Population pharmacokinetics of ofatumumab in patients with chronic lymphocytic leukemia, follicular lymphoma, and rheumatoid arthritis

Struemper, Herbert; Sale, Mark; Patel, B. J.; Østergaard, Mikkel; Österborg, Anders; Wierda, William G.; Hagenbeek, Anton; Jewell, Roxanne C.

doi:10.1002/jcph.268

Cited by 29 publications

(29 citation statements)

References 21 publications

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“…The covariate model was adapted from the population pharmacokinetic model for ofatumumab monotherapy. 27 Individual post hoc parameter estimates were generated for each patient, and pharmacokinetic parameter estimates were derived using standard equations.…”

Section: Methodsmentioning

confidence: 99%

Once-weekly ofatumumab in untreated or relapsed Waldenström's macroglobulinaemia: an open-label, single-arm, phase 2 study

Furman

Eradat

DiRienzo

et al. 2017

The Lancet Haematology

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Background This study determined the overall response rate (ORR) and safety of ofatumumab monotherapy in patients with untreated and relapsed Waldenström’s macroglobulinaemia (WM). Methods Patients (n=37) received up to three cycles of weekly ofatumumab. Cycle 1 (C1) administered ofatumumab 300 mg during Week 1 followed by 1,000 mg during Weeks 2–4 (Treatment Group A [TGA]; n=15) or 2,000 mg during Weeks 2–5 (TGB; n=22). Patients with stable disease or minor response (MR) after 16 weeks were eligible to receive a Redosing Cycle (RC) of ofatumumab at 300 mg during Week 1 and 2,000 mg during Weeks 2–5. Patients responding to C1 or RC who progressed within 36 months could receive Cycle 2 (C2) of ofatumumab at 300 mg during Week 1 and 2,000 mg during Weeks 2–5. Findings The ORR after C1 was 51% and improved to 59% (15 partial responses, 7 MRs) after the RC. Median time to response for responders was 78·5 days, and median progression-free survival was 536 days. Thirteen patients received C2. The ORR was 77% for patients after completing C2. All 37 patients experienced at least one adverse event (AE). Two patients had immunoglobulin M (IgM) flare, and 16 patients experienced Grade ≥3 AEs (32 Grade 3, 1 Grade 4). Interpretation Ofatumumab monotherapy demonstrated a high ORR and was well tolerated, with a low incidence of IgM flare. Funding Financial support for this study was provided by GlaxoSmithKline and Genmab. This trial was registered at www.ClinicalTrials.gov as #NCT00811733.

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Section: Methodsmentioning

confidence: 99%

Once-weekly ofatumumab in untreated or relapsed Waldenström's macroglobulinaemia: an open-label, single-arm, phase 2 study

Furman

Eradat

DiRienzo

et al. 2017

The Lancet Haematology

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“…The development and performance characteristics of the model have been described. 8 Serum ofatumumab concentrations for pharmacokinetic analysis were determined using a validated ELISA with a lower limit of quantification of 0.1 mg/mL, as previously described. …”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…Anders Österborg, 1 Roxanne C. Jewell, 2 Swami PadmanabhanIyer, 3 Thomas J. Kipps, 4 Jiří Mayer, 5 Stephan Stilgenbauer, 6 Cathy D. Williams, 7 Andrzej Hellmann, 8 Richard R. Furman, 9 Tadeusz Robak, 10 Peter Hillmen, 11 Marek Trnêný, 12 Martin J.S. Dyer, 13 Magdalena Piotrowska, 14 …”

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confidence: 99%

Ofatumumab monotherapy in fludarabine-refractory chronic lymphocytic leukemia: final results from a pivotal study

et al. 2015

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“…This necessitates, to set kdeg = kint, as made for canakinumab [42][43][44][45] (anti-IL-1β), bevacizumab [46] (anti-VEGF) and volociximab [47] (anti-integrins); -binding of mAb to its target assumed irreversible (figure 1C), i.e. koff = 0, as made for efalizumab [48,49] (an anti-CD11a mAb which was removed from the market in 2009) and ofatumumab [50] (anti-CD20).…”

Section: Approximations Of Tmdd Modelsmentioning

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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Population pharmacokinetics of ofatumumab in patients with chronic lymphocytic leukemia, follicular lymphoma, and rheumatoid arthritis

Cited by 29 publications

References 21 publications

Once-weekly ofatumumab in untreated or relapsed Waldenström's macroglobulinaemia: an open-label, single-arm, phase 2 study

Once-weekly ofatumumab in untreated or relapsed Waldenström's macroglobulinaemia: an open-label, single-arm, phase 2 study

Ofatumumab monotherapy in fludarabine-refractory chronic lymphocytic leukemia: final results from a pivotal study

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

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