Health economics, pharmacokinetics and patient compliance

1
Health economics, pharmacokinetics andpatient
compliance

• Dyfrig Hughes PhD
• Centre for the Economics of Health
• University of Wales, Bangor

2
Background

• Pharmacoeconomic evaluations require that both
  costs and health benefits are assessed to
  determine whether incremental health gains
  justify the costs

3
Background

• Health benefits are typically derived from
  randomised controlled efficacy trials whereas
  clinical effectiveness is based on real world
  outcomes
• Cost-efficacy studies may provide a precise
  answer to the wrong question

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Impact of non-compliance

• Non-compliance is a major contributor to the
  differences between efficacy and effectiveness
• Up to 15 of patients do not redeem prescriptions
• 5-year persistence with statins is 45 to 13
• Problems in timing and dose omission is
  significant

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Patterns of non-compliance
2400 1600 0800 0000
Time of day
2400 1600 0800 0000
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Drug forgiveness

• Ability of a drug to maintain therapeutic
  activity despite occasional missed doses
• F Duration of Action Dosing Interval
• Depends on pharmacokinetic, pharmacodynamic and
  physiological processes

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Drug forgiveness
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Example 1 atorvastatin

• Estimation of effectiveness based on measures of
  efficacy and compliance
• Population pharmacodynamic model
• Based on onset and offset of drug effect

Hughes Walley Clin Pharmacol Ther 2003 74 1-8
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Atorvastatin 40mg qid 2/52
Stern et al J Clin Pharmacol 1997 37 291-6
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Model for compliance and persistence

• Simple model for
• missed doses
• drug holidays and
• premature discontinuation
• Makes no assumption on reason for missing doses

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Sample results
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Persistence
Larsen et al Br J Clin Pharmacol 2002 53
375-8 Catalan et al Value Health 2000 3 417-26
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Population analysis
49.5 (95 CI, 30.5, 65.1)
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Example 2 metoprolol

• Association between compliance and healthcare
  utilisation of outpatients with heart failure
• Comparison of intended plasma concentration
  (Cpave) based on perfect compliance with
  projected concentration based on actual
  compliance (Cpave)

Tu et al J Clin Pharmacol Ther 2005 77 189-201
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Pharmacokinetic analysis

• 1-compartment pop-PK model
• Deviation from intended exposure
• ?Cpave Cpave Cpave
• ?Cpave associated with increased numbers of
  emergency department visits and hospital admission

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Example 3 oxybutynin

• Oxybutynin
• 5mg immediate release twice-daily vs
• 10mg extended release once-daily
• Better compliance qid (79) than with bid (69)
• Does this translate to clinical and
  cost-effectiveness advantages?

Hughes et al Clin Pharmacokinet submitted
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PK of Oxybutynin-IR
3 successive 5mg doses
100
R-oxybutynin
R-desethyloxybutynin
10
Concentration (ng/ml)
1
0.1
0.01
0
10
20
30
40
50
Time (hours)
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PK of Oxybutynin-XL
Single 10mg dose
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Oxybutynin
5mg IR twice daily 10mg XL once daily
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Coverage plot
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Incorporating non-compliance into economic
evaluations

• UK NHS perspective
• Benefits - incontinence-free weeks
• Costs include drugs, continence appliances and
  containment products, medical staff and
  overheads, and surgical interventions

Hughes et al Pharmacoeconomics 2004 in press
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Persistence
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Results
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Observations

• Atorvastatin is forgiving
• Difference between efficacy and effectiveness
  only due to persistence
• Metoprolol
• Difference between efficacy and effectiveness due
  lack of forgiveness

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Observations

• Large variation in cost-effectiveness of
  oxybutynin depending on
• Persistence
• Assumptions relating to events in discontinuers

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Summary

• Different approaches for analysing the impact of
  non-compliance
• Importance of accounting for non-compliance in
  pharmacoeconomics