A pharma perspective on the systems medicine and pharmacology of inflammation

Lahoz-Beneytez, Julio; Schnizler, Katrin; Eißing, Thomas

doi:10.1016/j.mbs.2014.07.006

Cited by 2 publications

(2 citation statements)

References 18 publications

(18 reference statements)

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“…This may explain the large variability of concentration-effect relationships to erroneous extrapolations. Multi-scale system models, which were previously developed in oncology, may be used to build models including signaling pathways (e.g., the MAPK [124], NF-jB [125], and IL-6 pathways [126]), the expression of genes of interest [127], the regulation of the immune system [126], inflammation [128], and clinical consequences. Multi-scale system biology modeling may allow the connecting of these phenomena and help to (i) optimize the dosing strategy of marketed mAbs, (ii) test and optimize diverse associations of biopharmaceuticals, e.g., adalimumab and tocilizumab, (iii) find new targets of clinical interest, and (iv) find new biomarkers of response to treatment.…”

Section: Discussionmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

et al. 2015

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Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-α drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3-4 L) and their elimination half-life usually ranges from 2 to 3 weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-α mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity.

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Section: Discussionmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

et al. 2015

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“…Drug administration considers mainly two phenomena, i.e., the pharmacokinetic (PK) and pharmacodynamic (PD). The PK regards the temporal distribution of drug concentration in different organs of host body, while the PD describes the effect of a drug on the organism (Lahoz-Beneytez et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Oseltamivir PK/PD Modeling and Simulation to Evaluate Treatment Strategies against Influenza-Pneumococcus Coinfection

Boianelli

Sharma-Chawla

Bruder

et al. 2016

Front. Cell. Infect. Microbiol.

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Influenza pandemics and seasonal outbreaks have shown the potential of Influenza A virus (IAV) to enhance susceptibility to a secondary infection with the bacterial pathogen Streptococcus pneumoniae (Sp). The high morbidity and mortality rate revealed the poor efficacy of antiviral drugs and vaccines to fight IAV infections. Currently, the most effective treatment for IAV is by antiviral neuraminidase inhibitors. Among them, the most frequently stockpiled is Oseltamivir which reduces viral release and transmission. However, effectiveness of Oseltamivir is compromised by the emergence of resistant IAV strains and secondary bacterial infections. To date, little attention has been given to evaluate how Oseltamivir treatment strategies alter Influenza viral infection in presence of Sp coinfection and a resistant IAV strain emergence. In this paper we investigate the efficacy of current approved Oseltamivir treatment regimens using a computational approach. Our numerical results suggest that the curative regimen (75 mg) may yield 47% of antiviral efficacy and 9% of antibacterial efficacy. An increment in dose to 150 mg (pandemic regimen) may increase the antiviral efficacy to 49% and the antibacterial efficacy to 16%. The choice to decrease the intake frequency to once per day is not recommended due to a significant reduction in both antiviral and antibacterial efficacy. We also observe that the treatment duration of 10 days may not provide a clear improvement on the antiviral and antibacterial efficacy compared to 5 days. All together, our in silico study reveals the success and pitfalls of Oseltamivir treatment strategies within IAV-Sp coinfection and calls for testing the validity in clinical trials.

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A pharma perspective on the systems medicine and pharmacology of inflammation

Cited by 2 publications

References 18 publications

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

Oseltamivir PK/PD Modeling and Simulation to Evaluate Treatment Strategies against Influenza-Pneumococcus Coinfection

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