Lec 2- Clinical pharmaceutics

Question 1

Checklist for claims

Answer 1

• Prove
  
  • Statistical analysis
    
    • Experimental design, sample size, power
    • Statistical parameters
• Demonstrate
• Indicate
• Suspect
• Claim
• State
• Imply
• Assume

Question 2

Checklist for evidence

Answer 2

• Systematic reviews and meta-analysis
  
  • Review and analysis of all reported studies
• Randomised controlled, double-blind trials
  
  • E.g. identical groups- one a control, one a test
• Cohort studies
  
  • Same patients followed over time
• Case-control study
  
  • Patients are compared on the basis of case history
• Case series
  
  • Collection of reports of single patients with similar conditions
• Case reports (yellow cards)
  
  • Medical history of a single patient

Question 3

Perceptions of evidence- some questions

Answer 3

• Interpretations may depend upon the observer
  
  • Are the results or conclusions possible
  • Are conclusions supported by the data
    
    • Does missing evidence present the wrong conclusion
  • Is the evidence ambiguous
    
    • Are we excluding information by focusing too closely
  • Are there hidden means in the data
  • Can we extrapolate meaningfully
  • Are the statistics adequate

Question 4

Two clinical trials

Answer 4

Question 5

Pharmaceutical factors influencing clinical outcomes

1) Packaging (co-amoxiclav- why an extra layer of foil)

Answer 5

• The patient feels “we care”
• Presents a quality image for the product
• Allows a premium price to be charged
• Presents a useful marketing image
• Protects from light
  
  • Foil also reduces ingress of moisture and reduces hydrolysis

Question 6

Evidence: structure, properties and stabilities

Answer 6

Question 7

The real reason for extra packaging

Answer 7

• Compared to amoxicillin
  
  • Clavulanic acid is much more susceptible to hydrolysis
  • Therefore, give extra protection from moisture

Question 8

2a) Rifampicin adsorption

Answer 8

• TB therapy
  
  • Almost 1/3 of humanity infected with TB
  • About 2 million deaths per annum
• Anti-TB drugs
  
  • Rifampicin and p-aminosalicylic acid (PAS)
• Bentonite added as an excipient to PAS granules- aid with flowability of formulation
• Combination therapy
  
  • Rifampicin adsorbs to bentonite
  • Bioavailability reduced

Question 9

2B) excipients and metabolism

Answer 9

• Amprenavir (Agenerase) GSK
  
  • HIV protease inhibitor
  • Available as capsules and oral solution
• Poorly water-soluble
  
  • Propylene glycol used as the solvent
• Propylene glycol metabolised by
  
  • Alcohol and aldehyde dehydrogenase activity

Question 10

2B) Metabolism of PG

Answer 10

• Alcohol and aldehyde dehydrogenase
  
  • Activity low in
    
    • Infants
    • Children U4
    • Pregnancy
    • Patients with hepatic and renal failure
    • Patients treated with disulfiram or metronidazole
• Failure to metabolise PG
  
  • Accumulation and potential adverse effects

Question 11

2C) Excipients intolerance

Answer 11

• Lactose
  
  • Present in ~20% of formulations
    
    • Intolerance in perhaps 5% of Europeans
    • Low intestinal lactase activity
    • Acts as a non-digestible, osmotic carbohydrate
• Colouring agents
  
  • Tartrazine
    
    • Hypersensitivity
• Preservatives
  
  • Contact sensitisation- eczemoid dermatitis
    
    • Chlorocresol- in Aq cream
    • Parabens- common in liquid preparations

Question 12

3) Bioavailability
Rifampicin combinations

TB therapy

Answer 12

• Rifampicin
• Isoniazid
• Pyranzinamide
• Ethambutol
• Combination products

Question 13

Rifampicin Bioavailability

Answer 13

• Concern over poor rifampicin absorption from combination products
• Bioavailability problems with formulations with adequate dissolution profiles
• Possible in vivo stability problems
  
  • Take on an empty stomach
  • pH 1.5-2.0

Question 14

PK parameters

Answer 14

• AUC for rifampicin was substantially lower when given in combination (34-29% decrease)

Question 15

Degradation in acidic conditions

Effect of other drugs

Answer 15

Question 16

Stability- conclusions

Answer 16

• At low pH of the stomach
  
  • A small amount of rifampicin degradation
  • Isoniazid and pyrazinamide are stable
• When rifampicin and isoniazid are co-administered
  
  • Large loss of rifampicin
  • Smaller loss of isoniazid
• Suggests reaction between these compounds and no interaction with other components

Question 17

Rifampicin combinations: Bioavailability assessment

Answer 17

• Current WHO recommendations
  
  • Asses bioavailability of formulation by comparing with a mixture of drugs in individual formulations
• BUT
  
  • If components interact and undergo degradation both test and control will show poor bioavailability
• BETTER
  
  • To use a single drug as the control in each study

Question 18

Opportunities

Answer 18

• Gene therapy- possibly at the germ cell level
  
  • Will eradicate inherited and many other diseases
  • Telomere control will dramatically increase longevity
• Vaccination will substantially limit
  
  • Infective disease
  • Cancers

Question 19

Threats

Answer 19

• Antibiotic resistant organisms
  
  • Almost total resistance of some organisms
    
    • E.g. MRSA, TB
  • Major threat to human health

Question 20

The future: Pharmacogenomics

Answer 20

• The scientific basis of patient variability
• Personalisation of therapy
• Design of medication regimen
  
  • According to
    
    • Individual patients’ genetic character
• Use genetic profiles to design
  
  • Most appropriate therapy
  • Elimination of trial and error