Pharmacokinetic Variability of Therapeutic Antibodies in Humans: A Comprehensive Review of Population Pharmacokinetic Modeling Publications

Bensalem, Amina; Ternant, David

doi:10.1007/s40262-020-00874-2

Cited by 40 publications

(45 citation statements)

References 185 publications

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“…Both baseline IgG and proteinuria levels were found to increase belimumab CL; such relationships are rarely investigated or identified in other monoclonal antibody population PK analyses. 22 The IgG-related increase in CL is mediated by increased competition for the saturating capacity of the FcRn-receptor, which protects endogenous and exogenous IgG from endosomal lysis. This mechanism manifests itself especially in populations with hypergammaglobulinemia and has been consistently demonstrated in autoimmune diseases such as SLE 12,13 or hematological malignancies such as multiple myeloma, [23][24][25] in which markedly increased IgG can occur.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Belimumab in Children With Systemic Lupus Erythematosus

Dimelow¹,

Ji²,

Struemper

2020

Clinical Pharm in Drug Dev

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The phase 2 placebo-controlled, double-blind PLUTO trial characterized the pharmacokinetics of belimumab plus standard systemic lupus erythematosus (SLE) therapy in patients with childhood-onset SLE (cSLE) and demonstrated similar efficacy and safety to that in adult SLE. Patients with active cSLE aged 5-17 years were randomized to intravenous belimumab 10 mg/kg every 4 weeks (n = 53). A linear 2-compartment population pharmacokinetics (popPK) model with first-order elimination was developed, and an exploratory exposure-response analysis assessed the impact of betweenpatient exposure variability on clinical response (SLE Responder Index 4 [SRI4]) in week 52, and occurrence of serious adverse events during the study. The popPK model estimated clearance of 158 mL/day, steady-state volume of distribution of 3.5 L, terminal half-life of 16.3 days, and distribution half-life of 0.8 days in the overall population. Fat-free mass (FFM) better characterized the pharmacokinetics than total body weight and was more consistent with allometric scaling theory; belimumab pharmacokinetics were largely determined by FFM. Age, sex, disease activity, and concomitant medication had no impact on pediatric belimumab exposure after accounting for body size. Individual and median steady-state pediatric pharmacokinetic profiles were similar to known adult profiles and pediatric exposure estimates for belimumab 10 mg/kg intravenously were consistent with adult exposures. Exposures were similar between SRI4 responders and nonresponders, and patients who did or did not experience a serious adverse event. There was no clinically relevant correlation between exposure and efficacy or safety, confirming belimumab 10 mg/kg intravenous dose every 4 weeks as appropriate for pediatric patients with cSLE.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Belimumab in Children With Systemic Lupus Erythematosus

Dimelow¹,

Ji²,

Struemper

2020

Clinical Pharm in Drug Dev

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“…The administration of Abs in children has been a challenge, especially anti-RSV Abs in premature infants. In general, Ab elimination seems to increase with young age [20]. The reasons remain unclear, even if a possible explanation is a decreased FcRn expression in infants.…”

Section: Endogenous (Non-specific) Catabolismmentioning

confidence: 98%

“…In addition to a multi-faceted PD, the Ab PK is unique, involving specific mechanisms of absorption, catabolism and elimination. The fate of the Ab depends on multiple parameters, thereby their PK displays a large inter-individual variability, which can be detrimental for clinical responses [20]. Understanding the parameters governing the Ab PK better remains critical to enhance the likelihood of an Ab response during RTI.…”

Section: Therapeutic Antibodies-main Featuresmentioning

confidence: 99%

“…When investigated in Ab PK studies, the presence of ADA is mostly associated with increased Ab clearance, and thus decreased exposure that altogether can lead to loss of efficacy. The presence of ADA is observed in approximately 2-20% of patients, variable with antibody and underlying disease [20], primarily with palivizumab [76] and nirsevimab [26].…”

Section: Elimination Mediated By Anti-drug Antibodymentioning

confidence: 99%

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Therapeutic Antibodies for the Treatment of Respiratory Tract Infections—Current Overview and Perspectives

et al. 2021

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Respiratorytract infections (RTIs) are frequent and life-threatening diseases, accounting for several millions of deaths worldwide. RTIs implicate microorganisms, including viruses (influenza virus, coronavirus, respiratory syncytial virus (RSV)), bacteria (Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus and Bacillus anthracis) and fungi (Pneumocystis spp., Aspergillus spp. and very occasionally Candida spp.). The emergence of new pathogens, like the coronavirus SARS-CoV-2, and the substantial increase in drug resistance have highlighted the critical necessity to develop novel anti-infective molecules. In this context, antibodies (Abs) are becoming increasingly important in respiratory medicine and may fulfill the unmet medical needs of RTIs. However, development of Abs for treating infectious diseases is less advanced than for cancer and inflammatory diseases. Currently, only three Abs have been marketed for RTIs, namely, against pulmonary anthrax and RSV infection, while several clinical and preclinical studies are in progress. This article gives an overview of the advances in the use of Abs for the treatment of RTIs, based on the analysis of clinical studies in this field. It describes the Ab structure, function and pharmacokinetics, and discusses the opportunities offered by the various Ab formats, Ab engineering and co-treatment strategies. Including the most recent literature, it finally highlights the strengths, weaknesses and likely future trends of a novel anti-RTI Ab armamentarium.

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“…Clinicopathological features are known to influence the PKs of monoclonal antibodies and may contribute to interpatient variability (16,37). Body weight is the most important patient variable influencing clearance of ICIs.…”

Section: Lessons Learnt From Early Phase Development Trialsmentioning

confidence: 99%

Extended-Interval Dosing Strategy of Immune Checkpoint Inhibitors in Lung Cancer: Will it Outlast the COVID-19 Pandemic?

2020

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Patients with lung cancer are particularly vulnerable to complications from coronavirus disease-2019 (COVID-19). Recurrent hospital visits and hospital admission are potential risk factors for acquiring infection with its causative pathogen, severe acute respiratory syndrome coronavirus−2 (SARS-CoV-2). As immune checkpoint inhibitors (ICIs) constitute the therapeutic backbone for the vast majority of patients with advanced lung cancer in the absence of actionable driver oncogenes, there have been intense discussions within the oncology community regarding risk-benefit of delaying these treatments or use of alternative extended-interval treatment strategies to minimize the risk of viral transmission secondary to unintended nosocomial exposures. In the midst of the COVID-19 pandemic, the U.S. Food and Drug Administration (FDA) granted accelerated approval for extended-interval strategy of pembrolizumab at a dose of 400 mg every 6 weeks for all already approved oncologic indications. Herein, we summarize the evidence from the in silico pharmacokinetic modeling/simulation studies supporting extended-interval dosing strategies for the ICIs used in lung cancer. We further review the evolving clinical evidence behind these approaches and predict that they will continue to be used in routine practice even long after the pandemic, particularly for patients with durable disease control.

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Pharmacokinetic Variability of Therapeutic Antibodies in Humans: A Comprehensive Review of Population Pharmacokinetic Modeling Publications

Cited by 40 publications

References 185 publications

Pharmacokinetics of Belimumab in Children With Systemic Lupus Erythematosus

Pharmacokinetics of Belimumab in Children With Systemic Lupus Erythematosus

Therapeutic Antibodies for the Treatment of Respiratory Tract Infections—Current Overview and Perspectives

Extended-Interval Dosing Strategy of Immune Checkpoint Inhibitors in Lung Cancer: Will it Outlast the COVID-19 Pandemic?

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