Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma

Wang, Erjian; Kang, Dongwoo; Bae, Kyun‐Seop; Marshall, Margaret A.; Pavlov, Dmitri; Parivar, Kourosh

doi:10.1002/jcph.309

Cited by 37 publications

(43 citation statements)

References 22 publications

(49 reference statements)

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“…The influence of disease activity on mAb pharmacokinetics is inconstant. Five publications reported an increase in mAb clearance with disease activity scores (figure 3, table 1): -Eastern Cooperative Oncology Group (ECOG) is an integer numeral score between 0 (asymptomatic) and 5 (death) in cancer patients that was associated with clearance of pembrolizumab [136] and tremelimumab [137] ; -Psoriasis Area Severity Index (PASI) is a decimal number between 0 (asymatomatic) and 72 (maximal) tha was associated with clearance of efalizumab [92] and guselkumab [138] (anti-IL-23); -Harwey-Bradshaw index (HBI) in Crohn's disease patients is an integer number between 0 (asymptomatic) and 26 (maximal) that was associated with clearance of infliximab. [103] …”

Section: Influence Of Disease Activitymentioning

confidence: 99%

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

et al. 2018

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Therapeutic antibodies are increasingly used to treat various diseases, including neoplasms and chronic inflammatory diseases. Antibodies exhibit complex pharmacokinetic properties, notably due to the influence of antigen mass, i.e. the amount of antigenic targets to which the monoclonal antibody binds specifically. This review focuses on the influence of antigen mass on the pharmacokinetics of therapeutic antibodies quantified by pharmacokinetic modelling in humans. Out of 159 pharmacokinetic studies, 85 reported an influence of antigen mass. This influence led to nonlinear elimination decay in 50 publications which was described using target-mediated drug disposition (TMDD) or derived models, as quasi-steady-state, irreversible binding and Michaelis-Menten models. In 35 publications, the pharmacokinetics was apparently linear and the influence of antigen mass was described as covariate of pharmacokinetic parameters. If some reported covariates, such as circulating antigen concentration or tumor size, are likely to be correlated to antigen mass, others, such as disease activity or disease type, may contain little information on the amount of antigenic targets. In some cases, antigen targets exist in different forms, notably in the circulation and expressed at cell surface. The influence of antigen mass should be soundly described during the early clinical phases of drug development. To maximize therapeutic efficacy, sufficient antibody doses should be administered to ensure the saturation of antigen targets by therapeutic antibody in all patients. If necessary, antigen mass should be taken into account in routine clinical practice. Key points-Current knowledge on the pharmacokinetics of monoclonal antibodies (mAbs) states that higher antigen amount was associated with mAb concentrations and higher mAb clearance. -Beacause of antigen mass, mAb pharmacokinetics may display nonlinear elimination shape. The influence of antigen mass on mAb pharmacokinetics is described using target-mediated drug disposition (TMDD) model, or approximations of this model. Antigen mass influence may be quantified using covariates. -Current mAb clinical development and use in clinical practice may be improved by optimization of dose, which should ensure the saturation of antigen targets in all patients.3

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Section: Influence Of Disease Activitymentioning

confidence: 99%

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

et al. 2018

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“…A second study (NCT01655888) of similar design (open‐label, single‐arm) was later conducted by the same investigator with a higher dose intensity (10 mg/kg q4w for up to week 24 followed by q12w until disease progression or unacceptable toxicity). The higher dose intensity was motivated by a retrospective exposure–response (E‐R) analysis of data from melanoma failed trials suggesting that higher exposure in patients was associated with higher response rate, coupled with in vitro data showing an interleukin‐2 release enhancement proportional to tremelimumab concentrations from whole blood samples of nine cancer donors . Study NCT01655888 enrolled 29 patients and showed similar efficacy, with a median survival time of 11.3 months (95% CI: 3.4–19.2 months).…”

mentioning

confidence: 99%

Exposure–Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status

Baverel¹,

Roskos²,

Tatipalli³

et al. 2019

Clinical Translational Sci

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Tremelimumab, an anti‐cytotoxic T‐lymphocyte antigen‐4 monoclonal antibody that enhances T‐cell activation, was evaluated in a randomized, double‐blind, placebo‐controlled, phase IIb study (NCT01843374) in patients with unresectable malignant mesothelioma. The study demonstrated no clinically meaningful differences in overall survival (OS). The objective of this analysis was to evaluate the relationship of exposure with OS. A population pharmacokinetic (PK) model adequately described the PK data. Three factors (sex, C‐reactive protein, and baseline tumor size) were identified as statistically significant PK predictors (P < 0.05 on clearance). A positive association between exposure and OS was observed. However, an association between key baseline factors with OS (regardless of treatment) and imbalances in prognostic factors favoring patients with higher exposure (upper vs. lower PK quartile) was seen. Taken together, these results suggest that the exposure OS relationship observed for tremelimumab in mesothelioma is likely spurious rather than a true association of exposure with efficacy.

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“…No subject had measurable HAHA suggesting minimal immunogenicity of tremelimumab after multiple 1-hour intravenous infusions. Taken together, these data indicate that the shorter infusion time did not alter the PK of tremelimumab, since the PK parameters are similar to those after a 5-hour infusion of tremelimumab [5,14]. …”

Section: Resultsmentioning

confidence: 89%

Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion

et al. 2012

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BackgroundCTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of tremelimumab allowed testing a shorter infusion time.MethodsA phase 1 multi-center study to establish the safety and tolerability of administering tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of tremelimumab.ResultsNo grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies.ConclusionsThis study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of tremelimumab. (Clinical trial registration number NCT00585000).

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Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma

Cited by 37 publications

References 22 publications

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

Exposure–Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status

Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion

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