Application of a linked pharmacometric/pharmacoeconomic model to assess the impact of non-adherence: Application to the treatment of gout
Daniel Hill-McManus (1), Scott Marshall (2), Elena Soto (2), Steven Lane (3), Dyfrig Hughes (1)
(1) Centre for Health Economic and Medicines Evaluation, Bangor University, (2) Pharmacometrics, Pfizer Ltd, (3) Department of Biostatistics, University of Liverpool
Introduction
A natural extension to pharmacometric analyses, exploiting the structural relationship between dose and response, is to link with pharmacoeconomic models which consider the resource constraints of payers of healthcare [1, 2]. One potential application is to estimate the impact of imperfect adherence patterns on modelled economic outcomes.
Medication adherence can be decomposed into three distinct phases; 1) initiation, 2) the degree to which a patient’s dose taking matches the prescribed regimen while nominally adhering (implementation) and 3) and persistence [3]. An important limitation of conventional economic modelling is its limited capacity to account for the impact of poor implementation, which may lead to biased estimates of treatment effect and confound the results of cost effectiveness analyses [4].
Dual urate-lowering therapy (ULT) with lesinurad in combination with either allopurinol or febuxostat is an option for gout patients unsuccessfully treated on either monotherapy. Medication adherence is known to be especially poor for ULTs [5] and may often result in treatment failure [6].
Objectives
The aim of the present study was to predict the impact of variable adherence, using PKPD simulations, on the cost-effectiveness of treatments for gout.
Methods
Compartmental pharmacokinetic models for allopurinol, febuxostat and lesinurad were obtained from the literature [7–9] and used to simulate drug plasma concentration time courses with varying implementation patterns in a hypothetical patient cohort. Three adherence scenarios were used in simulations, the first being the hypothetical best-case scenario of perfect adherence. The second and third used treatment persistence based on discontinuation observed in lesinurad pivotal trials [10, 11], and average levels of dose implementation of 50 and 80% respectively.
The time course of serum uric acid (sUA) was simulated using a semi-mechanistic, 4-compartment pharmacodynamic model which captured both the inhibition of sUA formation via the inhibition of xanthine oxidase (action of allopurinol and febuxostat) and its increased clearance via inhibition of URAT1 (action of lesinurad) [12]. Parameters were either extracted from previous PKPD studies and trial reports or were estimated using nonlinear mixed effects modelling in NONMEM 7 [13]. A bespoke pharmacoeconomic model was developed, with reference to previous economic evaluations of ULTs [14, 15]. The linked PKPD and pharmacoeconomic model was used to estimate the costs and quality-adjusted life-years (QALYs) accrued over patients’ lifetimes for different treatment and adherence scenarios.
Results
Providing lesinurad dual therapy to non-responders on allopurinol monotherapy is estimated to result in an additional 0.067 QALYs at an additional cost of £3,470 per patient. The resulting incremental cost effectiveness ratio (ICER) is therefore £51,622 per QALY. The estimated ICERs increased with worsening adherence, to £55,665 and £92,064 per QALY in scenarios including discontinuation and implementation rates of 80 and 50% respectively. The equivalent ICERs using febuxostat as monotherapy ranged from £42,052 to £147,934 per QALY.
The quarterly price of lesinurad resulting in an ICER of £20,000 per QALY (value-based price), assuming perfect medication adherence, was estimated to be £34.35 when used in dual ULT compared with allopurinol alone and £43.25 compared with febuxostat alone. This fell to £22.59 and <£0 respectively in simulations of worsening medication adherence. These quarterly prices fall below the list price of £85 per quarter quoted during its recent appraisal for reimbursement in the United Kingdom [16].
Conclusion
Linked PKPD and pharmacoeconomic modelling provide a means of studying the implications of drug pharmacology and adherence on the economic potential of new medicines [17]. Medication adherence has a significant influence on the potential cost effectiveness of second-line dual-ULT with lesinurad compared with either allopurinol or febuxostat alone. The highest value-based price of lesinurad found assuming perfect drug adherence was still below that which has been proposed for the UK market [16]. For health care payers, prescribers and patients these results provide an indication of the extent to which poor adherence to ULTs erodes the cost effectiveness of these medicines when translating from clinical trials to routine practice.
References
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