Use of Therapeutic Drug Monitoring Does Not Add Clinical Value for Voclosporin in Patients with Lupus Nephritis
Bibliographic record
Abstract
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 Conclusions: 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
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.006 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".