2 Infliximab: From the Idea to the Product

2 Infliximab: From the Idea to the Product

M. Wiekowski, Ch. E. Antoni

2.1

Characteristics and Biological Activity

2.1.1

Antibody Characteristics

Infliximab is a monoclonal antibody that neutralizes the cytokine tumor necrosis factor (TNF)- [ by binding selectively and with high affinity to soluble and mem- brane-bound TNF- [ . Infliximab does not bind to TNF- q (lymphotoxin [ ), a related cytokine that utilizes the same receptors as TNF- [ . Thus infliximab was devel- oped as a therapeutic agent for various inflammatory chronic diseases that are believed to be driven by the pro-inflammatory cytokine TNF- [ .

Infliximab was developed by fusing the TNF- [ bind- ing site of the murine antibody A2 to the constant region of human IgG1 κ immunoglobulin. This created a chimeric antibody with an acceptable immunogenic and pharmacokinetic profile (Knight et al. 1993).

Infliximab binds the trimeric form of soluble TNF- [ with an affinity of K

100 pM but also binds to its mono- meric form (Scallon et al. 1995, 2002). Although the tri- meric form of TNF- [ is the bioactive form, binding of TNF- [ monomers might be clinically important by slowing down or even preventing the formation of tri- meric TNF- [ .

When testing the binding affinity of infliximab on a cell line that expresses only membrane-bound recom- binant human TNF- [ , the affinity of the antibody to TNF- [ was about twofold higher when compared to the affinity to soluble TNF- [ (K

46 pM) (Scallon et al.

1995). In addition, the binding affinities of the dimeric F(ab’)2 fragment were 50-fold higher than that of the monomeric FAB fragment (Scallon et al. 1995). This verified that the strong avidity of the antibody binding to TNF- [ is in part based on the bivalent interaction of the antibody with its ligand.

The stability of the infliximab-TNF- [ complex was confirmed by its slow dissociation rate. In fact, no dis- sociation of infliximab was observed within 4 h from soluble or within 2 h from membrane-bound TNF- [ in an in vitro assay (Scallon et al. 2002).

2.1.2

Other Mechanisms of Infliximab Activity

Binding and neutralization of soluble TNF- [ is proba- bly not the only activity mediated by infliximab.

Indeed, in vitro assays have shown that infliximab also

binds to membrane-bound TNF- [ and induces cell

death (Scallon et al. 1995). However, clinical observa-

tions suggest that infliximab mediated cytotoxicity in

vivo is limited. Infliximab infusions are very well toler-

ated and patients do not experience a cell lysis syn-

drome (Scallon et al. 1995). Similarly, the number of

circulating mononuclear cells does not decrease follow-

ing infliximab infusions. In contrast, programmed cell

death (apoptosis) has been observed in Crohn’s

patients treated with infliximab within 24 h of a single

infusion. In these patients a significant increase in the

number of apoptotic T cells was noted in the lamina

propria. Interestingly, infliximab dependent apoptosis

of T cells appears to be restricted to activated T cells

since in an in vitro experiment infliximab only lysed

activated, but not resting, Jurkat (a T-cell line) cells (ten

Hove et al. 2002). These experiments suggest that the

efficacy of infliximab observed in chronic inflammato-

ry conditions is not only mediated through the neutral-

ization of TNF- [ , but also through other activities like

induction of cell death in selected cells.

membrane-bound TNF-α soluble TNF-α

infliximab soluble TNF-α membrane-bound forms of TNF-α

Fig. 2.1. Bivalent interaction of infliximab with its ligand cross-links soluble and membrane-bound TNF-[ (modified from Scallon B et al. 2002. J Pharmacol Exp Ther 301:418 – 426, with per- mission)

2.2

Administration

Infliximab is commercially formulated for intravenous infusions. It is administered to patients as an induction therapy with infusions at weeks 0, 2 and 6 followed by maintenance therapy with infusions every 8 weeks.

Infusions are performed over a 2-h period.

2.3

Therapeutic Indications

TNF- [ antagonists are used in inflammatory condi- tions that are characterized by elevated TNF- [ levels at the site of inflammation as well as systemically increased levels. For instance, increased TNF- [ expression has been detected in lesional skin of psori- atic patients (Johansen et al. 2006) or in the inflamed intestine in Crohn’s disease patients (Raddatz et al.

2005). Thus, treatment of these inflammatory condi- tions with TNF- [ antagonists results in the binding, neutralization and elimination of surplus TNF- [ from the blood circulation and from sites of inflam- mation and translates into clinical benefit for the patient.

Infliximab is the only TNF- [ antagonist that is administered directly into the circulation by intrave- nous (i.v.) infusions; other TNF- [ antagonists like eta- nercept and adalimumab are administered by subcuta- neous (s.c.) injections. While subcutaneous injections may be more convenient to the patient, subcutaneously administered drugs have to be absorbed from the injec- tion site into the circulation before they can reach sites

of inflammation and can become active. Thus, based on the different routes of administration, TNF- [ antago- nists present with different pharmacokinetics charac- terized by either a more even steady-state concentra- tion of the subcutaneous drugs adalimumab or etaner- cept, or a serum profile characterized by peaks and troughs as for infliximab.

The presence of peak concentrations of TNF- [ antagonist in the serum following infusions raises con- cern about the increased susceptibility of patients to infections by eliminating TNF- [ below a perceived safety window for an undefined time. However, accu- mulated data from registries that follow patients for extended period of times do not show differences in the infection rates between subjects receiving TNF- [ blockers by either s.c. or i.v. administration (Wolfe et al. 2006). Rather, increased rates of serious infec- tions appear to be linked to elevated susceptibility of patients due to their disease (Askling et al. 2005) or concomitant medications (Wolfe et al. 2006; Westho- vens et al. 2006; Lichtenstein et al. 2006). In contrast, high concentrations of TNF- [ antagonist in serum and peripheral tissue following administration might pro- vide the opportunity for a rapid clinical response.

Indeed, a clinical response to infliximab treatment was detected as early as 2 weeks following the first infu- sion in patients suffering from rheumatoid arthritis, Crohn’s disease and ulcerative colitis (Maini et al. 1999;

Rutgeerts et al. 2005; Targan et al. 1997; Kavanaugh et al. 2000).

Infliximab is currently (2006) approved for the treat-

ment of six chronic inflammatory conditions:

1. For the reduction of signs and symptoms as well as improvement in physical function in patients with

2. For severe and active Crohn’s disease in patients who do not respond to corticosteroid or immuno- suppressant therapy or those with fistulating, active Crohn’s disease

3. For ulcerative colitis in patients who do not respond to conventional therapy

4. For ankylosing spondylitis in patients who have severe axial symptoms, elevated serological mark- ers of inflammatory activity and who have responded inadequately to conventional therapy 5. For active and progressive psoriatic arthritis in

combination with methotrexate

6. For moderate to severe plaque psoriasis in patients who are intolerant to other systemic therapies

2.4

Pharmacokinetics

The pharmacokinetics of infliximab has been deter- mined in clinical studies in a variety of indications. In general, maximal or trough serum concentrations of infliximab are proportional to the dose of antibody administered independent of the inflammatory condi- tion of the patient (summarized in Table 2.1). The vol- ume of distribution is independent of the dose and indicates that infliximab is primarily distributed in the vascular space. The terminal half-life of infliximab is 8.0 – 9.5 days and the antibody is still detectable in the serum 12 weeks after the last infusion (Kavanaugh et al.

2000; Centocor 2006; Cornillie et al. 2001).

2.4.1

Pharmacokinetics in Rheumatoid Arthritis Patients

The pharmacokinetics of infliximab has also been determined in patients with active RA. Patients with active rheumatoid who were on a stable dose of metho- trexate received single infusions of 5, 10 or 20 mg/kg infliximab. Following infusions serum concentrations for infliximab peaked between 1- and 4- h post infusion and then declined exponentially from day 3 through week 12. The mean terminal half-life for infliximab was 9 – 12 days in doses of 5 – 20 mg/kg. Maximal serum concentrations (C

) as well as overall infliximab con- centrations over time (area under the curve, AUC)

increased proportionally with an increase in the dose.

Clearance, volume of distribution, mean residence time and terminal half-life were relatively constant for all three doses. The value of C

and the volume of dis- tribution suggest that the total dose of infliximab dis- tributes into the vascular space. Regardless of the dose, infliximab was still detectable in most patients at week 10 after the infusion.

In this study, after having received only one dose of infliximab, most patients experienced a clinical response by week 1 or 2 and maintained improvement through week 10 – 12. The ACR20 response rates were similar for all three doses, with 81 % of patients responding at week 1 and 52 % maintaining the response at week 12. More patients in the higher dose groups achieved an ACR50 response at week 1 and more patients in the 20-mg/kg group achieved an ACR50 response at week 12 when response was com- pared across all dose groups.

Of note is the rapid onset of a clinical response in this study as more than half of the patients on inflixi- mab experienced a clinical response as early as week 1 after the first infusions (Kavanaugh et al. 2000).

In the extension of this study, patients received 10 mg/kg infliximab infusions every 8 weeks. In these patients the serum infliximab concentrations stayed constant, suggesting that repeated administrations of this antibody did not substantially change its pharma- cokinetics (Table 2.1). Most patients still had detectable serum inflixmab concentrations 12 weeks after the last infusion. Fifty-three percent of the patients in the extension study maintained an ACR20 response through week 40 (Kavanaugh et al. 2000).

Dose and dosing frequency of infliximab and their effect on pharmacokinetics, efficacy and safety were also explored over a 30-week trial in rheumatoid arthritis patients. Patients who had active rheumatoid arthritis and remained on a stable dose of methotrex- ate received 3-mg/kg or 10-mg/kg infliximab infu- sions at weeks 0, 2 and 6, and then every 4 or 8 weeks thereafter.

The trough infliximab serum concentrations at week 30 were determined [mean (SD) 1.5 (1.6) μg/ml for 3 mg/kg every 8 weeks, 9.7 (8.6) μg/ml for 3 mg/kg every 4 weeks, 8.9 (8.1) μg/ml for 10 mg/kg every 8 weeks and 35.8 (23.7) μg/ml for a 10-mg/kg dose every 4 weeks].

In all groups, over 50 % of patients experienced an

ACR20 response as early as 2 weeks after the first infu-

sion; this proportion of responders increased to 90 % at

Table 2.1. Pharmacokinetics of infliximab

Dose Times of dosing Trough concentration (μg/ml) Clinical response Ref.

Rheumatoid arthritis

3 mg/kg 3 mg/kg 10 mg/kg 10 mg/kg Placebo

Week 0, 2, 6, then every 4 weeks 8 weeks 4 weeks 8 weeks

At week 30 Mean (SD) 9.7 (8.6) 15.0 (1.6) 35.8 (23.7)

8.9 (8.1)

At week 30 ACR50 29 %**

27 %**

26 %**

31 %**

5 %

ACR70 11 %**

8 %**

11 %**

18 %**

0 %

**p e 0.002

Maini et al. 1999

3 mg/kg Week 0, 2, 6, 14 At week 2 At week 6 At week 14

22.3 μg/ml (15.3 – 29.4) 14.5 μg/ml (7.3 – 22) 2.8 μg/ml (0.6 – 6.8)

DAS 28 response at week 14 in 78 % of patients Non-responders had significantly lower trough than responders 0.5 (0.2 – 2.2) vs 3.6 (1.4 – 8.2) μg/ml

Wolbink et al. 2006

10 mg/kg 5, 10 or 20 mg/kg at week 0 then 10 mg/kg at week 12, 20 and 28

At week 20 At week 28 At week 36

8.5 μg/ml (2.6 – 19.6) 7.9 μg/ml (0 – 20.3) 9.9 μg/ml (0.3 – 23.5)

At week 40 ACR20 58 %

ACR50 37 %

Kavanaugh et al. 2000

Psoriasis

5 mg/kg 10 mg/kg

Week 0, 2, 6

At week 1

*2/9 patients had levels < 0.1 0.67 μg/ml (< 0.1*–6.09) 7.11 μg/ml (2.38 – 15.13)

Gottlieb et al. 2003

5 mg/kg

Week 0, 2, 6 then every 8 weeks

2.8 – 3.7 μg/ml between weeks 22 and 46

Week 10 IFX Placebo Week 24 IFX Placebo Week 50 IFX

PASI75 80 %

3 % 82 % 4 % 61 %

PASI90 57 %

1 % 58 % 1 % 15 %

Reich et al. 2005

Crohn’s disease

10 mg/kg Every 8 weeks Week 20 Week 28 Week 36 Week 44

7.9 μg/ml 10.0 μg/ml 8.1 μg/ml 8.0 μg/ml

Maintenance of remission At week 44

Placebo 35 % IFX 60 %

Rutgeerts et al. 1999

week 6 or 4 weeks following the second infusion. The total response rate was maintained at week 30 between 50 % and 60 %. The ACR50 response at week 30 ranged

from 26 % to 31 %, and the ACR70 response from 8 % to

18 % across all dose groups with no apparent dose

response (Table 2.1) (Maini et al. 1998).

Week Infusion

1000

100

10

1

0.1

0 2 6 10 14 18

5 mg/kg Infliximab (n = 28) 10 mg/kg Infliximab (n = 30) Infliximab serum concentration (μg/mL)

Week Infusion

1000

100

10

1

0.1

0 2 6 10 14

5 mg/kg Infliximab 10 mg/kg Infliximab

Infliximab serum concentration (μg/mL) 5421

2.4.2

Pharmacokinetics in Crohn’s Disease

Patients with active Crohn’s disease were originally randomized to receive placebo or a single infusion of 5, 10 or 20 mg/kg infliximab. If they did not show a response by week 4, they received an additional dose of 10 μg/ml infliximab. Eight weeks later responders were eligible to enter an extension study where they were randomized to either placebo or 10-mg/kg infusions of infliximab. Patients were retreated every 8 weeks and evaluated at week 40.

In these patients the analysis of the infliximab serum concentrations before an infusion every 8 weeks showed that median trough concentrations remained stable over time at about 8 – 10 μg/ml between weeks 20 and 44 (Table 2.1). Most patients had still detectable concentrations of serum infliximab 12 weeks after the final infusion (median 2.2 μg/ml). Patients who contin- ued infliximab treatment during the extension phase were able to maintain the initial clinical benefit (Rut- geerts et al. 1999).

In another study in Crohn’s disease patients, again dose-dependent serum concentrations were observed in Crohn’s disease patients after single infusions of 5, 10 or 20 mg/kg infliximab. At the recommended 5-mg/kg dose, the maximal serum concentration was 118 μg/ml and the median half-life 9.5 days. In this study at week 12 no antibody levels were detected in the serum after the 5-mg/kg infusion (Cornillie et al. 2001).

Fig. 2.2. Profile of serum infliximab concentrations vs time for fistula patients who received three infusions of 5 or 10 mg/kg infliximab at weeks 0, 2 and 6 (arrows). Serum samples were obtained before and after each infusion and at the indicated time points after the third infusion. Each point represents the median result for that time period and dose group

2.4.3

Pharmacokinetics in Psoriasis

The pharmacokinetics of infliximab was determined in psoriasis patients in a phase 2 clinical trial (Gottlieb et al. 2003). Patients received doses of 5 mg/kg or 10 mg/

kg infliximab at weeks 0, 2 and 6.

The highest serum concentrations of infliximab were observed in patients at week 2 immediately after the second dose: median 158.14 and 298.89 μg/ml for the 5- and 10-mg/kg dose groups, respectively. The concentra- tions were directly proportional to the administered dose. The lowest serum concentrations of 0.67 μg/ml were observed at week 14 for the 5-mg/kg group (range

< 0.1 – 6.09 μg/ml) while at week 14 the serum levels for the 10-mg/kg group were 7.11 μg/ml (Fig. 2.3). The median half-life of infliximab was determined as 7.62 days (interquartile range 6.62 – 10.15 days) for the 5-mg/kg dose group and 9.97 days (interquartile range 6.17 – 10.14 days) for the 10-mg/kg dose group (Gottlieb et al. 2003).

2.4.4

Pharmacokinetics in Pediatric Crohn’s Patients

In pediatric Crohn’s patients (mean age 10.5 ± 3.3 years), the levels of serum infliximab were determined after infusions of 5 mg/kg at week 2 and at week 6, 4 weeks after the second infusion. The trough infliximab concentration was 16.7 + 7.3 μg/ml at week 2 and

Fig. 2.3. The median half-life of infliximab was determined as 7.62 days (interquartile range 6.62 – 10.15 days) for the 5-mg/

kg dose group and 9.97 (interquartile range 6.17 – 10.14) days for the 10-mg/kg dose group (Gottlieb et al. 2003)

8.8 ± 7.1 μg/ml at week 6. This translates into a terminal half-life of 9.5 days and a mean residence time of 13 days. No infliximab (detection limit 1.8 μg/ml) was detected in serum of children at week 8 after sequential treatment with 5-mg/kg doses (Candon et al. 2006).

2.5

Relationship Between Infliximab Concentration and Clinical Response

The relationship between serum infliximab concentra- tions and clinical response was tested in the ATTRACT trial for rheumatoid arthritis. Doses of 3 mg/kg or 10 mg/kg infliximab resulted in maximal maximum serum concentrations that were directly proportional to the intravenous dose; serum concentrations of 68.8 μg/ml and 219.1 μg/ml were detected 1 h post-infu- sion (St Clair et al. 2002). The trough concentration was also dependent on the amount and frequency of dose.

Patients receiving 10 mg/kg every 4 weeks had the high- est trough levels, while patients receiving 3 mg/kg every 8 weeks had the lowest trough levels. The median trough levels were comparable in patients receiving 10 mg/kg every 8 weeks and 3 mg/kg every 4 weeks (Kavanaugh et al. 2000; St Clair et al. 2002).

When the trough serum levels of infliximab at week 54 were correlated with clinical response it became apparent that a higher ACR-N response was significantly associated with a higher trough serum concentration of infliximab. While no significant dif- ference in the ACR20 response was detected for patients receiving 3 mg/kg or 10 mg/kg infliximab at either 4- or 8-week intervals, the ACR50 response rates were significantly lower in the group receiving 3 mg/kg every 8 weeks compared to the other groups. This sug- gested that clinical response relates to trough serum concentrations of infliximab.

Indeed, when clinical responses were correlated with trough serum concentrations, most patients with a response of less than ACR20 had undetectable trough serum levels of infliximab, while the highest propor- tion of ACR50 and ACR70 responders had the highest trough serum levels (St Clair et al. 2002).

In another open label study the relationship between infliximab levels and clinical response to infliximab treatment in RA was confirmed. Patients received 3- mg/kg inflixmab infusions at weeks 0, 2, 6 and 14. At week 2 the median serum trough level for inflixi-

mab was 22.3 (15.3 – 29.4) μg/ml, at week six 14.6 (7.2 – 22) μg/ml, and at week fourteen 2.8 (0.6 – 6.8) μg/

ml. While trough serum concentrations varied consid- erably between patients, a better clinical response was associated with higher median trough serum concen- trations (Wolbink et al. 2006). In general, in RA, a trough concentration of > 1.0 μg/ml is associated with a good therapeutic response (St Clair et al. 2002) and the clinical response declines rapidly after serum inflixi- mab levels drop below this threshold (Markham and Lamb 2000).

The relationship between trough infliximab serum concentrations and clinical response was also deter- mined in a 1-year psoriasis study. Patients were receiv- ing 5 mg/kg inflixmab treatment every 8 weeks after induction therapy. Between week 22 and week 46 the median pre-infusion inflixmab concentration stabi- lized between 2.8 μg/ml and 3.7 μg/ml. Patients who maintained their clinical response through week 50 had trough infliximab serum concentrations above 1 μg/ml, while in about 25 % of patients who lost the response the median pre-infusion infliximab concentrations dropped below 1 μg/ml (Reich et al. 2005).

2.6

Antibody Formation Against Infliximab

The presence of antibodies to infliximab in patients is determined by an enzyme linked immunosorbent assay (ELISA). However, the detection of antibodies to infliximab can be hindered by the presence of inflixi- mab in the serum. Thus, since infliximab can remain in the circulation for at least 4 – 12 weeks after infusion, serum samples are usually collected for analysis 12 weeks or later after the last infusion.

When the formation of antibodies against inflixi-

mab (HACA) was determined 12 weeks after the last

infusion in RA patients, HACA were detected in about

17 % of all treated patients. The rate of HACA responses

was inversely proportional to the dosage; HACA forma-

tion occurred in 53 %, 21 % and 7 % of patients treated

with 1, 3 and 10 mg/kg infliximab, respectively. Con-

comitant treatment with methotrexate decreased the

rate to 15 %, 7 % and 3 % for the three respective dos-

ages. The smaller proportion of patients on higher

doses of infliximab who are developing HACA suggest

that anti-TNF- [ treatment induces a phenomenon

resembling tolerance (Maini et al. 1998).

A significantly higher incidence of antibodies to infli- ximab was detected in Crohn’s patients who received episodic treatment, i.e., they received one dose of inflixi- mab at the beginning of the trial, but then only placebo until week 14 or later until the disease worsened. While 30 % of patients on this treatment schedule developed HACA, only 8 % of patients who received infliximab infusions every 8 weeks developed HACA. In addition, the incidence of HACA was higher in patients who did not receive immunomodulators compared to those who did (18 % vs 10 %, p = 0.02) (Hanauer et al. 2004).

This suggests that higher doses of infliximab at scheduled (every 8 weeks) infusions and perhaps in combination with an immunomodulator are the best treatment paradigm to reduce the possibility of devel- oping HACA.

2.6.1

HACA Formation and Clinical Response

Administration of a chimeric human-mouse antibody can lead to the formation of antibodies against the chi- meric protein and the formation of immune complexes.

The presence of antibodies directed against therapeutic antibodies in patients can lead to adverse reactions upon administration or loss of efficacy due to accelerat- ed elimination of the therapeutic antibody from the cir- culation.

Preclinical studies in cynomolgus monkeys provid- ed information on the formation and size of immune complexes between infliximab and anti-inflixmab anti- bodies, the distribution of these complexes in the whole body, and the rate and mechanism of their elimination.

Cynomolgus monkeys received infusions of 1.74 mg/kg inflixmab followed by either an intravenous bolus of 0.5 mg/kg radio-labeled rhesus monkey anti-infliximab IgG (test) or radio-labeled rhesus monkey non- immune IgG (control antibodies).

In these monkeys the immune complexes between infliximab and the anti-infliximab antibodies formed quickly within 5 min of administration, while no com- plexes were formed between infliximab and the control antibodies. The terminal half-life of the anti-infliximab immune complex was approximately 38 h compared to 86 h for the control antibody, thus implying an about twofold accelerated clearance of infliximab in complex with an antibody (Rojas et al. 2005).

In a cohort of infliximab treated Crohn’s disease patients, titers of anti-infliximab antibodies were cor-

related with clinical response. Again, anti-infliximab antibody concentrations of 8 μg/ml or greater were positively correlated with a higher risk for infusion reactions and a decreased duration of a therapeutic response to infliximab (Baert et al. 2003).

These studies suggest that scheduled treatment in combination with an immunosuppressive drug carries the least risk of antibody formation against infliximab and offers the best probability to maintain the response.

2.7

Infusion Reactions/Delayed Hypersensitivity Reactions

The highest frequency of adverse events in response to infliximab treatment are infusion reactions occurring within 2 h of the infusion. They typically consist of fever, shills, nausea, dyspnea, and headaches, and symptoms can be controlled with drug treatment (e.g., antihistamines). Infusion reactions led to discontinua- tion of treatment in approximately 3 % of patients, and were considered serious in less than 1 % of patients (St Clair et al. 2004; Sands et al. 2004; Lipsky et al. 2000;

Gottlieb et al. 2004). Delayed reactions like myalgias, arthralgias, fever, rash, pruritus, facial, hand or lip ede- ma, dysphagia, urticaria, sore throat and headache may occur within 3 – 12 days following the infusion (Lipsky et al. 2000).

However, while the rate of infusion reactions posi- tively correlated with the development of HACA, just the presence of HACA antibodies in the serum of patients proved to be poorly predictive for these events (Hanauer et al. 2004; Baert et al. 2003).

2.8

Alternative Routes of Administration

For the treatment of rheumatoid arthritis, infliximab is

approved in combination with methotrexate for intra-

venous dosing at 3 mg/kg every 8 weeks. As an alterna-

tive to the intravenous dosing route, an experimental

formulation for subcutaneous and intramuscular (i.m.)

dosing was evaluated in RA patients who are refractory

to methotrexate therapy in a phase I clinical study. Fif-

teen patients were randomized to receive s.c. doses at

0.5 mg/kg, 1.5 mg/kg and 3 mg/kg. After evaluation of

the pharmacokinetic data from this group, a 100-mg s.c. dose was chosen to treat patients either s.c. at weeks 0, 2 and 4, or after 3-mg/kg i.v. infusions of Remi- cade at weeks 0 and 2 with s.c. injections at weeks 4, 6 and 8. Another group of patients received 100-mg i.m.

injections at weeks 0, 2 and 4.

After a single s.c. injection at doses ranging from 0.5 to 3 mg/kg, the median half-life ranged from 8.0 to 8.4 days and the C

and AUC increased in a roughly dose-proportional manner across these dose groups.

At day 7, a 6.7-fold higher C

and a 6.3-fold higher AUC were determined in the 3-mg/kg dose when com- pared to the 0.5-mg/kg group. Subjects receiving three doses of 100 mg s.c. every 4 weeks had trough concen- trations of infliximab above or equal to 1 μg/ml. Over 80 % of subjects receiving multiple doses of 100 mg infliximab s.c. achieved an ACR20 response when eval- uated 2 weeks after the last dose of infliximab. In con- trast, the response to i.m. infliximab administration appeared to be delayed since at 2 weeks post-treatment

~57 % of patients achieved an ACR20 response, while at 4 weeks post-treatment 83 % or five out of six patients achieved an ACR20 response. Individual patients in this study achieved higher clinical responses even after a single s.c. administration, and the majority after mul- tiple s.c. injections achieved an ACR50 response, as did about one-third of patients in the i.m. group.

Irrespective of s.c. or i.m. administration, 34 out of 43 patients experienced transient AEs of mild to mod- erate severity. This included ten subjects having mild to moderate infections. There were no serious injection site reactions. In addition, the humoral response to either route of administration was not suppressed.

Thus this exploratory study described alternative routes of administration for infliximab that resulted in trough levels above or equal to 1 μg/ml at week 4, which is considered the serum concentration required to achieve a clinical response. However, this study is too small to draw general conclusions regarding safety or efficacy (Westhovens et al. 2006).

2.9 Summary

Intravenous administration of infliximab results in serum levels that are proportional to the dose in patients suffering from a variety of inflammatory dis- eases. Infliximab treatment is characterized by a clini-

cal response that occurs as early as 2 weeks following the first infusion. The maintenance of the clinical response correlates with the presence of detectable infliximab concentrations of > 1 μg/ml in the serum at trough which can be maintained by infusions every 8 weeks in most patients.

Formation of antibodies against infliximab has been observed in patients, and can lead to infusion reactions and faster elimination of the antibody from the circula- tion. While routes of administration other than infu- sion have been demonstrated to result in clinical bene- fit for patients, infliximab is commercially available only in the intravenous formulation.

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