203 Population pharmacokinetics of MEDI4736, a fully human antiprogrammed death ligand 1 (PD-L1) monoclonal antibody, in patients with advanced solid tumors

Song, Xie‐Yan; Pak, Min Gyoung; Chavez, Carlos M.; Lu, Hiep; Blake-Haskins, Andy; Robbins, Paul B.; Jin, Xueying; Gupta, Akshita; Roskos, L; Narwal, Rajesh

doi:10.1016/s0959-8049(16)30091-0

Cited by 6 publications

(4 citation statements)

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“…The geometric mean steady state volume of distribution was 5.6 L [ 3 ]. As with therapeutic monoclonal antibodies in general, durvalumab undergoes target-mediated clearance [ 20 ]. Durvalumab clearance decreases over time, but is not considered clinically relevant; the geometric mean terminal half-life of durvalumab is ≈17 days [ 3 ].…”

Section: Scientific Summarymentioning

confidence: 99%

Durvalumab: First Global Approval

Syed

2017

Drugs

131

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Intravenous durvalumab (Imfinzi™; AstraZeneca) is a fully human monoclonal antibody that blocks programmed cell death ligand-1 binding to its receptors (PD-1 and CD80), resulting in enhanced T-cell responses against cancer cells. The US FDA has granted durvalumab accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Durvalumab ± tremelimumab is under phase III clinical trials in urothelial carcinoma, non-small cell lung cancer, small cell lung cancer and head and neck squamous cell carcinoma. The drug is also being evaluated in phase I or II clinical trials in a wide range of solid tumours and haematological malignancies. This article summarizes the milestones in the development of durvalumab leading to this first approval for urothelial carcinoma.

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Section: Scientific Summarymentioning

confidence: 99%

Durvalumab: First Global Approval

Syed

2017

Drugs

131

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“…9,10 Of note, MEDI4736, another anti-PD-L1 mAb, also exhibited nonlinear PK over the dose range of 0.1 to 10 mg.kg ¡1 every 2 weeks (q2w) in the Phase 1 study and approached linearity at 3 mg.kg ¡1 q2w. 17,18 Using Equation 1 (see Method section), it is anticipated that »90% and »96% saturation of PD-L1 is achieved at »0.18 and »0.5 mg¢mL ¡1 , respectively. The result of the calculation is consistent with experimental observation from the PK/PD study, which showed a relationship between antibody dose and duration of PD-L1 saturation on peripheral blood lymphocytes in mice, and PD-L1 on the peripheral blood lymphocytes was fully saturated when the anti-PD-L1 concentration was > »0.5 mg¢mL ¡1 .…”

Section: Discussionmentioning

confidence: 99%

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

Deng¹,

Bumbaca²,

Pastuskovas³

et al. 2016

mAbs

173

167

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MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development.The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg¢kg ¡1 and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg¢kg ¡1 were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined.The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above »0.5 mg¢mL ¡1 . Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was »0.3; saturation of target-mediated uptake in non-tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent.The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.

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“…57,58 Based on PK and PD data, as well as clinical safety data, the 10 mg/kg every-2-week dosing schedule was selected for further development.…”

Section: Dose Selectionmentioning

confidence: 99%

“…38,65 The PK parameters of all 6 agents were typically characterized using 2-compartment models with linear elimination (the exception was durvalumab, for which both linear and nonlinear PK was characterized); a summary for each is shown in Table 1. [30][31][32]40,41,44,46,51,52,[56][57][58][66][67][68][69][70][71][72][73] PK characteristics listed and described here are not an exhaustive characterization of each agent. Characteristics were linear over at least a part of the dose ranges tested for all 6 agents, although the PK for pembrolizumab, durvalumab, and avelumab was nonlinear at doses of <0.1, 46 <3, 32 and <10 mg/kg, 52 respectively.…”

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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203 Population pharmacokinetics of MEDI4736, a fully human antiprogrammed death ligand 1 (PD-L1) monoclonal antibody, in patients with advanced solid tumors

Cited by 6 publications

References 0 publications

Durvalumab: First Global Approval

Durvalumab: First Global Approval

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

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