Population pharmacokinetic and exposure–response analyses of intravenous and subcutaneous rituximab in patients with chronic lymphocytic leukemia

Gibiansky, Ekaterina; Gibiansky, Leonid; Chavanne, Clarisse; Frey, Nicolas; Jamois, Candice

doi:10.1002/psp4.12665

Cited by 12 publications

(28 citation statements)

References 36 publications

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“…doses (all patients received their first dose as R‐i.v.). The CLL PopPK model is reported elsewhere (based on 4,739 concentrations from 255 patients) 26 …”

Section: Resultsmentioning

confidence: 99%

“…In patients with CLL, the covariates BSA, body mass index, sex, white blood cell count, and tumor size, 26 and the individual parameters from 140 patients from SAWYER were used to predict and demonstrate that the ratios for geometric mean C trough for s.c. relative to i.v. dosing exceeded 1.…”

Section: Resultsmentioning

confidence: 99%

“…SABRINA, SAWYER (stage 2), PrefMab, and MabEase also supported evaluation of R‐s.c. efficacy and safety 1,19,20,23–26 . SparkThera and SAWYER were two‐stage studies of R‐s.c.…”

Section: Methodsmentioning

confidence: 99%

“…and s.c. formulations. Times needed to saturate the time‐varying elimination pathway of rituximab were also compared 26 . To assess rituximab ER relationships (safety and efficacy), C trough at EOI (FL) or at the end of treatment (CLL; C tr LD) and average concentrations over the induction period (C mean LD) were also computed.…”

Section: Methodsmentioning

confidence: 99%

“…In FL, relationships among exposure, patient characteristics, or disease‐specific covariates, and progression‐free survival (PFS) were explored using semiparametric Cox proportional hazard (CPH) models 26 in patients who received ≥ 7 rituximab doses. The relationship between rituximab exposure (continuous variables of C trough at the end of C7 (primary measure per protocol, utilizing rituximab concentration 21 days after the C7 dose), log (C trough at the end of C7), AUCτ at the end of C7 (AUC7, exploratory secondary measure, AUCτ from time of C7 dose until 21 days postdose), log (AUC7), and tertiles of C trough at the end of C7) and PFS was first characterized using a base CPH model (i.e., without covariates).…”

Section: Methodsmentioning

confidence: 99%

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Quantitative Clinical Pharmacology Supports the Bridging From i.v. Dosing and Approval of s.c. Rituximab in B‐Cell Hematological Malignancies

Jamois

Gibiansky²,

Gibiansky³

et al. 2021

Clin Pharma and Therapeutics

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A fixed-dose subcutaneous (s.c.) formulation of the anti-CD20 antibody, rituximab, has been developed to address safety, infusion time, and patient comfort concerns relating to intravenous (i.v.) dosing, and has been approved based upon a pharmacokinetic (PK)-clinical bridging strategy, which demonstrated noninferiority of s.c. vs. i.v. dosing in malignancies, including follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). A clinical development plan was undertaken to identify rituximab s.c. doses achieving noninferior exposure to rituximab i.v., and to confirm PK-clinical bridging, with the same efficacy and similar safety. This drew upon data from 1,579 patients with FL, CLL, or diffuse large B-cell lymphoma in 5 clinical studies, and showed minimum steady-state serum concentration (C trough ) as the most appropriate exposure bridging measure. Population PK models were developed, simulations were run using covariates and PK parameters from clinical studies, and exposure-efficacy and -safety analyses performed. Population PKs showed a two-compartment model with time-dependent and -independent clearances. Clearance and volume were predominantly influenced by body surface area; disposition and elimination were similar for the s.c. and i.v. formulations. After s.c. administration, patients with FL and CLL achieved noninferior exposures to i.v. dosing. Overall, rituximab exposure and route of administration did not influence clinical responses in patients with FL or CLL, and there was no association between exposure and safety events. C trough was shown to be an effective pharmacologic-clinical bridging parameter for rituximab in patients with FL or CLL. Clinically effective exposures are achieved with either s.c. or i.v. dosing.

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“…doses (all patients received their first dose as R‐i.v.). The CLL PopPK model is reported elsewhere (based on 4,739 concentrations from 255 patients) 26 …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…SABRINA, SAWYER (stage 2), PrefMab, and MabEase also supported evaluation of R‐s.c. efficacy and safety 1,19,20,23–26 . SparkThera and SAWYER were two‐stage studies of R‐s.c.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Quantitative Clinical Pharmacology Supports the Bridging From i.v. Dosing and Approval of s.c. Rituximab in B‐Cell Hematological Malignancies

Jamois

Gibiansky²,

Gibiansky³

et al. 2021

Clin Pharma and Therapeutics

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Clinical study design strategies to mitigate confounding effects of time‐dependent clearance on dose optimization of therapeutic antibodies

Proctor,

Wong

2024

CPT Pharmacom & Syst Pharma

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Time‐dependent pharmacokinetics (TDPK) is a frequent confounding factor that misleads exposure‐response (ER) analysis of therapeutic antibodies, where a decline in clearance results in increased drug exposure over time in patients who respond to therapy, causing a false‐positive ER finding. The object of our simulation study was to explore the influence of clinical trial designs on the frequency of false‐positive ER findings. Two previously published population PK models representative of slow‐ (pembrolizumab) and fast‐onset (rituximab) TDPK were used to simulate virtual patient cohorts with time‐dependent clearance and the frequency of false‐positive ER findings. The impact of varying the number of dose groups, dose range, and sample size was evaluated over time. Study designs with a single tested dose level showed a high probability of showing a false‐positive ER finding. When TDPK has a slow onset, use of exposure measures from early timepoints in ER analysis significantly reduces the risk of a false‐positive, while with fast onset it did not. Randomization of patients to two dose levels greatly reduced the risk, with a threefold or greater dose range offering the greatest benefit. The likelihood of false‐positive increases with a larger sample size, where greater care should be taken to identify confounding factors. Clinical trial simulation supports that appropriate clinical study design and analysis with adequate dose exploration can reduce but cannot entirely eliminate the risk of misleading ER findings.

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Mechanisms of resistance to anti-CD20 antibodies in lymphoid malignancies

Bordron,

Morel,

Bagacean

2024

Resistance to Anti-Cd20 Antibodies and Approaches for Their Reversal

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Population pharmacokinetic and exposure–response analyses of intravenous and subcutaneous rituximab in patients with chronic lymphocytic leukemia

Abstract: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 12 publications

References 36 publications

Quantitative Clinical Pharmacology Supports the Bridging From i.v. Dosing and Approval of s.c. Rituximab in B‐Cell Hematological Malignancies

Quantitative Clinical Pharmacology Supports the Bridging From i.v. Dosing and Approval of s.c. Rituximab in B‐Cell Hematological Malignancies

Clinical study design strategies to mitigate confounding effects of time‐dependent clearance on dose optimization of therapeutic antibodies

Mechanisms of resistance to anti-CD20 antibodies in lymphoid malignancies

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