Influence of interferon β-1a dose frequency on PBMC cytokine secretion and biological effect markers

Rothuizen, Laura E.; Buclin, Thierry; Spertini, François; Trinchard, Isabelle; Munafo, Alain; Buchwalder, P. A.; Ythier, Arnaud; Biollaz, J.

doi:10.1016/s0165-5728(99)00029-6

Cited by 90 publications

(66 citation statements)

References 46 publications

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“…Initial modeling without neopterin inhibitory feedback resulted in overestimating the neopterin concentration ϳ2 to 3 days after PEG-IFN ␤-1a dosing. It is known that continuous exposure of interferon reduces the magnitude of neopterin response in both humans and monkeys (Rothuizen et al, 1999;Mager et al, 2003). This phenomenon is attributed to either the down-regulation of the type 1 IFN receptor (Pestka et al, 1987) or inhibitory feedback by prolonged elevation of neopterin concentrations (Liberati et al, 1988 50 , drug concentration to achieve 50% of the maximum stimulatory effect; E max , maximum stimulatory effect by IFN ␤-1a or PEG-IFN ␤-1a; IC 50 , neopterin concentration to inhibit 50% of the stimulatory effect from IFN ␤-1a or PEG-IFN ␤-1a; Ka, absorption rate; Ke, elimination rate; KTR, first-order rate exiting transit compartment; LOSS, first-order loss rate; NEOP, neopterin concentration; Q, intercompartment clearance; SYN, baseline synthesis rate; V C , central compartment volume of distribution; V P , peripheral compartment volume of distribution; TR1, transit compartment 1; TR5, transit compartment 5.…”

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confidence: 99%

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

Hu¹,

Olivier²,

Polack³

et al. 2011

J Pharmacol Exp Ther

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Human interferon (IFN) ␤ has well established beneficial effects in treating relapsing forms of multiple sclerosis, but current first-line treatment requires frequent (from daily to weekly) parenteral administration. A 20-kDa polyethylene glycol (PEG)-conjugated IFN ␤-1a (PEG-IFN ␤-1a) is being developed to decrease the frequency of administration and improve patient convenience and compliance. We present pharmacokinetic (PK) and pharmacodynamic (PD) parameters, immunogenicity, and safety of PEG-IFN ␤-1a in Rhesus monkeys in support of a phase 1 clinical trial. Two single-dose PK/PD studies and one 5-week repeat-dose toxicity study compliant with good laboratory practice were conducted. The PK of IFN ␤-1a and PEG-IFN ␤-1a were modeled with a two-compartment model, and the link between drug concentration and neopterin response (PD marker) was described with an indirect stimulatory model. PEG-IFN ␤-1ashowed greater exposure, longer half-life, lower clearance, and reduced volume of distribution than unmodified IFN ␤-1a. Consistent with the pharmacology of type I IFNs, PEG-IFN ␤-1a resulted in the elevation of neopterin concentration, a transient body temperature increase, and a reversible lymphocyte count decrease. As expected, neutralizing antibodies to PEG-IFN ␤-1a formed in almost all monkeys after 5 weeks of treatment, which resulted in significantly reduced drug exposure and abrogation of neopterin induction. There were no drug-related adverse effects at doses up to 100 g/kg (11 MIU/kg) given subcutaneously or intramuscularly once weekly for 5 weeks. The no-observed-adverse-effect level was determined to be 100 g/kg (11 MIU/kg), the highest dose tested.

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confidence: 99%

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

Hu¹,

Olivier²,

Polack³

et al. 2011

J Pharmacol Exp Ther

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“…Adverse reactions such as those associated with a flu-like syndrome show a slow onset and dissipation, and there were suggestions that IFN-␤1a may be better tolerated than IFN-␤1b (Buraglio et al, 1999). A number of biomarkers, including plasma neopterin and ␤2-microglobulin concentrations, intracellular 2Ј,5Ј-oligodenylate synthetase activity as well as peripheral blood mononuclear cell cytokine secretion have been used to assess the effects of IFN-␤ in vivo (Chiang et al, 1993;Alam et al, 1997;Munafo et al, 1998;Rothuizen et al, 1999). It was shown recently that IFN-␤-induced immunomodulation in vivo strongly depends on the administration schedule, with the effect being 2 to 3 times greater when the same weekly dose is divided into three injections in healthy volunteers (Rothuizen et al, 1999).…”

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confidence: 99%

“…A number of biomarkers, including plasma neopterin and ␤2-microglobulin concentrations, intracellular 2Ј,5Ј-oligodenylate synthetase activity as well as peripheral blood mononuclear cell cytokine secretion have been used to assess the effects of IFN-␤ in vivo (Chiang et al, 1993;Alam et al, 1997;Munafo et al, 1998;Rothuizen et al, 1999). It was shown recently that IFN-␤-induced immunomodulation in vivo strongly depends on the administration schedule, with the effect being 2 to 3 times greater when the same weekly dose is divided into three injections in healthy volunteers (Rothuizen et al, 1999). Plasma neopterin, as a biomarker for IFN-␤ effects, displays similar behavior in humans (Chiang et al, 1993;Alam et al, 1997;Munafo et al, 1998) as well as in monkeys (this study).…”

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confidence: 99%

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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“…Whereas pharmacodynamic measurements of IFN β showed a greater activity after a single high dose (Williams and Witt 1998;Stürzebecher et al 1999), studies in healthy volunteers demonstrated a sustained response to IFN β 1a when administered 3 times a week rather than once weekly (Rothuizen et al 1999).…”

Section: Evidence Trialmentioning

confidence: 90%

“…Laboratory and clinical studies have in fact shown that it inhibits MS activity, acting on a variety of processes and molecular mediators within the immune system. IFN β modifi es the cytokine production in favor of the antinfl ammatory subset, such as Il-10 and Il-4, inhibiting the release of proinfl ammatory cytokines such as IFN β and tumor necrosis factor (Rothuizen et al 1999;Yong et al 1998). Other pharmacodinamic properties of IFN β include inhibition of T-cell activation, block of production of oxygen free radicals by mononuclear phagocytes, and reduced expression of major histocompatibility complex class II molecules, which in turn reduces self-antigen presentation in the CNS (Dhib-Jalbut 2002).…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Review of the clinical evidence for interferon β 1a (Rebif®) in the treatment of multiple sclerosis

Manfredonia

Pasquali²,

Dardano³

et al. 2008

NDT

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Interferon (INF) β 1a 22 or 44 µg (Rebif ® ) administered s.c. 3 times a week (t.i.w) is a well established immunomodulating treatment for relapsing remitting multiple sclerosis (RRMS). This review focuses on its mechanisms of action, evidence of effi cacy, safety, and tolerability. Several pharmacodynamic properties explain the immunomodulatory actions of INF β 1a 22 or 44 µg s.c. t.i.w. Pivotal trials and post-marketing studies proved that the drug is effective in reducing disease activity and likely in slowing disease progression. Head-to-head comparative studies with other marketed INFs β in RRMS suggested a better therapeutic response associated with higher doses and frequency of administration of Rebif ® . Additional evidence indicated a benefi cial effect of INF β 1a in patients with clinically isolated syndromes (CIS) suggestive of MS, as treatment reduced time to conversion to clinically defi nite (CD) disease. Further, although the drug did not prove to slow time to progression there were benefi ts on relapse-and MRI-related secondary outcome measures in secondary progressive (SP) MS. Pivotal trials, their cross-over extensions, and post-marketing studies consistently showed that INF β 1a 22 or 44 µg s.c. t.i.w. is safe and well tolerated, as adverse drug reactions are usually mild and manageable.

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Influence of interferon β-1a dose frequency on PBMC cytokine secretion and biological effect markers

Cited by 90 publications

References 46 publications

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

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

Review of the clinical evidence for interferon β 1a (Rebif®) in the treatment of multiple sclerosis

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Influence of interferon β-1a dose frequency on PBMC cytokine secretion and biological effect markers

Cited by 90 publications

References 46 publications

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

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

Review of the clinical evidence for interferon &beta; 1a (Rebif&reg;) in the treatment of multiple sclerosis

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Review of the clinical evidence for interferon β 1a (Rebif®) in the treatment of multiple sclerosis