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      Applications of Quantitative Systems Pharmacology in Model‐Informed Drug Discovery: Perspective on Impact and Opportunities

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          Abstract

          Quantitative systems pharmacology (QSP) approaches have been increasingly applied in the pharmaceutical since the landmark white paper published in 2011 by a National Institutes of Health working group brought attention to the discipline. In this perspective, we discuss QSP in the context of other modeling approaches and highlight the impact of QSP across various stages of drug development and therapeutic areas. We discuss challenges to the field as well as future opportunities.

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          Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.

          Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses. Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis. In this double-blind, randomised, placebo-controlled, parallel group phase III study, 623 patients with moderate to severe active rheumatoid arthritis were randomly assigned with an interactive voice response system, stratified by site with a randomisation list provided by the study sponsor, to receive tocilizumab 8 mg/kg (n=205), tocilizumab 4 mg/kg (214), or placebo (204) intravenously every 4 weeks, with methotrexate at stable pre-study doses (10-25 mg/week). Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20% improvement in both swollen and tender joint counts. The primary endpoint was the proportion of patients with 20% improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria (ACR20 response) at week 24. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00106548. The intention-to-treat analysis population consisted of 622 patients: one patient in the 4 mg/kg group did not receive study treatment and was thus excluded. At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59%] patients in the 8 mg/kg group, 102 [48%] in the 4 mg/kg group, 54 [26%] in the placebo group; odds ratio 4.0 [95% CI 2.6-6.1], p<0.0001 for 8 mg/kg vs placebo; and 2.6 [1.7-3.9], p<0.0001 for 4 mg/kg vs placebo). More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69%] in the 8 mg/kg group; 151 [71%] in the 4 mg/kg group; 129 [63%] in the placebo group). The most common serious adverse events were serious infections or infestations, reported by six patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group. Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis. F Hoffmann-La Roche, Chugai Pharmaceutical.
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            The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.

            To compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment. This was a 2-year, multicenter, double-blind, active comparator-controlled study of 799 RA patients with active disease of < 3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co-primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score. Combination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P < or = 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28-joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found among patients receiving either monotherapy. The adverse event profiles were comparable in all 3 groups. In this population of patients with early, aggressive RA, combination therapy with adalimumab plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms of disease, inhibiting radiographic progression, and effecting clinical remission.
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              Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial.

              To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor alpha antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX. In a 24-week, randomized, double-blind, placebo-controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long-term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks. An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg, 40-mg, and 80-mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20-mg, 40-mg, and 80-mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events. The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.
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                Author and article information

                Contributors
                erica.pierce@takeda.com
                Mary.Spilker@pfizer.com
                Journal
                CPT Pharmacometrics Syst Pharmacol
                CPT Pharmacometrics Syst Pharmacol
                10.1002/(ISSN)2163-8306
                PSP4
                CPT: Pharmacometrics & Systems Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                2163-8306
                25 October 2019
                November 2019
                : 8
                : 11 ( doiID: 10.1002/psp4.v8.11 )
                : 777-791
                Affiliations
                [ 1 ] Takeda San Diego California USA
                [ 2 ] Pfizer Worldwide Research and Development San Diego California USA
                [ 3 ] Genentech Inc. South San Francisco California USA
                [ 4 ] GlaxoSmithKline King of Prussia Philadelphia USA
                [ 5 ] Novartis Institutes for Biomedical Research East Hanover New Jersey USA
                [ 6 ] AstraZeneca Cambridge UK
                [ 7 ] Agios Cambridge Massachusetts USA
                [ 8 ] UCB, Celltech Slough Berkshire UK
                [ 9 ] Eisai Inc Woodcliff Lake New Jersey USA
                [ 10 ] Merck & Co., Inc Kenilworth New Jersey USA
                [ 11 ] Vertex Pharmaceuticals Incorporated Boston Massachusetts USA
                [ 12 ] Sanofi Bridgewater New Jersey USA
                [ 13 ] Abbvie Inc North Chicago Illinois USA
                [ 14 ] Eli Lilly and Company Indianapolis Indiana USA
                Author notes
                [*] [* ]Correspondence: Erica L. Bradshaw and Mary E. Spilker ( erica.pierce@ 123456takeda.com ; Mary.Spilker@ 123456pfizer.com )
                [†]

                Authors contributed equally.

                Article
                PSP412463
                10.1002/psp4.12463
                6875708
                31535440
                6b533b4a-d59f-4f23-86f9-d0c9520e892c
                © 2019 Takeda California, Inc CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 15 April 2019
                : 19 July 2019
                Page count
                Figures: 4, Tables: 1, Pages: 15, Words: 11902
                Categories
                White Paper
                White Paper
                White Paper
                Custom metadata
                2.0
                psp412463
                November 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.7.2 mode:remove_FC converted:25.11.2019

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