In lupus nephritis, mycophenolic acid C12 linked to 12-hour AUC, renal flare, infection and anemia

Mycophenolic acid C12 appeared to be associated with the 12-hour area under the curve, and was linked to renal flare, infection and anemia, according to findings published in Nephrology Dialysis Transplantation.

“There is emerging preliminary data on the level of mycophenolic acid exposure that is associated with favorable response to induction immunosuppression for lupus nephritis,” Desmond Y.H. Yap, MD, of the division of nephrology, Department of Medicine at the University of Hong Kong, and colleagues wrote. “In contrast, there is little data on the relationship between MPA exposure and disease status or drug-induced adverse events such as marrow suppression and infection during the maintenance phase.”
In the study, researchers evaluated 88 individuals with biopsy-proven, stable lupus nephritis who had undergone continuous treatment with prednisolone and mycophenolate mofetil as both induction and maintenance immunosuppressive therapy. Additionally, eligible patients had responded favorably to treatment, with more than 12 months elapsed between the start of induction immunosuppression and the last incidence of active nephritis.
Study participants received prednisolone 0.8 mg/kg per day and mycophenolate mofetil 1 g twice per day. At approximately 6 months, the prednisolone dose was decreased to 7.5 mg per day, and at 12 months, it was decreased to 5 to 7.5 mg per day. Investigators administered mycophenolate mofetil at a target dose of 1,000 mg twice daily for 6 months, 750 mg twice a day between month 7 and month 12, and 500 to 750 mg twice per day in the second year of treatment.

The researchers evaluated blood concentrations of MPA at 1, 2, 4, 8, 10 and 12 hours after the dose of mycophenolate mofetil (C1, C2, C4, C8, C10 and C12). They used the trapezoid method to calculate the 12-hour area under the curve (AUC 0-12).

Investigators also assessed the relationship between MPA exposure and single nucleotide polymorphisms (SNPs) of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2; rs2273697, rs3740066, rs717620 and rs16222623) organic anion-transporting polypeptides (OATPs; rs7311357 and rs4148117) and uridine diphosphate glucuronosyltransferase (UGT; rs17863762, rs6714486, rs17868320 and rs72551330). These SNPs have reportedly affected MPA exposure in kidney transplant patients.

The researchers found that at one hour after the dose, the blood levels of MPA were 8.3±6.6 mg/L at C1, 7.2±5.2 mg/L at C2, and 2.0±1.4 mg/dL at C12. All were associated with the 12-hour area under the curve (AUC_0-12; r = 0.51; P = .02; r = 0.85; P <.001; and r = 0.72; P < .001, respectively). MPA at 12 hours was negatively associated with hemoglobin level (r = 0.438; P < .001) and white cell count (r = 0.302; P < .018).

Over the course of 96 weeks, the following events were reported: 5 renal flares, 11 infections and 10 episodes of anemia (hemoglobin <10 g/dL). At 12 hours post-dose, these patients had MPA concentrations of 1.3±0.5 mg/L for renal flares (P = .041), 4.3±2.6 mg/L for infection (P < .001) and 2.9±1.5 mg/L for anemia (P = .004). Researchers observed a significant association the rs2273697 genotype A/G in the ABCC2 gene and lower MPA drug exposure vs. genotype G/G (1075.9±239.9 vs. 1891.5±9.18.9 mg/L per g/kg; P = .003). No correlation was observed between rs2273697 A/G and the incidence of clinical flares.

No correlation was seen between SNPs of OATP or UGT and MPA concentration.

“The C12 MPA level correlates with AUC_10-12 and is related to hematological parameters, immunoglobulin level suppression, infection and renal flare in lupus nephritis patients on low-dose corticosteroid plus mycophenolate treatment during the maintenance phase,” the researchers wrote. “SNP rs2273697 A/G genotype of the ABCC2 gene is associated with lower MPA exposure.” - by Jennifer Byrne

Disclosure: The study was funded by the Health and Medical Research Fund 2013 of the Hong Kong Special Administrative Region Food and Health Bureau. The authors report no relevant financial disclosures.

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Yap DY t al. Nephrology Dialysis Transplantation. 2018;doi:10.1093/ndt/gfy284