How should mycophenolate be dosed for use in rheumatology?

Fråga: How should mycophenolate be dosed for use in rheumatology (especially scleroderma, morphea, and systemic lupus erythematosus)? Is therapeutic drug monitoring necessary when treating for these diagnoses? If so, are through values enough, or should one measure AUC?

Mycophenolate is increasingly used off-label in rheumatology. In adult rheumatology the doses used are usually the same as those given for prophylaxis of organ rejection (for which the drug is actually registered). The dose is adjusted so as to avoid adverse reactions and therapeutic drug monitoring is not usually performed. Off-label use of mycophenolate is increasing even in paediatric rheumatology.

Sammanfattning: The therapeutic intervals used MMF are based on treatment to avoid transplant rejection, but studies suggest that the same concentration, or higher, should apply for rheumatic diseases. It could therefore be of value to monitor blood drug concentrations of MMF even when treating rheumatic disease. This is especially important in children, where little is known about the treatment. Note that an AUC measurement is needed for estimating blood drug concentrations.

Svar: Mycophenolate mofetil (MMF) is an immunosuppressive agent approved for the treatment of acute transplant rejection after kidney, heart or liver transplants in combination with cyclosporine and corticosteroids (1). Off-label use of the drug, including for rheumatic diseases, has become increasingly common, e.g. for treatment of lupus nephritis, rheumatoid arthritis and scleroderma (2). Lupus nephritis is the indication for which the use of MMF has been studied the most, and for this disease there are also dose studies in adult patients. These show different results, but suggest that doses > 2g/day provide better treatment outcome (most studies have 3g/day that target dose) (2-5). These studies therefore advocate slightly higher doses of MMF for rheumatic diseases than those recommended for prevention of transplant rejection. However, it is well known at the dose - concentration relationship for MMF is highly variable, and blood drug concentrations should therefore be monitored (6). Trough levels do not correlated well with AUC and the AUC is recommended for concentration determination (6).

There are few concentration - effect studies of MMF in transplanted patients, but it has been suggested that an AUC (0-12 hours) of 95-190 µmol*h/L reduces the risk of rejection in patients with renal transplants (7). A review study of MMF treatment in patients with autoimmune disease, which also contains a few paediatric studies, concludes that an AUC (0-12 hours) of > 100 µmol*h/L leads to better treatment response (8). No difference in concentration between adult and paediatric patients is reported (8). CellCept. Fass 2014 Touma Z, Gladman DD, Urowitz MB, Beyene J, Ulerik EM, Shah PS. Mycophenolate mofetil for induction treatment of lupus nephritis: a systematic review and metaanalysis. J Rheumatol 2011;38(1):69-78 Sundel R, Solomons N, Lisk L, Aspreva Lupus Management Study (ALMS) Group. Efficacy of mycophenolate mofetil in adolescent patients with lupus nephritis: evidence from a two-phase, prospective randomized trial. Lupus 212;21(13):1433-43 Elyan M, Ballou S. The effectiveness and safety of mycophenolate mofetil in lupus nephritis. Clin Rheumatol 2009;28(7):835-40 Schiff M, Beaulieu A, Scott DL, Rashford M. Mycophenolate mofetil in the treatment of adults with rheumatoid arthritis: three 24-week, randomized, double-blind, placebo- or ciclosporin-controlled trials. Clin Drug Investig 2010;30(9):613-24 Tett SE, Saint-Marcoux F, Staatz CE, Brunet M, Vinks AA, Miura M, Marquet P, Kuypers DR, van Gelder T, Cattaneo D. Mycophenolate, clinical pharmacokinetics, formulations, and methods for assessing drug exposure. Transplant Rev (Orlando) 2011;25(2):47-57 van Gelder T, Hillbrands LB, Vanrenterghem Y, Weimar W, de Fijter JW, Squifflet JP, Hene RJ, Verpooten GA, Navarro MT, Hale MD; Nicholls AJ. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantion. Transplantation 1999;68(2):261-6 Abd Rahman AN, Tett SE, Staatz CE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease. Clin Pharmacokinet 2013;52(5):303-31