Population Pharmacokinetic Meta-Analysis of Denosumab in Healthy Subjects and Postmenopausal Women with Osteopenia or Osteoporosis

Sutjandra, Liviawati; Rodriguez, Rachelle; Doshi, Sameer; Ma, Mark; Peterson, Mark; Jang, Graham; Chow, Andrew; Pérez-Ruixo, Juan José

doi:10.2165/11594240-000000000-00000

Cited by 97 publications

(67 citation statements)

References 43 publications

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“…Following s.c. denosumab administration, the absolute bioavailability was 61% (25) and the absorption was slow, reaching peak serum concentrations (C max ) within 4 weeks postdose. After reaching C max, serum denosumab concentrations decline over 4 to 5 months with a mean halflife of approximately 25 to 30 days, with sustained concentrations higher than 2,000 ng/mL, at which the RANKLmediated clearance pathway is almost fully saturated (25,26). Following repeat monthly administration, approximately 2.7-fold accumulation at steady state and no evidence of time-dependent PK was observed under the dosage regimens examined.…”

Section: Introductionmentioning

confidence: 94%

Denosumab Dose Selection for Patients with Bone Metastases from Solid Tumors

Doshi

Sutjandra

Zheng

et al. 2012

Clinical Cancer Research

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Purpose: To quantitatively characterize the longitudinal dose exposure-response [urinary N-telopeptide normalized to urinary creatinine (uNTx/Cr) suppression] relationship for denosumab in patients with bone metastases from solid tumors.Experimental Design: Data from 373 patients who received denosumab as single or multiple subcutaneous doses ranging from 30 to 180 mg (or 0.01 to 3 mg/kg) administered every 4 or 12 weeks for up to 3 years were used in this analysis. An inhibitory sigmoid I Max model was used to characterize the time course of uNTx/Cr as a function of serum denosumab concentrations and the M3 method was used to analyze the 52% of uNTx/Cr values below the limit of quantification in the context of a mixed-effects model. Age, weight, sex, race, and cancer type were evaluated as potential covariates for model parameters. Model-based simulations were undertaken to explore and predict the role of denosumab dose and dosing intervals on uNTx/Cr suppression.Results: The typical value (between-subject variability; %) for uNTx/Cr at baseline was 49.2 nmol/L/ mmol/L (76.8%), denosumab maximal uNTx/Cr suppression (efficacy) was 93.7% (127%), and the denosumab concentration providing half-maximal uNTx/Cr suppression (potency) was 31.8 ng/mL (287%). No effect of covariates on denosumab efficacy and potency was identified. Simulations indicated that a s.c. denosumab dose of 120 mg administered every 4 weeks provides more than 90% suppression of uNTx/Cr in the maximum proportion of patients relative to other every 4-and 12-week doses evaluated.Conclusions: Over the wide range of dosing regimens examined, a s.c. denosumab dose of 120 mg administered every 4 weeks is the optimal dosing regimen to suppress uNTx/Cr in patients with bone metastases from solid tumors.

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Section: Introductionmentioning

confidence: 94%

Denosumab Dose Selection for Patients with Bone Metastases from Solid Tumors

Doshi

Sutjandra

Zheng

et al. 2012

Clinical Cancer Research

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“…For these antibodies, significant inhibition of soluble target in plasma is generally necessary for demonstration of efficacy (6)(7)(8)(9). To enable robust target engagement, optimization of multiple properties like binding affinity, is required to select the best candidate with optimal projected human efficacious dose.…”

Section: Introductionmentioning

confidence: 99%

Factors Influencing Magnitude and Duration of Target Inhibition Following Antibody Therapy: Implications in Drug Discovery and Development

Chimalakonda

Yadav

Marathe

2013

AAPS J

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Abstract. Antibodies or antibody-related fusion proteins binding to soluble antigens in plasma form an important subclass of approved therapeutics. Pharmaceutical companies are constantly trying to accelerate the pace of drug discovery and development of these antibodies and identify superior candidates in face of significant attrition rates. Understanding the interplay between drug-and targetrelated factors on magnitude and duration of target inhibition is imperative for successful advancement of these therapeutics. Simulations using a target-mediated drug disposition model were performed to evaluate the influence of antibody-target binding affinity, baseline target concentration, and target turnover on magnitude and duration of soluble target inhibition. These simulations assumed intravenous dosing of the antibody and evaluated multiple parameters over a wide range. These simulations reveal that improvement in affinity reaches a point of diminishing returns following which further improvement in affinity does not alter the magnitude and more importantly the duration of target inhibition. Evaluation of unbound antibody and target kinetics indicated that point of diminishing returns in duration of inhibition was due to target-mediated binding and subsequent elimination of antibody at later time points. Similarly, influence of baseline target concentration and target turnover on magnitude and duration of target inhibition in plasma is shown. Additionally, the fraction of dose eliminated via target mediated elimination (Fel ™ ) can be a useful tool to enable selection of strategies to increase duration of target inhibition. The implications of these simulations in drug discovery and development with regard to target identification, antibody optimization, and backup candidate selection are discussed.

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“…The structural models for filgrastim and denosumab were obtained from the literature [34,42]. A full target-mediated drug disposition (TMDD) model well described the pharmacokinetics of filgrastim in healthy adults whereas the pharmacokinetics of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis was reasonably well described with the quasi-steady-state approximation of the TMDD model.…”

Section: Methods Structural Pharmacokinetic Modelmentioning

confidence: 99%

“…An overproportional increase in systemic exposure with increasing dose is usually observed when elimination through receptor-mediated endocytosis starts to become saturated [28]. As a result, an apparently dose-dependent bioavailability is frequently observed in many therapeutic proteins including interferon-1a (27 71%) [31], filgrastim (62 72%) [33] and denosumab (36 78%) [34,35]. However, much of this apparent dose-dependency is likely only the consequence of using bioavailability assessment methodology with the invalid assumption of a constant clearance.…”

Section: Chapter 3 Challenges In the Apparent Bioavailability Estimamentioning

confidence: 99%

“…An open, two-compartment pharmacokinetic model with a quasi-steady-state approximation of the TMDD model was developed by Sutjandra and colleagues to describe the pharmacokinetics of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis [34]. Denosumab (AMG 162; Prolia ) is a fully human monoclonal antibody of the IgG2 subclass that has high affinity (KD = 3 × 10 -12 mol/L) and specificity for the receptor activator of nuclear factor -B ligand (RANKL).…”

Section: Quasi-steady-state Approximation Of the Tmdd Model For Denosmentioning

Population Pharmacokinetic Meta-Analysis of Denosumab in Healthy Subjects and Postmenopausal Women with Osteopenia or Osteoporosis

Abstract: The non-linearity in denosumab pharmacokinetics is probably due to RANKL binding, and denosumab dose adjustment based on the patient demographics is not warranted.

Cited by 97 publications

References 43 publications

Denosumab Dose Selection for Patients with Bone Metastases from Solid Tumors

Denosumab Dose Selection for Patients with Bone Metastases from Solid Tumors

Factors Influencing Magnitude and Duration of Target Inhibition Following Antibody Therapy: Implications in Drug Discovery and Development

Challenges in the Pharmacokinetics of Therapeutic Proteins

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