Population pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide metabolite in patients with autoimmune glomerulonephritis.

OBJECTIVES

To develop a simultaneous population pharmacokinetic model of cyclophosphamide (CY) and 4-hydroxycyclophosphamide (4-OH) in patients with glomerulonephritis.

METHODS

In total, 23 patients participated in a pharmacokinetic evaluation using dense plasma sampling. A population pharmacokinetic model was developed in Monolix Suite 2020R1 that simultaneously describes the kinetics of CY and 4-OH. Several structural and residual error models were evaluated and patient variables were tested as potential covariates. The final model was selected based on visual predictive check and bootstrap. Simulations of plasma concentrations for various doses were conducted.

KEY FINDINGS

A model including two compartments for CY and one for 4-OH was found to best describe the data. A proportional error model for both compounds was chosen. The following estimates were found for the main CY pharmacokinetic parameters: total clearance, 13.3 l/h with inter-individual variability (IIV) 32%, and central volume of distribution, 59.8 l with IIV 12%. The metabolite elimination rate constant was 4.3 h-1 with IIV 36% and the proportion of metabolism 64%. Sex was a significant covariate on the central volume of CY, with females exhibiting 25% lower value than males.

CONCLUSIONS

A population pharmacokinetic model was developed for CY and 4-OH in patients with autoimmune glomerulonephritis. Simulations using various dose regimens allow for informed dosing before the initiation of therapy.