Pharmacokinetics of Enteric Coated Mycophenolate Sodium in Lupus Nephritis

The drug Mycophenolate mofetil (MMF) was introduced into routine clinical practice in 1995 to prevent the rejection of kidney transplants in the USA and in Europe in 1996. A second formulation of its active metabolite, mycophenolic acid (MPA), became available as an enteric-coated tablet called mycophenolate sodium (EC-MPS). and clinical trials showed that EC-MPS was as effective and safe as MMF. Equipotent doses of EC-MPS and MMF result in equivalent amounts of active metabolite ie MPA in the blood. On this basis MMF was trialled in patients with autoimmune and several immunologically mediated renal diseases. A recent meta-analysis of randomized controlled trials showed that MMF was not only better at gaining control of severe lupus nephritis (LN), an immunologically mediated kidney disease,, but also caused fewer side effects than the historically best treatment of pulsed cyclophosphamide. Up to 2 g of MMF each day were initially used to treat LN. Subsequent dosing regimens started with 2g MMF/day but subsequently titrated up to a maximum of 3 g/day . In one study a median dosage of 42mg/kg body weight MMF was used for 20-24 weeks and most patients (91.3%) tolerated MMF doses of up to 2.5-3.0 g/day. MMF 1000mg equates to about 720mg of MPS . However the amount of MPA in the blood varies from patient to patient. The factors causing these differences have been studied in transplant patients but not in LN patients. Nor has the relationship between MPA concentration and its effect on the kidney disease been described in LN patients. We propose using therpeutic drug monitoring of MPS to 1) describe any inter–patient variability in MPA blood concentrations among LN patients treated with MPS 2) correlate dose used with its efficacy and safety and 3) explore the relationship between treatment failures and underdosing of MPS in patients with LN. The results of these studies will tell us whether we ought to change our clinical practice, specifically whether therapeutic drug monitoring, not currently done, and consequent personalisation of MPS doses ought to become part of how we manage LN.