Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors

Ahamadi, Malidi; Freshwater, Tomoko; Prohn, Marita; Ch, Li; Alwis, DP de; Greef, Rik de; Elassaiss-Schaap, Jeroen; Kondic, Anna G.; Stone, JA

doi:10.1002/psp4.12139

Cited by 130 publications

(152 citation statements)

References 18 publications

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“…These studies helped to establish that the approved pembrolizumab dose of 2 mg/kg every 3 weeks without dose adjustment in a variety of patient subpopulations is probably the best regimen available at present. (Ahamadi et al 2017). The authors found no clinical significance for variations in sex, baseline performance status, renal and hepatic function, 24:12 tumor type and burden or prior ipilimumab treatment on pembrolizumab exposure (Ahamadi et al 2017).…”

Section: :12mentioning

confidence: 93%

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Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

Cunha

Marcello

Rocha-Santos

et al. 2017

Endocrine-Related Cancer

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Immune checkpoint inhibitors are agents that act by inhibiting the mechanisms of immune escape displayed by various cancers. The success of immune checkpoint inhibitors against several tumors has promoted a new treatment strategy in clinical oncology, and this has encouraged physicians to increase the number of patients who receive the immune checkpoint therapy. In the present article, we review the main concepts regarding immune checkpoint mechanisms and how cancer disrupts them to undergo immune escape. In addition, we describe the most essential concepts related to immune checkpoint inhibitors. We critically review the literature on preclinical and clinical studies of the immune checkpoint inhibitors as a treatment option for thyroid cancer, ovarian carcinoma, pancreatic adenocarcinoma, adrenocortical carcinoma and neuroendocrine tumors. We present the challenges and the opportunities of using immune checkpoint inhibitors against these endocrine malignancies, highlighting the breakthroughs and pitfalls that have recently emerged.

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Section: :12mentioning

confidence: 93%

“…(Ahamadi et al 2017). The authors found no clinical significance for variations in sex, baseline performance status, renal and hepatic function, 24:12 tumor type and burden or prior ipilimumab treatment on pembrolizumab exposure (Ahamadi et al 2017).…”

Section: :12mentioning

confidence: 93%

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

Cunha

Marcello

Rocha-Santos

et al. 2017

Endocrine-Related Cancer

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“…Statistically significant covariates identified through population PK analysis for approved immune checkpoint inhibitors are shown in Table 2. 66,76,77 Covariates identified as statistically significant varied between the approved agents, but in at least half of cases for clearance included sex, Eastern Cooperative Oncology Group (ECOG) performance status, body weight, tumor type, tumor burden, baseline LDH, estimated glomerular filtration rate, albumin, and immunogenicity and for central volume of distribution included sex and body weight.…”

Section: Pharmacokineticsmentioning

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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“…The duration of neurologic irAEs is unclear and may be varied. ICPI half‐life varies from 4 to 27.3 days . In 1 study, nivolumab demonstrated 70% occupancy of PD‐1 receptors at ≥2 months with a high affinity and unclear reversibility .…”

Section: Icpi‐associated Aes/toxicitiesmentioning

confidence: 99%

“…Although not specifically studied in the ICPIs, traditional pheresis techniques are sufficient to remove monoclonal antibody therapies such as rituximab . The half‐lives of the ICPI therapies vary widely from 4 to 27 days as do the onset of neuromuscular irAEs . With receptor occupancy as high as 70% for drugs like nivolumab, the role of PLEX specifically to remove ICPIs and the resulting effect on cancer outcomes remains unclear …”

Section: Treatmentmentioning

confidence: 99%

Neuromuscular complications of immune checkpoint inhibitor therapy

et al. 2018

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Immune checkpoint inhibitor (ICPI) therapy unleashes the body's natural immune system to fight cancer. ICPIs improve overall cancer survival, however, the unbridling of the immune system may induce a variety of immune-related adverse events. Neuromuscular immune complications are rare but they can be severe. Myasthenia gravis and inflammatory neuropathy are the most common neuromuscular adverse events but a variety of others including inflammatory myopathy are reported. The pathophysiologic mechanism of these autoimmune disorders may differ from that of non-ICPI-related immune diseases. Accordingly, while the optimal treatment for ICPI-related neuromuscular disorders generally follows a traditional paradigm, there are important novel considerations in selecting appropriate immunosuppressive therapy. This review presents 2 new cases, a summary of neuromuscular ICPI complications, and an approach to the diagnosis and treatment of these disorders. Muscle Nerve, 2018.

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Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors

Cited by 130 publications

References 18 publications

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Neuromuscular complications of immune checkpoint inhibitor therapy

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