Population pharmacokinetics and limited sampling strategy for therapeutic drug monitoring of mycophenolate mofetil in Japanese patients with lupus nephritis

Tomoko Mizaki; Hironobu Nobata; Shogo Banno; Makoto Yamaguchi; Hiroshi Kinashi; Shiho Iwagaitsu; Takuji Ishimoto; Yukiko Kuru; Masafumi Ohnishi; Ken-Ichi Sako; Yasuhiko Ito

doi:10.1186/s40780-022-00271-w

Population pharmacokinetics and limited sampling strategy for therapeutic drug monitoring of mycophenolate mofetil in Japanese patients with lupus nephritis

J Pharm Health Care Sci. 2023 Jan 9;9(1):1. doi: 10.1186/s40780-022-00271-w.

Authors

Affiliations

¹ Department of Pharmacy, Aichi Medical University Medical Center, 17-33 Nikkicho, Okazaki, Aichi, 444-2148, Japan.
² Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
³ Medical Education Center, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
⁴ Department of Pharmacy, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
⁵ Department of Clinical Pharmacy, Nihon Pharmaceutical University, 10281 Komuro, Kitaadachigun Inamachi, Saitama, 362-0806, Japan.
⁶ Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan. yasuito@aichi-med-u.ac.jp.

Abstract

Background: Mycophenolate mofetil (MMF), a prodrug of the immunosuppressive agent mycophenolic acid (MPA), is difficult to administer because of the pharmacokinetic complexity of MPA. Although dosage adjustment according to the 12-h area under the concentration-time curve (AUC_0-12) is thought to be desirable, multiple blood samplings for AUC calculation may pose a clinical challenge. A limited sampling strategy (LSS) would provide a solution; however, little is known about MPA pharmacokinetics in lupus nephritis patients, especially in those with Asian backgrounds, or few, if any, LSSs are reported for them.

Methods: Thirty-four adult Japanese patients receiving MMF for lupus nephritis were examined retrospectively. MPA pharmacokinetics were investigated, and a PPK model was developed using Phoenix® NLME™ software. Single and double blood sampling strategies from Bayesian estimation using the PPK model and from multiple linear regression were compared. Tolerability was also evaluated.

Results: In the pharmacokinetic analysis, renal function and serum albumin had significant effects on dose-normalized AUC_0-12; and serum albumin, concomitant proton pump inhibitor (PPI) and iron/magnesium oxide did on dose-normalized maximum concentration. As a PPK model, a two-compartment model was developed with a transit absorption model and first-order elimination, in which creatinine clearance and serum albumin were covariates for MPA clearance. The double sampling strategy at 1 and 4 h by multiple linear regression showed the best agreement with the observed AUC_0-12 (r² = 0.885). Of the single sampling strategies, the one at 6 h by Bayesian estimation performed best (r² = 0.769). The tolerability evaluation showed that correlations were suggested for gastrointestinal involvement.

Conclusions: The present study developed the first PPK model of MPA for Japanese lupus nephritis patients. As for LSSs, a double sampling strategy at 1 and 4 h by multiple linear regression would work best; when only a single blood sampling is allowed, a strategy at 6 h by Bayesian estimation using the PPK model developed in this study would be best. The LSSs good enough for clinical use may facilitate safer, more effective, and individualized therapy.

Keywords: Limited sampling strategy; Lupus nephritis; Mycophenolate mofetil; Mycophenolic acid; Population pharmacokinetics.

Grants and funding

2020-7/Aichi Kidney Foundation