Impact of Sampling Time Variability on Tacrolimus Dosage Regimen in Pediatric Primary Nephrotic Syndrome: Single-Center, Prospective, Observational Study.

Lingfei Huang,Junyan Wang,Luo Fang,Jing Miao,Huifen Zhang,Jufei Yang,Yan Hu,Jianhua Mao

doi:10.3389/fphar.2021.726667

Abstract

Background: Tacrolimus (TAC) is an important immunosuppressant for children with primary nephrotic syndrome (PNS). The relationship between sampling time variability in TAC therapeutic drug monitoring and dosage regimen in such children is unknown. Methods: In this single-center, prospective, observational study, we evaluated the sampling time variability, concentration error (CE), relative CE (RCE), and the impact of the sampling time on TAC dosage regimens in 112 PNS children with 188 blood samples. Nominal concentration (Cnom) at 12-h after last TAC dose was simulated based on observed concentration (Cobs) via previously published pharmacokinetic models, then CE and RCE were calculated. Inappropriate dosing adjustments resulting from deviated sampling time were evaluated based on a target Cnom of 5–10 ng/ml. Results: We found that 32 and 68% of samples were respectively collected early (2–180 min) and delayed (4–315 min). Furthermore, 24, 22, 22, and 32% of blood samples were drawn within deviations of ≤0.5, 0.5–1, 1–2, and >2 h, respectively, and 0.3 ng/ml of CE and 6% RCE per hour of deviation occurred. Within a deviation of >2 h, 25% of Cobs might result in inappropriate dosing adjustments. Early and delayed sampling might result in inappropriate dose holding or unnecessary dose increments, respectively, in patients with Cobs ∼ 5 ng/ml. Conclusions: Variable sampling time might lead to inappropriate dosing adjustment in a minority of children with PNS, particularly those with TAC Cobs ∼ 5 ng/ml collected with a deviation of >2 h.

Highlights

Tacrolimus (TAC) is a cornerstone of immunosuppression after organ transplantation (Kidney Disease Improving Global Outcomes KDIGO Transplant Work Group, 2009;Ericson et al, 2017)
We identified the following scenarios of inappropriate dosing decisions associated with sampling time deviation (STD): 1) inappropriate dose adjusting: when Cnom was within the target range (5–10 ng/ml) but Cobs was outside the target range and clinicians altered the TAC treatment; 2) inappropriate dose holding: when Cnom was outside the target range (10 ng/ml) and Cobs was within it, but dosing was not altered
CE and inappropriate clinical decision were estimated based on 160 measurable blood samples from 101 patients, and 93 samples of 59 patients within 6 months after initial treatment, respectively (Figure 1; Table 1)

Summary

Introduction

Tacrolimus (TAC) is a cornerstone of immunosuppression after organ transplantation (Kidney Disease Improving Global Outcomes KDIGO Transplant Work Group, 2009;Ericson et al, 2017). Owing to the substantial individual variability of its pharmacokinetic profile, TAC doses are usually adjusted based on trough concentrations (C0) determined by therapeutic drug monitoring (TDM) (Brunet et al, 2019). The consensus target C0 of TAC in pediatric PNS is 5–10 ng/ml during the first few months of treatment (usually first 6 months), recommended by several professional societies, including the organization of Kidney Disease: Improving Global Outcomes, and Chinese Medical Association (Lombel et al, 2013; Subspecialty Group of Nephrology Society of Pediatrics Chinese Medical Association, 2017). The relationship between sampling time variability in TAC therapeutic drug monitoring and dosage regimen in such children is unknown

Methods

Results

Discussion

Conclusion