Drug Development of Therapeutic Monoclonal Antibodies

Mould, Diane R.; Meibohm, Bernd

doi:10.1007/s40259-016-0181-6

Cited by 76 publications

(61 citation statements)

References 121 publications

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“…Antidrug antibodies (ADAs) and low serum albumin concentrations were associated with higher infliximab clearance, whereas body weight was found to be predictive of volume of distribution. Albumin is a frequently identified covariate for monoclonal antibodies, with low albumin generally being associated with higher clearance owing to its association with disease severity . Because albumin is recycled using the FcRn, it is subjected to the same impact of endogenous and exogenous antibodies, and in IBD may be lost because of protein‐losing enteropathy .…”

mentioning

confidence: 99%

Prediction of Individual Serum Infliximab Concentrations in Inflammatory Bowel Disease by a Bayesian Dashboard System

Eser

Primas

Reinisch

et al. 2018

The Journal of Clinical Pharma

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Despite a robust exposure-response relationship of infliximab in inflammatory bowel disease (IBD), attempts to adjust dosing to individually predicted serum concentrations of infliximab (SICs) are lacking. Compared with labor-intensive conventional software for pharmacokinetic (PK) modeling (eg, NONMEM) dashboards are easy-to-use programs incorporating complex Bayesian statistics to determine individual pharmacokinetics. We evaluated various infliximab detection assays and the number of samples needed to precisely forecast individual SICs using a Bayesian dashboard. We assessed long-term infliximab retention in patients being dosed concordantly versus discordantly with Bayesian dashboard recommendations. Three hundred eighty-two serum samples from 117 adult IBD patients on infliximab maintenance therapy were analyzed by 3 commercially available assays. Data from each assay was modeled using NONMEM and a Bayesian dashboard. PK parameter precision and residual variability were assessed. Forecast concentrations from both systems were compared with observed concentrations. Infliximab retention was assessed by prediction for dose intensification via Bayesian dashboard versus real-life practice. Forecast precision of SICs varied between detection assays. At least 3 SICs from a reliable assay are needed for an accurate forecast. The Bayesian dashboard performed similarly to NONMEM to predict SICs. Patients dosed concordantly with Bayesian dashboard recommendations had a significantly longer median drug survival than those dosed discordantly (51.5 versus 4.6 months, P < .0001). The Bayesian dashboard helps to assess the diagnostic performance of infliximab detection assays. Three, not single, SICs provide sufficient information for individualized dose adjustment when incorporated into the Bayesian dashboard. Treatment adjusted to forecasted SICs is associated with longer drug retention of infliximab.

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mentioning

confidence: 99%

Prediction of Individual Serum Infliximab Concentrations in Inflammatory Bowel Disease by a Bayesian Dashboard System

Eser

Primas

Reinisch

et al. 2018

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

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“…All currently clinically used therapeutic antibodies are immunoglobulin G (IgG) monoclonal antibodies (mAbs) and possess the same basic structure ( Figure ): they are large heterodimeric protein molecules with a molecular weight of ∼150 kDa and are composed of four polypeptide chains, two identical heavy chains (50 kDa), and two light chains (25 kDa). The heavy and light chains are held together by disulfide bonds to form a Y‐shape consisting of constant domains (C H and C L ) and variable domains (V H and V L ).…”

Section: Structure and Originmentioning

confidence: 99%

Pharmacokinetics of Monoclonal Antibodies

Ryman

Meibohm

2017

CPT Pharmacom & Syst Pharma

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584

547

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Monoclonal antibodies (mAbs) have developed in the last two decades into the backbone of pharmacotherapeutic interventions in a variety of indications, with currently more than 40 mAbs approved by the US Food and Drug Administration, and several dozens more in clinical development. This tutorial will review major drug disposition processes relevant for mAbs, and will highlight product‐specific and patient‐specific factors that modulate their pharmacokinetic (PK) behavior and need to be considered for successful clinical therapy.

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“…Because most mAbs are in the range of 100 to 1000 kDa, renal impairment has less potential to influence the PK of these large molecules. 65 Generally, the effect of renal impairment is assessed using a population PK approach. As described above, renal function was a statistically significant covariate for clearance for several of the approved checkpoint inhibitors; however, the magnitude of impact on PK was <20% to 30%.…”

Section: Renal and Hepatic Impairmentmentioning

confidence: 99%

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Sheng

Srivastava

Sanghavi

et al. 2017

The Journal of Clinical Pharma

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Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti-cytotoxic T-lymphocyte antigen-4 antibody) and, more recently, nivolumab and pembrolizumab (both anti-programmed death-1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti-programmed death ligand-1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno-oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure-response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno-oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches. Keywords immunopharmacology, oncology, clinical pharmacology, clinical trials, pharmacology, immunotherapy, checkpoint inhibitorsIt could be said that if there were a book chronicling the history and progression of cancer treatment, we are now moving on from the chapter describing the time of sole reliance on chemotherapy, the chapter outlining the advent of targeted therapy is partially completed, and a new chapter on immuno-oncology is just beginning. The past few years have seen the regulatory approval of several immuno-oncology agents (Figure 1), including 6 immune checkpoint inhibitors: ipilimumab (Yervoy; Bristol-Myers Squibb), pembrolizumab (Keytruda; Merck), nivolumab (Opdivo; Bristol-Myers Squibb), atezolizumab (Tecentriq; Genentech), avelumab (Bavencio; EMD Serono), and durvalumab (Imfinzi; AstraZeneca). 1,2Immunotherapy in oncology is a switch from the cell-killing modality using relatively nonspecific cytotoxic methods (chemotherapy) or therapies that target cancer-specific pathways to methods that employ the patients' immune system to attack cancer. The immuno-oncology approach calls on the understanding of complex signaling processes of effector and regulatory...

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Drug Development of Therapeutic Monoclonal Antibodies

Cited by 76 publications

References 121 publications

Prediction of Individual Serum Infliximab Concentrations in Inflammatory Bowel Disease by a Bayesian Dashboard System

Prediction of Individual Serum Infliximab Concentrations in Inflammatory Bowel Disease by a Bayesian Dashboard System

Pharmacokinetics of Monoclonal Antibodies

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

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