Impact of Target‐Mediated Elimination on the Dose and Regimen of Evolocumab, a Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

Gibbs, John P.; Doshi, Sameer; Kuchimanchi, Mita; Grover, Anita; Emery, Maurice G.; Dodds, Michael; Gibbs, Megan; Somaratne, Ransi; Wasserman, Scott M.; Blom, Dirk

doi:10.1002/jcph.840

Cited by 35 publications

(59 citation statements)

References 47 publications

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“…[38,53,76,156] An evolocumab study using a TMDD model showed that PCSK9 levels were higher in patients treated with statins. [38] This increase in PCSK9 levels may lead to higher target-mediated clearance of anti-PCSK9 mAbs.…”

Section: Influence Of Concomitant Treatmentmentioning

confidence: 99%

“…These predictions are achieved with the determination of TMDD parameters. [22] For some mAbs, TMDD models were used to estimate the dose needed to saturate mAb targetmediated elimination in most of patients, as for evolocumab [38] or obinutuzumab. [91] This approach may however lead to over-exposure of patients with low target antigen levels.…”

Section: Antigenic Targets Present In Several Tissuesmentioning

confidence: 99%

“…KSS = (koff + kint)/kon (figure 1B). The QSS approximation was used to describe target-mediated kinetics of omalizumab [35][36][37] (anti-IgE mAb) and of evolocumab [38] (anti-PCSK9).…”

Section: Quasi-steady-state (Qss) Approximationmentioning

confidence: 99%

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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 Concomitant Treatmentmentioning

confidence: 99%

Section: Antigenic Targets Present In Several Tissuesmentioning

confidence: 99%

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

et al. 2018

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“…4,10 In the assay, evolocumab was used for capture, and a second bioconjugated anti-PCSK9 antibody was used for detection to ensure PCSK9 bound to evolocumab was not measured. 4,10 In the assay, evolocumab was used for capture, and a second bioconjugated anti-PCSK9 antibody was used for detection to ensure PCSK9 bound to evolocumab was not measured.…”

Section: Methodsmentioning

confidence: 99%

“…4 Current US Food and Drug Administration recommendations offer minimal guidance on the disposition of therapeutic proteins in patients with RI. The available clinical evidence supports a lack of effect of mild or moderate RI on the clearance of evolocumab, which is similar to the clearance of other large monoclonal antibodies.…”

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confidence: 99%

Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety

Lee

Gibbs

Emery

et al. 2019

Clinical Pharm in Drug Dev

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We evaluated the pharmacokinetics, pharmacodynamics, and safety of evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open‐label, parallel‐design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end‐stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140‐mg dose of evolocumab. The effects of evolocumab treatment on low‐density lipoprotein cholesterol (LDL‐C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups. Geometric mean C max and AUC last values in the severe RI and ESRD hemodialysis groups compared with the normal renal function group were lower but within 37% of the normal renal function group (Jonckheere‐Terpstra trend test; C max , P = .23; AUC last , P = .22) and within 26% after adjusting for body weight (mean body weight was approximately 9% higher in the renally impaired groups compared with the normal renal function group). No correlations were observed between exposure and baseline creatinine clearance. No adverse event was determined by the investigators to be related to evolocumab, and there were no trends indicative of clinically important effects on laboratory variables or vital signs. Overall, there were no meaningful differences in evolocumab exposure, as assessed by C max and AUC last , in patients with severe RI and ESRD hemodialysis compared with patients with normal renal function, and LDL‐C‐lowering effects were similar across groups. These results support the use of evolocumab without dose adjustment in patients who have severe RI or ESRD.

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Comparative Pharmacokinetics and Pharmacodynamics of Bococizumab Following a Single Subcutaneous Injection Using Drug Substance Manufactured at Two Sites or Administration via Two Different Devices

Wang

Plotka

Salageanu

et al. 2018

Clinical Pharm in Drug Dev

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The pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, were compared following a single 150-mg subcutaneous dose administered to healthy subjects (n = 156-158/arm) via: (1) a prefilled syringe (PFS) using drug substance (DS) manufactured by Pfizer, (2) a PFS using DS manufactured by Boehringer Ingelheim Pharma, (3) a prefilled pen using DS manufactured by Pfizer (NCT02458209). Blood samples were collected for 12 weeks postdose. Safety was monitored throughout. Mean maximum plasma concentration (C ) ranged between 11.0 and 11.3 μg/mL, and area under the plasma concentration-time curve (AUC ) ranged between 177.6 and 185.0 μg·day/mL across treatments. The 90% confidence intervals for the ratios of adjusted geometric means for C and AUC fell within the 80%-125% range for both DS and delivery device comparisons. Comparable low-density lipoprotein cholesterol profiles were observed, with nadir values of 54.3-56.1 mg/dL across treatments. Similar PCSK9 responses were also observed. Safety profiles were similar across treatments, and the majority of adverse events (AEs) were mild. Three subjects reported serious AEs. The most frequently reported AEs were headache, injection-site reaction, and upper respiratory tract infection, with no clear differences across treatments. Comparable PK, PD, and safety were observed following a single bococizumab 150-mg subcutaneous injection regardless of site of DS manufacture or delivery device used.

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Impact of Target‐Mediated Elimination on the Dose and Regimen of Evolocumab, a Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

Cited by 35 publications

References 47 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

Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety

Comparative Pharmacokinetics and Pharmacodynamics of Bococizumab Following a Single Subcutaneous Injection Using Drug Substance Manufactured at Two Sites or Administration via Two Different Devices

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