2018 - Montreux - Switzerland

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Daniel Hill-McManus

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


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].


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.


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.


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].


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.

[1] Swift B, Jain L, White C, Chandrasekaran V, Bhandari A, Hughes D, et al. Innovation at the Intersection of Clinical Trials and Real-World Data Science to Advance Patient Care. SUBMITTED.
[2] Hughes D, Cowell W, Koncz T, Cramer J. Methods for Integrating Medication Compliance and Persistence in Pharmacoeconomic Evaluations. Value Heal. 2007;10(6):498-509.
[3] Vrijens B, De Geest S, Hughes DA, Przemyslaw K, Demonceau J, Ruppar T, et al. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol. 2012;73(5):691-705.
[4] Breckenridge A, Aronson JK, Blaschke TF, Hartman D, Peck CC, Vrijens B. Poor medication adherence in clinical trials: consequences and solutions. Nat Rev Drug Discov. 2017;16(3):149-150.
[5] De Vera MA, Marcotte G, Rai S, Galo JS, Bhole V. Medication adherence in gout: A systematic review. Arthritis Care Res. 2014;66(10):1551-1559.
[6] Stamp LK, Merriman TR, Barclay ML, Singh JA, Roberts RL, Wright DF, et al. Impaired response or insufficient dosage? - examining the potential causes of “inadequate response” to allopurinol in the treatment of gout. Semin Arthitis Rheum. 2014;44(2):170-174.
[7] Wright DFB, Duffull SB, Merriman TR, Dalbeth N, Barclay ML, Stamp LK. Predicting allopurinol response in patients with gout. Br J Clin Pharmacol. 2015;81(2):277-289.
[8] Centre for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics Review (NDA 21-856).; 2008.
[9] Centre for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics Review (Application Number: 207988Orig1s000).; 2014.
[10] Saag KG, Fitz-Patrick D, Kopicko J, Fung M, Bhakta N, Adler S, et al. Lesinurad Combined With Allopurinol: Randomized, Double-Blind, Placebo-Controlled Study in Gout Subjects With Inadequate Response to Standard of Care Allopurinol (A US-based Study). Arthritis Rheumatol. 2017;69(1):203-212.
[11] Bardin T, Keenan RT, Khanna PP, Kopicko J, Fung M, Bhakta N, et al. Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study). Ann Rheum Dis. 2016;76(5):811-820.
[12] Hill-McManus D, Soto E, Marshall S, Lane S, Hughes. Impact of non-adherence on the safety and efficacy of uric acid-lowering therapies in the treatment of gout. Br J Clin Pharmacol. 2018;84(1):142-152.
[13] TAP Pharmaceutical Products Inc. TMX-99-001 Study Report. 2004:Obtained via the EMA on 16/06/16.
[14] Beard SM, Scheele BG Von, Nuki G, Pearson I V. Cost-effectiveness of febuxostat in chronic gout. Eur J Heal Econ. 2014;15:453-463.
[15] National Institute for Health and Care Excellence. Single Technology Appraisal [ID761]: Lesinurad for treating chronic hyperuricaemia in people with gout, Committee Papers. 2016.
[16] National Institute for Health and Care Excellence. Final Appraisal Determination: Lesinurad for Treating Chronic Hyperuricaemia in People with Gout.; 2017.
[17] Pink J, Lane S, Hughes DA. Mechanism-based approach to the economic evaluation of pharmaceuticals: Pharmacokinetic/pharmacodynamic/pharmacoeconomic analysis of rituximab for follicular lymphoma. Pharmacoeconomics. 2012;30(5):413-429.

Reference: PAGE 27 (2018) Abstr 8445 [www.page-meeting.org/?abstract=8445]
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