Pharmacokinetics of Mycophenolate Mofetil in Omani Patients on Cyclosporine or Tacrolimus

Mohsin, Nabil; Al-Raisi, Fatma; Militsala, E.; Kamble, Pramod; Razek, E. Abdel; Baddruddin, M.

doi:10.1016/j.transproceed.2015.01.023

Cited by 2 publications

(2 citation statements)

References 19 publications

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“…The overall contribution of enterohepatic circulation to interpatient variability in mycophenolic acid pharmacokinetics is primarily impacted by concurrent calcineurin inhibitor . It is hypothesized that cyclosporine contributes to lower mycophenolic acid exposure by interfering with enterohepatic circulation of mycophenolic acid glucuronide to mycophenolic acid .…”

Section: Discussionmentioning

confidence: 99%

Influence of Calcineurin Inhibitor and Sex on Mycophenolic Acid Pharmacokinetics and Adverse Effects Post–Renal Transplant

Meaney

Sudchada²,

Consiglio

et al. 2019

The Journal of Clinical Pharma

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Tacrolimus or cyclosporine is prescribed with mycophenolic acid posttransplant and contributes to interpatient variability in mycophenolic acid pharmacokinetics and response. Cyclosporine inhibits enterohepatic circulation of the metabolite mycophenolic acid glucuronide, which is not described with tacrolimus. This study investigated mycophenolic acid pharmacokinetics and adverse effects in stable renal transplant recipients and the association with calcineurin inhibitors, sex, and race. Mycophenolic acid and mycophenolic acid glucuronide area under the concentration‐time curve from 0 to 12 hours (AUC0‐12h) and apparent clearance were determined at steady state in 80 patients receiving cyclosporine with mycophenolate mofetil and 67 patients receiving tacrolimus with mycophenolate sodium. Gastrointestinal adverse effects and hematologic parameters were evaluated. Statistical models evaluated mycophenolic acid pharmacokinetics and adverse effects. Mycophenolic acid AUC0‐12h was 1.70‐fold greater with tacrolimus (68.9 ± 30.9 mg·h/L) relative to cyclosporine (40.8 ± 17.6 mg·h/L); P < .001. Target mycophenolic acid AUC0‐12h of 30–60 mg·h/L was achieved in 56.3% on cyclosporine compared with 34.3% receiving tacrolimus (P < .001). Mycophenolic acid clearance was 48% slower with tacrolimus (10.6 ± 4.7 L/h) relative to cyclosporine (20.5 ± 10.0 L/h); P < .001. Enterohepatic circulation occurred less frequently with cyclosporine (45%) compared with tacrolimus (78%); P < 0.001; with a 2.9‐fold greater mycophenolic acid glucuronide AUC0‐12h to mycophenolic acid AUC0‐12h ratio (P < .001). Race did not affect mycophenolic acid pharmacokinetics. Gastrointestinal adverse effect scores were 2.2‐fold higher with tacrolimus (P < .001) and more prominent in women (P = .017). Lymphopenia was more prevalent with tacrolimus (52.2%) than cyclosporine (22.5%); P < 0.001. Calcineurin inhibitors and sex contributed to interpatient variability in mycophenolic acid pharmacokinetics and adverse effects post–renal transplant, which could be attributed to differences in enterohepatic circulation.

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Section: Discussionmentioning

confidence: 99%

Influence of Calcineurin Inhibitor and Sex on Mycophenolic Acid Pharmacokinetics and Adverse Effects Post–Renal Transplant

Meaney

Sudchada²,

Consiglio

et al. 2019

The Journal of Clinical Pharma

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“…Enterohepatic circulation of the mycophenolic acid glucuronide to the active drug, mycophenolic acid, contributes to interpatient pharmacokinetic variability and is influenced by the concurrent calcineurin inhibitor and its dosing protocol. [43][44][45][46][47][48][49] It is postulated that cyclosporine contributes to lower mycophenolic acid exposure by interfering with enterohepatic circulation, possibly through inhibition of multiple resistance protein 2 efflux transporter, resulting in elimination of the second peak of the active moiety. 19,20,50 This inhibition in enterohepatic circulation of mycophenolic acid glucuronide to mycophenolic acid does not appear to occur with concurrent tacrolimus.…”

Section: Discussionmentioning

confidence: 99%

Association of ABCC2 Haplotypes to Mycophenolic Acid Pharmacokinetics in Stable Kidney Transplant Recipients

Brazeau

Meaney

Consiglio

et al. 2021

The Journal of Clinical Pharma

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Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is mediated by the multidrug resistance‐associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes ‐24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross‐sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC0‐12h (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h. The wild‐type haplotype ABCC2 CGC had greater mycophenolic acid AUC0‐12h (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine‐mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment.

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Pharmacokinetics of Mycophenolate Mofetil in Omani Patients on Cyclosporine or Tacrolimus

Cited by 2 publications

References 19 publications

Influence of Calcineurin Inhibitor and Sex on Mycophenolic Acid Pharmacokinetics and Adverse Effects Post–Renal Transplant

Influence of Calcineurin Inhibitor and Sex on Mycophenolic Acid Pharmacokinetics and Adverse Effects Post–Renal Transplant

Association of ABCC2 Haplotypes to Mycophenolic Acid Pharmacokinetics in Stable Kidney Transplant Recipients

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