Mycophenolic acid pharmacokinetics and pharmacogenomics in lupus nephritis patients on maintenance immunosuppression

Abstract

INTRODUCTION AND AIMS: There is little data on mycophenolic acid (MPA) pharmacokinetics and pharmacogenomics in lupus nephritis (LN) patients on long-term maintenance immunosuppression. METHODS: Blood MPA level at 1, 2, 4, 8, 10 and 12 hours post-dose (i.e. C1, C2, C4, C8, C10 and C12) was measured in clinically stable LN patients receiving maintenance prednisolone and MMF, and repeated every 6 months. The relationship between MPA exposure and single nucleotide polymorphisms (SNP) related to the ATP Binding Subfamily C Member 2 (ABCC2) (rs2273697, rs3740066, rs717620 and rs17222723), organic anion transporting polypeptides (OATP) (rs7311358 and rs4149117) and uridine diphosphate glucuronosyltransferase (UGT) (rs17863762, rs6714486, rs17868320 and rs72551330) was investigated. RESULTS: Seventy-three LN patients receiving prednisolone (6.8±2.4 mg/D) and MMF (1151.5±501.7 mg/D) were included. C1, C2 and C12 MPA levels were 9.4±8.1 mg/L, 8.1±5.9 mg/L and 2.1±1.7 mg/L respectively, and all correlated with AUC0-12 (r= r=0.521, 0.852 and 0.765, p=0.004, <0.001 and <0.001 respectively). C12 level inversely correlated with hemoglobin, total immunoglobulin, IgG, IgA and IgM levels, and leukocyte and platelet counts (p<0.05, for all). Four episodes of disease flares occurred during 17.8±7.3 months of follow-up, giving a relapse rate of 1 in 320 patient-months. C12 MPA levels were similar between relapse and non-relapse patients (2.1±0.9 mg/L vs. 2.4±1.2 mg/L, p=0.738). Higher MPA C12 levels were associated with anaemia (2.9±1.5 mg/L and 1.7±1.1 mg/L in patients with haemoglobin below or >10 g/dL respectively, p=0.003). MPA exposure was not related to infection (n=2) or gastrointestinal upset (n=3). SNP rs2273697 G/G in the ABCC2 gene was associated with higher MPA exposure (1891.5±918.9 mghL-1/gkg-1 vs. 1075.9±239.9 mghL-1/gkg-1, p=0.003) and lower total lymphocyte count (1.6±0.8 vs. 2.1±0.2 109/mL, p=0.01) compared with A/G genotype. SNPs of OATP and UGT were not related to MPA exposure. CONCLUSIONS: C12 MPA level correlated with AUC0-12 and is related to haematological parameters and immunoglobulin suppression. SNP rs2273697 G/G genotype of the ABCC2 gene is associated with higher MPA exposure and lymphopenia.