first pass metabolism
- Gases are rapidly absorbed
What are the disadvantages of respiratory administration (inhalers)?
DISADVANTAGES:
- Propelled liquids or solids (powders) can be absorbed if size is below 0.5 µm
- Patient training and proficiency
What do we know about inhalation general anaesthesia?
Volatiles anaesthetic agents –> Alveolar uptake
Systemic effects (anaesthesia): immobility, muscle relaxation and unconsciousness
Speed of uptake related to blood-gas solubility
What are the advantages of nasal administration?
ADVANTAGES:
- Localised or systemic action
- Over the counter medications (decongestants)
- Hormones (insulin) or vaccines
What are the disadvantages of nasal administration?
DISADVANTAGES:
- Drugs can be degraded locally
- Clearance by cilia (nasopharynx)
- Need improved formulations to increase uptake
What do we know about nose to Brain delivery?
- Direct access to brain (bypasses blood brain barrier)
- New area of CNS research (anti-alzheimer drugs)
- Anatomical differences between animal species (models)
What do we know about nanotechnologies?
Structures 1 to 100nm
Includes antibodies, polymer conjugates, nanoparticles and liposomes
Enhanced solubility and dissolution rate (BCS II and IV)
What are the factors affecting the selection of the delivery route?
Drug physico-chemical properties:
- Drug molecular weight
- Chemical size
- Particle size
Desired pharmacological effect:
- Local vs systemic
- Immediate/delayed response
- Dose size
Solubility:
- Hydrophobicity / hydrophilicity
- pH/temperature
- pKa - ionisation
- Concentration / crystallinity
Drug biological interactions:
- half life
- Sensitive to first pass effect
- Drug interactions
Patient factor:
- Preference - lifestyle
- Dexterity - cooperation
- Conscious or not
