Impact of non‐adherence on the safety and efficacy of uric acid‐lowering therapies in the treatment of gout

• Published in: British journal of clinical pharmacology Vol. 84; no. 1; pp. 142 - 152
• Main Authors: Hill‐McManus, Daniel, Soto, Elena, Marshall, Scott, Lane, Steven, Hughes, Dyfrig
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.01.2018
• Subjects: Computer Simulation; Drug Therapy, Combination; febuxostat; Febuxostat - pharmacology; Febuxostat - therapeutic use; Gout - blood; Gout - drug therapy; Gout Suppressants - pharmacology; Gout Suppressants - therapeutic use; Humans; hyperuricosuria; lesinurad; Male; Medication Adherence; Models, Biological; pharmacodynamics; pharmacokinetics; Risk Assessment - methods; Therapeutics; Thioglycolates - pharmacology; Thioglycolates - therapeutic use; Treatment Outcome; Triazoles - pharmacology; Triazoles - therapeutic use; urate‐lowering therapy; Uric Acid - blood; Xanthine Oxidase - antagonists & inhibitors; pharmacokinetics; urate-lowering therapy; febuxostat; lesinurad; pharmacodynamics; hyperuricosuria
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.13427

Aims Dual‐urate‐lowering therapy (ULT) with xanthine oxidase inhibitor and uricosuric medications is a treatment option for severe gout. Uricosuric agents can cause hyperuricosuria, a risk factor for nephrolithiasis and acute uric acid nephropathy. The aims of the present study were to simulate the relationship between suboptimal drug adherence and efficacy, and to quantify the risk of hyperuricosuria in gout patients receiving mono‐ and dual‐ULTs. Methods The impact of poor medication adherence was studied using two‐compartment pharmacokinetic (PK) models based on published evidence, and a semi‐mechanistic four‐compartment pharmacodynamic (PD) model. The PKPD model was used to simulate mono and dual‐ULT in gout patients with either under‐excretion (lowered clearance) or overproduction of uric acid, with suboptimal adherence modelled as either a single drug holiday of increasing duration or doses taken at random. Results Simulation results showed a surge in urinary uric acid occurring when dosing is restarted following missed doses. For under‐excreters taking a 20‐day drug holiday, the addition of 200 mg (or 400 mg) lesinurad to 80 mg febuxostat increased the percentage of patients experiencing hyperuricosuria from 0% to 1.4% (or 3.1%). In overproducers, restarting ULTs following drug holidays of more than 5 days leads to over 60% of patients experiencing hyperuricosuria. Conclusions Suboptimal medication adherence may compromise the safety and efficacy of mono‐ and dual‐ULTs, especially in patients with gout resulting from an overproduction of uric acid. Clinicians and pharmacists should consider counselling patients with respect to the risks associated with partial adherence, and offer interventions to improve adherence or tailor treatments, where appropriate. What is Already known about this Subject Uricosuric agents, used for the treatment of gout, increase the risk of hyperuricosuria and therefore also acute kidney injury. Adherence to urate‐lowering therapies for treating gout is among the worst of any chronic disease. What this Study Adds Restarting uricosuric treatment following a drug holiday increases the rate of episodic hyperuricosuria. Suboptimal medication adherence may compromise the safety and efficacy of mono‐ and dual‐urate‐lowering therapies, especially in patient groups such as those with gout resulting from an overproduction of uric acid. Clinicians and pharmacists should consider counselling patients with respect to the risks associated with partial adherence, and offer interventions to improve adherence or tailor treatments, where appropriate.