Pharmacokinetics and pharmacogenomics of mycophenolic acid and its clinical correlations in maintenance immunosuppression for lupus nephritis.

Abstract

There is little data on mycophenolic acid (MPA) pharmacokinetics and pharmacogenomics and optimal MPA exposure in lupus nephritis (LN) patients during long-term maintenance. We measured blood MPA levels at 1, 2, 4, 8, 10 and 12-h post-dose (i.e. C1, C2, C4, C8, C10 and C12) in 88 stable LN patients receiving maintenance prednisolone and mycophenolate mofetil, repeated every 6 months. The relationship between MPA exposure and single nucleotide polymorphisms (SNPs) of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2; rs2273697, rs3740066, rs717620 and rs17222723), organic anion-transporting polypeptides (OATPs; rs7311358 and rs4149117) and uridine diphosphate glucuronosyltransferase (UGT; rs17863762, rs6714486, rs17868320 and rs72551330) was also investigated. C1, C2 and C12 were 8.3 ± 6.6 , 7.2 ± 5.2 and 2.0 ± 1.4 mg/L and all correlated with the 12-h area under the curve (AUC0-12; r = 0.51, 0.85 and 0.73; P = 0.02, <0.001 and <0.001, respectively). C12 inversely correlated with hemoglobin, immunoglobulins and leukocyte levels (P < 0.05 for all). Five renal flares, 11 episodes of infection and 10 episodes of anemia (hemoglobin <10 g/dL) occurred over 96 weeks, with a corresponding C12 of 1.3 ± 0.5, 4.3 ± 2.6 and 2.9 ± 1.5 mg/L, respectively (versus 2.4 ± 1.2, 1.8 ± 1.2 and 1.7 ± 1.1 mg/L in patients without these complications; P = 0.041, <0.001 and 0.004). SNP rs2273697 A/G in the ABCC2 gene was associated with lower MPA exposure compared with G/G (1075.9 ± 239.9 versus 1891.5 ± 918.9 mgh/L per g/kg; P = 0.003). SNPs of OATP and UGT were unrelated to MPA level. MPA C12 correlates with the AUC0-12 and is related to renal flare, infection and anemia. SNP rs2273697 A/G is associated with lower MPA exposure.