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Abstract: PO1918

Use of Therapeutic Drug Monitoring Does Not Add Clinical Value for Voclosporin in Patients with Lupus Nephritis

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • van Gelder, Teun, Universiteit Leiden, Leiden, Zuid-Holland, Netherlands
  • Huizinga, Robert B., Aurinia Pharmaceuticals Inc Victoria, Victoria, British Columbia, Canada
  • Noukens, Jan, Curare Consulting, Leiden, Netherlands
  • Lisk, Laura Jane, Aurinia Pharmaceuticals Inc Victoria, Victoria, British Columbia, Canada
  • Solomons, Neil, Aurinia Pharmaceuticals Inc Victoria, Victoria, British Columbia, Canada
Background

In a phase III clinical trial in patients with active lupus nephritis (LN), patients treated with 23.7 mg voclosporin bid in combination with MMF, achieved renal response rates of 40.8% vs. 22.5% for the control arm (OR 2.65; p < 0.001). The dose of voclosporin (VCS) was adjusted in response to decreases in eGFR. The objective of the present analysis was to evaluate the potential added value for therapeutic drug monitoring (TDM) in the LN patient population

Methods

Pharmacokinetic (PK) data was analyzed from patients with LN treated with VCS. Based on a population PK model, the influence of various covariates on the disposition of voclosporin was evaluated. Calcineurin inhibition (CNI) was estimated using concentration data in the LN population and previously measured inhibition. Obtained exposure were put into perspective of renal response and the established safety margin

Results

Sex, body weight, race, age, serum albumin, total bilirubin and eGFR demonstrated no significant or clinically relevant effect on the PK parameters. VCS has linear PK, and the goodness-of-fit plots (Figure 1 a/b) indicate that the model adequately describes observed and predicted concentrations of VCS. A strong correlation between VCS concentration and calcineurin inhibition is observed. VCS inhibits calcineurin in a dose-dependent manner up to maximum of 64 mg bid. In healthy subjects, a 96 mg bid dose was considered to be the upper limit of tolerability though did not present any safety concerns. At the 4-fold lower therapeutic dose of 23.7 mg bid, CNI was estimated to be 15.7% at Ctrough and 58.1% at Cmax. In a quartile exposure analysis, no relationship with the odds ratio for renal response was observed and favored VCS in all quartiles

Conclusion

At a therapeutic dose of 23.7 mg bid, sex, body weight, race, age, serum albumin, total bilirubin and eGFR demonstrated no clinically relevant effect on VCS PK parameters. The linear PK profile of VCS allows the use of a pharmacodynamic approach instead of a pharmacokinetic approach, in which the dose of VCS is adjusted in response to decreases in eGFR. These data suggest that TDM is unlikely to be of added benefit to patient management