Population pharmacokinetics model and initial dose optimization of tacrolimus in children and adolescents with lupus nephritis based on real‑world data

Abstract

The present study aimed to establish a population pharmacokinetics model of tacrolimus and further optimize the initial dosing regimen of tacrolimus in pediatric and adolescent patients with lupus nephritis (LN). Pediatric and adolescent patients with LN were recruited between August 2014 and September 2019 at the Children's Hospital of Fudan University (Shanghai, China). Relevant information was used to set up a population pharmacokinetics model with a Nonlinear Mixed Effect Model and the initial dosage regimen was simulated with the Monte Carlo method. Body weight and co-administration of wuzhi capsule were indicated to influence tacrolimus clearance in pediatric and adolescent patients with LN, and at the same body weight, the rate of tacrolimus clearance in patients without vs. with co-administration of wuzhi capsule was 1:0.71. In addition, in patients who were not administered wuzhi capsule, an initial dosage regimen of 0.15 mg/kg/day was recommended for a body weight of 10-23 kg and 0.10 mg/kg/day for 23-60 kg; in patients who were administered wuzhi capsule, an initial dosage regimen of 0.10 mg/kg/day was recommended for a body weight of 10-23 kg and 0.05 mg/kg/day for 23-60 kg. To the best of our knowledge, the present study was the first to establish a population pharmacokinetics model of tacrolimus in order to determine the optimal initial dosage regimen of tacrolimus in pediatric and adolescent patients with LN.

Controversial Interactions of Tacrolimus with Dietary Supplements, Herbs and Food

“…Side effects, such as hyperkalaemia or fever, were reported after SchE and tacrolimus co-administration and were accounted for as a result of an increased tacrolimus blood concentration [ 78 , 86 ]. Several population pharmacokinetic models have been developed to support the individualization of tacrolimus dosing for different groups: renal transplant recipients [ 81 , 83 , 85 , 87 , 88 ], liver transplant recipients [ 89 , 90 ], cardiac transplant recipients [ 91 , 92 ], patients with refractory nephrotic syndrome [ 93 , 94 ], membranous nephropathy [ 95 , 96 ], lupus nephritis [ 97 , 98 ] or myasthenia gravis [ 99 ]. SchE may significantly increase tacrolimus bioavailability and reduce its therapeutic costs by 40–60%, nevertheless, authors highly recommend blood tacrolimus concentration monitoring while co-administering with SchE [ 78 , 79 , 82 , 85 ].…”

Population Pharmacokinetics of Tacrolimus in Pediatric Patients With Umbilical Cord Blood Transplant

“…The model was parameterized in terms of CL, V, K a , and D2 of tacrolimus. K a was fixed at 4.48/h according to the pieces of published literature, 26–29 and D2 was fixed as 24 hours. The interindividual variability was modeled using the exponential error model and was then estimated for CL.…”

“…The PK parameters included clearance (CL), volume of distribution (V), absorption rate constant (K a ), and duration parameter of that input (D2). K a was fixed at 4.48/h [26][27][28][29] and D2 was fixed at 24 hours.…”