Pharmacokinetics and Pharmacodynamics of IFN-β1a in Healthy Volunteers

Buchwalder, P. A.; Buclin, Thierry; Trinchard, Isabelle; Munafo, Alain; Biollaz, J.

doi:10.1089/10799900050163226

Cited by 98 publications

(86 citation statements)

References 40 publications

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“…4. The overall profiles demonstrate a delayed onset and slow return toward baseline, which is qualitatively similar to the response observed in humans (Buchwalder et al, 2000).…”

Section: Resultssupporting

confidence: 72%

“…This is consistent with the relatively large size of IFN-␤1a and, with the exception of specific and nonspecific binding, the compound jpet.aspetjournals.org should mostly reside in the plasma. Although this study was conducted in monkeys, the metabolism and elimination of interferons are similar across most species (Gloff and Wills, 1992), and the model has been shown to be relevant in humans (Buchwalder et al, 2000;Mager and Jusko, 2002).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Interferon-β1a in Monkeys

Mager¹,

Neuteboom²,

Efthymiopoulos³

et al. 2003

J Pharmacol Exp Ther

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A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to simultaneously characterize interferon after i.v. and s.c. dosing at various dose levels. A sequential study in monkeys (n ϭ 18) was conducted, where single doses of 1, 3, and 10 MIU/kg of recombinant-human interferon-␤ (IFN-␤) 1a were given i.v. and then s.c. Plasma concentrations of IFN-␤ were determined and biphasic neopterin concentrations were used as the pharmacodynamic (PD) endpoint. Multiple dosing also was evaluated by giving 1 MIU/kg s.c. doses once daily for 7 days (n ϭ 3). The integrated model uses target-mediated drug disposition to describe drug elimination by receptor binding and internalization, and well characterizes the observed nonlinear pharmacokinetic (PK) profiles. The s.c. doses exhibited an absorption phase (T max ϭ 3 h) and incomplete bioavailability (F ϭ 0.3-0.7). An indirect response model for stimulation of neopterin triphosphate production by activated receptor complex followed by conversion to neopterin was used to jointly model the formation and loss of neopterin with a capacity factor S max ϭ 23.8. Greater relative neopterin response after s.c. dosing was accounted for by prolonged receptor activation relative to the SC 50 value. Repeated daily s.c. dosing produced modestly elevated IFN-␤1a concentrations and neopterin concentrations that were lower than simulated from single-dose modeling. Although several mechanisms could be involved, these phenomena were simply remodeled as down-regulation of S max and receptors. The PK/PD model for IFN-␤1a depicts receptor binding as a key feature controlling nonlinear elimination, nonstationary kinetics, and neopterin induction in a manner consistent with known processes controlling its disposition and pharmacological effects.The interferons (IFNs) represent a family of endogenous proteins that exhibit antiviral, antiproliferative, and immunomodulatory effects (Pestka et al., 1987;Leonard, 1999). These compounds are being investigated for a variety of clinical indications. IFN-␤, in particular, has shown dosedependent efficacy in several clinical trials and is being used for treatment of multiple sclerosis (for review, see Goodin et al., 2002). The mechanism of action for this indication is still unclear and is likely that the activity is due to a combination of some of the biological activities of IFN-␤ (Yong et al., 1998), including antiviral activity, changes in cell distribution, activation of cytotoxic activities of lymphocytes, macrophages, and natural killer cells, regulation of cytokine and cytokine receptor gene expression, and an increase in expression of some tumor-associated antigens (Pestka et al., 1987;Leonard, 1999).Limited analyses of the pharmacokinetics/pharmacodynamics (PK/PD) of IFN-␤ have been reported. In general, plasma concentrations of IFN-␤ decline rapidly in a biexponential manner after i.v. administration, with a terminal half-life of approximately 5 h in humans (Wills, 1990;Chiang et al., 1993;Salmon et al., 1996). After s.c. or i.m. dosing, ...

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“…4. The overall profiles demonstrate a delayed onset and slow return toward baseline, which is qualitatively similar to the response observed in humans (Buchwalder et al, 2000).…”

Section: Resultssupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Interferon-β1a in Monkeys

Mager¹,

Neuteboom²,

Efthymiopoulos³

et al. 2003

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

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“…25 It also is a potent inhibitor of proliferation for many cancer cells in vitro. 18,19 However, it cannot be used effectively as cancer therapy because the maximum tolerated dose is not high enough to attain these effects when given systemically [26][27][28] and it has a short half-life. Although it has been shown that serum levels of interferon delivered by engineered stem cells are insignificant in contrast to interferon given systemically, 15 the local production of IFN-b appears to be the key for tumor growth attenuation.…”

Section: Discussionmentioning

confidence: 99%

Development of human umbilical cord matrix stem cell-based gene therapy for experimental lung tumors

et al. 2007

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Umbilical cord matrix stem (UCMS) cells are unique stem cells derived from Wharton's jelly, which have been shown to express genes characteristic of primitive stem cells. To test the safety of these cells, human UCMS cells were injected both intravenously and subcutaneously in large numbers into severe combined immunodeficiency (SCID) mice and multiple tissues were examined for evidence of tumor formation. UCMS cells did not form gross or histological teratomas up to 50 days posttransplantation. Next, to evaluate whether UCMS cells could selectively engraft in xenotransplanted tumors, MDA 231 cells were intravenously transplanted into SCID mice, followed by intravenous transplantation of UCMS cells 1 and 2 weeks later. UCMS cells were found near or within lung tumors but not in other tissues. Finally, UCMS cells were engineered to express human interferon beta -designated 'UCMSÀIFN-b'. UCMSÀIFN-b cells were intravenously transplanted at multiple intervals into SCID mice bearing MDA 231 tumors and their effect on tumors was examined. UCMSÀIFN-b cells significantly reduced MDA 231 tumor burden in SCID mouse lungs indicated by wet weight. These results clearly indicate safety and usability of UCMS cells in cancer gene therapy. Thus, UCMS cells can potentially be used for targeted delivery of cancer therapeutics.

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“…Finally, our findings support the clinical attractiveness to use IFN-h in the treatment of GEP-NETs, considering that IFN-h inhibited cell proliferation and stimulated apoptosis already at very low concentrations (1-10 IU/mL). These concentrations can be achieved in vivo because 12.3 IU/mL is the maximal IFN-h serum concentration reported in healthy subjects after s.c. administration of this cytokine (47,48). Translation of these findings into a clinical application is, however, not easy, considering the short half-life of IFN-h.…”

Section: Discussionmentioning

confidence: 99%

IFN-β Is a Highly Potent Inhibitor of Gastroenteropancreatic Neuroendocrine Tumor Cell Growth In vitro

et al. 2006

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IFN-A controls hormone secretion and symptoms in human gastroenteropancreatic neuroendocrine tumors (GEP-NET) but it rarely induces a measurable tumor size reduction. The effect of other type I IFNs, e.g., IFN-B, has not been evaluated. We compared the antitumor effects of IFN-A and IFN-B in BON cells, a functioning human GEP-NET cell line. As determined by quantitative reverse transcription-PCR analysis and immunocytochemistry, BON cells expressed the active type I IFN receptor mRNA and protein (IFNAR-1 and IFNAR-2c subunits). After 3 and 6 days of treatment, IFN-B significantly inhibited BON cell growth in a time-and dose-dependent manner. IC 50 and maximal inhibitory effect on day 6 were 8 IU/mL and 98%, respectively. In contrast, the effect of IFN-A resulted significantly in a less potent effect (IC 50 : 44 IU/mL, maximal inhibition: 26%). IFN-A induced only cell cycle arrest, with an accumulation of the cells in S phase. IFN-B, apart from a more potent delay in S-G 2 -M phase transit of the cell cycle, also induced a strong stimulation of apoptosis, evaluated by flow cytometry (Annexin V and 7-AAD) and measurement of the DNA fragmentation. Besides, only IFN-B severely suppressed chromogranin A levels in the medium from BON cells after 6 days of treatment. In conclusion, IFN-B is much more potent, compared with IFN-A, in its inhibitory effect on GEP-NET cell proliferation in vitro through the induction of apoptosis and cell cycle arrest. Further studies are required to establish whether IFN-B has comparable potent tumor growth inhibitory effects in vivo. (Cancer Res 2006; 66(1): 554-62)

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Pharmacokinetics and Pharmacodynamics of IFN-β1a in Healthy Volunteers

Cited by 98 publications

References 40 publications

Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Interferon-β1a in Monkeys

Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Interferon-β1a in Monkeys

Development of human umbilical cord matrix stem cell-based gene therapy for experimental lung tumors

IFN-β Is a Highly Potent Inhibitor of Gastroenteropancreatic Neuroendocrine Tumor Cell Growth In vitro

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