Total and Free Plasma Concentrations of the Active Metabolite of Leflunomide in Relation to Therapeutic Outcome in Kidney Transplant Recipients With BK-Virus Nephropathy

Hüttemann, Maik; Shipkova, Maria; Klett, Corinne; Hasche, Georg; Wilhelm, J.; Bolley, R.; Olbricht, Christoph J.; Wieland, Eberhard

doi:10.1016/j.transproceed.2012.12.017

Cited by 6 publications

(3 citation statements)

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“…Although it is reported [27][28][29] that cidofovir and leflunomide can be effectively used for antiviral treatment of PVAN, it is still a lack of accepted, standard treatment. For the treatment of PVAN, dose reduction of immunosuppressants was the core principle [9], All the patients diagnosed with PVAN reduced their tacrolimus dose and discontinued mycophenolate mofetil, i.e.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Pathological Study of Polyomavirus-Associated Nephropathy after Renal Transplantation

Ji¹,

Xie²,

Chen³

et al. 2014

J Transplant Technol Res

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Polyomavirus infection has emerged as an important cause of polyomavirus-associated nephropathy (PVAN) leading to allograft dysfunction and loss. The aim of this study is to investigate pathological features and clinical characteristics of PVAN. We prospectively investigated 351 renal allografts performed in Jinling Hospital. PVAN was diagnosed by light microscopic examination and a positive immunohistochemistry staining of anti-SV40 large T antibody in a biopsy specimen. 31 patients were diagnosed with PVAN (8.8%). The patients with PVAN typically presented as allograft dysfunction with an asymptomatic rise in serum creatinine about 3 to 39 months posttransplant. Urinary decoy cells were positive in 4 patients (12.9%). The histologic changes of PVAN are not pathognomonic and can be mistaken for allograft rejection, i.e. tubulointerstitial nephritis with varying degrees of inflammatory infiltrates, tubulitis, tubular atrophy and fibrosis. Typical findings on histology are focal interstitial mononuclear inflammatory cell infiltrates, presence of plasma cells, necrotic tubular epithelium, and presence of homogenous intranuclear inclusion bodies. Immunohistochemistry with SV40 staining is positive in allograft. CD3, CD4, CD8, CD68 positive cells are increased in PVAN group than the non-PVAN group, but none of HLA-DR and IL-2R expression is positive in PVAN patients. MPA AUC 0-12 and TAC trough levels are increased in PVAN group than non-PVAN group at biopsy. We have treated 31 patients with biopsy-proven PVAN with leflunomide. Increased intensity of immunosuppression appears to increase the likelihood of PVAN. The definitive diagnosis of PVAN requires renal biopsy. Immunohistochemistry with SV40 staining has been used as an indirect method to document the presence of PVAN.

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Section: Discussionmentioning

confidence: 99%

Clinical and Pathological Study of Polyomavirus-Associated Nephropathy after Renal Transplantation

Ji¹,

Xie²,

Chen³

et al. 2014

J Transplant Technol Res

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“…Leflunomide is commonly used in the treatment of rheumatoid arthritis (RA) and psoriatic arthritis, with new therapeutic uses under investigation . Activity is mediated via the active metabolite teriflunomide, itself now registered for multiple sclerosis (MS) .…”

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confidence: 99%

“…2 Leflunomide is commonly used in the treatment of rheumatoid arthritis (RA) and psoriatic arthritis, with new therapeutic uses under investigation. [5][6][7] Activity is mediated via the active metabolite teriflunomide, itself now registered for multiple sclerosis (MS). 8 Oral leflunomide is almost completely metabolized during its first pass through the liver and is undetectable in plasma.…”

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confidence: 99%

Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients

Hopkins

Wiese

Proudman

et al. 2015

CPT Pharmacometrics Syst. Pharmacol.

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A semiphysiologically based pharmacokinetic (semi-PBPK) population model was used to evaluate the influence of enterohepatic recycling and protein binding, as well as the effect of genetic variability in CYP1A2, CYP2C19, and ABCG2, on the large interindividual variability of teriflunomide (active metabolite) concentrations following leflunomide administration in rheumatoid arthritis (RA) patients. The model was developed with total and free teriflunomide concentrations determined in RA patients taking leflunomide, as well as mean teriflunomide concentrations following the administration of leflunomide or teriflunomide extracted from the literature. Once developed, the 15-compartment model was able to predict total and free teriflunomide concentrations and was used to screen demographic and genotypic covariates, of which only fat-free mass and liver function (ALT) improved prediction. This approach effectively evaluated the effects of multiple covariates on both total and free teriflunomide concentrations, which have only been explored previously through simplistic one-compartment models for total teriflunomide.

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LC-MS/MS Method for the Quantification of the Leflunomide Metabolite, Teriflunomide, in Human Serum/Plasma

Rule

Rockwood

Johnson-Davis

2018

Methods in Molecular Biology

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Total and Free Plasma Concentrations of the Active Metabolite of Leflunomide in Relation to Therapeutic Outcome in Kidney Transplant Recipients With BK-Virus Nephropathy

Cited by 6 publications

References 1 publication

Clinical and Pathological Study of Polyomavirus-Associated Nephropathy after Renal Transplantation

Clinical and Pathological Study of Polyomavirus-Associated Nephropathy after Renal Transplantation

Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients

LC-MS/MS Method for the Quantification of the Leflunomide Metabolite, Teriflunomide, in Human Serum/Plasma

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