Tacrolimus Population Pharmacokinetic Model in Adult Chinese Patients with Nephrotic Syndrome and Dosing Regimen Identification Using Monte Carlo Simulations

Background: The study aimed to establish a population pharmacokinetic (PPK) model of tacrolimus for Chinese patients with nephrotic syndrome using the patient's genotype and Wuzhi capsule dosage as the main test factors. Methods: Ninety-six adult patients with nephrotic syndrome, who were receiving tacrolimus treatment, were enrolled. A nonlinear mixed-effects model was used to determine the influencing factors of interindividual tacrolimus metabolism variation and establish a PPK model. To optimize the tacrolimus dosage, 10,000 Monte Carlo simulations were performed. Results: The 1-chamber model of first-order absorption and elimination was the most suitable model for the data in this study. The typical population tacrolimus clearance ( CL/F ) value was 16.9 L/h. The percent relative standard error (RSE%) of CL/F was 12%. Increased Wuzhi capsule and albumin doses both decreased the tacrolimus CL/F . In CYP3A5 homozygous mutation carriers, the CL/F was 39% lower than that of carriers of the wild-type and heterozygous mutation. The tacrolimus CL/F in patients who were coadministered glucocorticoids was 1.23-fold higher than that of the control. According to the patient genotype and combined use of glucocorticoids, 26 combinations of Wuzhi capsule and tacrolimus doses were matched. The Monte Carlo simulation identified the most suitable combination scheme. Conclusions: An improved tacrolimus PPK model for patients with nephrotic syndrome was established, and the most suitable combination of Wuzhi capsule and tacrolimus doses was identified, thus, facilitating the selection of a more economical and safe administration regimen.