Optimising dosage regimen design Flashcards
W1
Factors which ultimately impact on the rate and extent of systemic drug absorption?
- Route of administration
- dosage form
- physiochemical properties of drug
Rapid absorption of tablets/capsules effect on Tmax? What is it ideally used for?
Short Tmax.
drugs with rapid theraputic effects, eg: analgesics
What are ‘modified’ or ‘sustained release’ tablets used for?
- Slower absorption into bloodstream
- Longer Tmax but drug remains above MEC
- More controlled release of drug, patient doesn’t have to take formulation multiple times a day -? increased patient compliance
Lipinski’s rule of 5
relates optimum physicochemical properties to oral absorption.
- Log P > 5
- Molecular weight > 500 Da
- Number of H-bond donors > 5
- Number of H-bond acceptors > 10
Alternative Routes of Administration
- Oral
- Occular
- Nasal
- Pulmonary
- Buccal
- Sublingual
- Intravenous
- Subcutaneous
- Intramuscular
- Transdermal
- Vaginal
- Rectal
What individuals may have trouble taking oral formulation & may need alternative route of administration?
- a baby
- elderly individuals with difficulty swallowing
- individuals who are suffering from nausea or vomiting
- individuals who have recently had gastric surgery
Physicochemical properties drugs need to have good absorption across single/multiple layers of epithelial cells.
- Moderate lipophilicity in order to partition into the lipophilic domain of the epithelium
- Low molecular weight in order to diffuse through the multilayered lining of multilayered epithelia
- Low polar surface area in order to retain some solubility but not remain trapped in the epithelium
Calculation of the correct dose when changing from intravenous to other routes of administration
- Use equation: Css= (F.Dose/CL.τ)
- When the 2 unknowns are: Dose & τ -> best to always provide τ a value first which is close to the half life of the drug (which is crucial for maintenance of Css), which leaves only the dose to be calculated.
- Solve
CYL:
Relative to an immediate release tablet containing paracetamol, a slow release oral tablet containing paracetamol would provide which of the following effects: a) Delayed analgesia which lasts shorter, b) Delayed analgesia which lasts longer, c) Quicker analgesia which lasts longer, d) Quicker analgesia which lasts shorter.
b) Delayed analgesia which lasts longer.
Because of the slower release of paracetamol from the slow release tablet, the Tmax will be later and plasma levels will be above the MEC for longer
CYL:
Which of the following formulations are appropriate for intravenous administration? Suspension, Solution, Solution & Suspension, Ointment
Solution ✅ . Suspensions have solute particles which may block in systemic circulation→ detrimental
CYL:
Which of the following parameters should first be allocated when converting a patient from one route of administration to another route of administration when you want the same therapeutic effect to be observed? Fraction of dose absorbed, Dose, Dosing interval, Elimination rate constant
Dosing interval, τ. The dosing interval should first be chosen as it matches the half life the closest, which is important for maintenance of steady state.
IL:
A hospital inpatient is currently controlled on a novel 1.5 kDa peptide for their diabetes which is not controlled by any other treatment available on the market. The benefit of this peptide is that it not only maintains normal glucose levels when the patient is stable, but can have an acute glucose lowering effect if administered rapidly during a hyperglycaemic attack.
- The patient is currently stabilised on a 0.25 µg intravenous dose of this peptide every 12 hours and is ready to be discharged. You are consulted by the endocrinologist on whether the transdermal formulation or pulmonary formulation of this peptide (which has a short half life) would be appropriate for maintaining the patient’s glucose levels.
The transdermal formulation has an absolute bioavailability of 4.5% and the pulmonary formulation has an absolute bioavailability of 9.5%.
a) Which formulation would you advise the patient to be prescribed for routine maintenance of their diabetes with this peptide?
b) Why would you recommend this formulation/route of delivery?
c) Given the benefits of this peptide in also rapidly reducing glucose levels during hyperglycaemia, would you recommend the patient administer a second transdermal patch of the peptide during a hyperglycaemic attack or inhale the pulmonary formulation?
a + b) Formulation:
- Transdermal route for maintaining BGLs→ allows for slower absorption due to multilayer epithelium of membrane
- Pulmonary formulation for hyperglycemic attacks. Lung has only 1 layer into bloodstream → faster absorption, rapid effect w/shorter duration of action
b) Inhale pulmonary formulation for rapid effect → rapidly reducing glucose lvls.
Route of admin to use to achieve rapid absorption of drug?
-> Rapid & shorter effect
Travel route with thinner membrane eg: Pulmonary epithelium, sublingual
Route of admin to use to achieve controlled absorption?
-> Controlled = slower & longer effect
Travel route with thicker membrane eg: skin & nasal mucosa, buccal
IL:
The endocrinologist is happy with your decisions and now asks you for a dosing regimen for the transdermal formulation (for tmaintenance control). What dosing regimen would you provide? Please note that the peptide is available as 0.2 µg and 0.4 µg transdermal patches.
a) Do you have ample information?
b) What further information would you require?
a) NO
b) Info we need: Half-life of drug, bioavailability of drug, Clearance of drug (or Vd to find Cl).
Use Css= (F.Dose/CL.τ) equation. WE can match τ closely to half-life then find dose req.
