Lecture 6 - PK and PD consideration formulations Flashcards
What are PK and PD profiles of the drug influenced by?
physiochemical properties of the drug
product/ formulation
administration route
patients intrinsic and extrinsic factors eg organ dysfunction, diseases, concomitant medications, and food
what are the PK/PD parade,maters predicate or antimicrobial efficacy and antiviral efficacy ?
PK / PD parameters predictive of antimicrobial efficacy
1. Cmac/ mIC
2. AUC/ MIC
3. Time above MIC
PK/PD parameters predictive of antiviral efficacy
1. Cmin/ IC50
what are the sites of absorption?
parentally from subcutaneous tissue and/ or muscle
the nasal , buccal, rectal, vaginal, cavity
orally from the oral cavity, stomach, and small and large intestines
what are the properties of sites of absorption?
buccal cavity pH 7, good blood supply, small surface area, short transit time
Nasal cavity pH 7, good blood supply, large surface area and short transit time
stomach pH is 1-3, good blood supply, small surface area and short transit time
small intestine has pH 6-8, good blood supply, very large surface area and long transit time
large intestine has pH 5.5-7, good blood supply, large surface area and very long transit time
outline the process of how an orally administered drug is delivered to the systemic circulation.
Precipitation: When an aqueous solution or an aqueous suspension is ingested, it may form a fine particulate suspension. In the case of solid dosage forms like a hard gelatin capsule or an uncoated tablet, they first disintegrate into smaller particles – aggregates or granules.
Disintegration: The aggregates or granules from the hard gelatin capsule or the uncoated tablet further break down to form a fine particulate suspension.
Dissolution: The fine particulate suspension undergoes dissolution, where the drug is dissolved within the gastrointestinal (GI) fluids.
how is pharmacokinetics during drug development considered?
traget exposure;
pre-clinical work will provide a target PK profile for a given drug product. concentration at the receptor in vitro models will be defined. need to calculate ho to get that concentration achieved via systemic distribution
safety studies
during development there is a need to maximise exposure to learn about toxicity and side effects
what are formulations enabled to improve exposure form poorly soluble drugs?
nanosuspension
solid dispersion
lipid based formulations
what is pharmacokinetic variability?
Inter-individual variations of a drugs pharmacokinetic parameters, resulting in fairly different plasma concentration-time profiles after administration of the same dose to different patients
for a typical drug
bioavailability is 20%
clearance is 50%
Vd is 30%
Therefore, 95% of the time, the average concentration (Cav) will be between 35% and 270% of the target value.
what are factors that influence variability?
Genetic
Disease
Age and body size
Concomitant drugs
Environmental factors (e.g. foods, pollutants)
Other factors include compliance, pregnancy, alcohol intake, seasonal variations, gender, or conditions of drug intake.
what are rate limiting steps in drug absorption and strategies to improve solubility/dissolution to maximise absorption?
solubility or dissolution and permeability are rate limiting steps
strategies to improve solubility/dissolution to maximise absorption are:
Particle size
Co-solvent/surfactant approach
Salt form or amorphous form
what are population factors affectign distribution ?
Blood flow: rate of regional blood flows
Example: in heart failure cardiac output is reduced reduced volume of distribution of certain drugs
Plasma protein binding
Most significant for highly bound drugs eg warfarin; albumin is reduced in chronic renal disease leading to higher concentrations of free drugs
Body composition
Lipophilic drugs have a higher volume of distribution in obese patients
Hydrophilic drugs show poor penetration into adipose tissue
what are population factors affecting metabolism
Liver function (the liver is the primary site of drug metabolism)
Liver disease may lead to drug accumulation and increased risk of adverse drug reactions– mainly through decreased clearance.
Genetic polymorphism
Expression of certain metabolizing enzymes is subject to genetics
Example: CYP2D6 metabolises many antidepressants, antiarrhythmic agents, beta blockers, opiates, neuroleptic agents and other drugs
Poor metabolisers do not express CYP2D6 at the same levels
Consequences include accumulation of certain drugs
No analgesic effect from codeine
what are population factored affecting excretion ?
Most commonly linked to kidney function
Kidney failure can lead to reduced renal blood flow and reduced excretion
Urine pH
Tubular secretion, is an active process whereby certain molecules and ions are removed from the blood and actively secreted into the tubules.
When the pH of the blood decreases, more hydrogen ions need to be secreted (thus removing them) to maintain the balance.
Changing the pH of urine can affect excretion of drugs; increasing urine pH aids in barbiturate overdose
