Pharmacokinetics in Rheumatoid Arthritis Patients

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The pharmacokinetics of infliximab has also been determined in patients with active RA. Patients with active rheumatoid who were on a stable dose of methotrexate 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 (Cmax) as well as overall infliximab concentrations 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 Cmax and the volume of distribution suggest that the total dose of infliximab distributes 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 compared 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 infusions 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) ^g/ml for

3 mg/kg every 8 weeks, 9.7 (8.6) ^g/ml for 3 mg/kg every

4 weeks, 8.9 (8.1) ^g/ml for 10 mg/kg every 8 weeks and 35.8 (23.7) ^g/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 infusion; this proportion of responders increased to 90 % at

Table 2.1. Pharmacokinetics of infliximab

Times of dosing Trough concentration (^g/ml) Clinical response

Rheumatoid arthritis

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





At week 30

At week 6 At week 14

10 mg/kg 5,10 or 20 mg/kg At week 20 at week 0 then

At week 28

10 mg/kg at week 12,20 and At week 36 28

Mean (SD) 9.7 (B.6) 15.0 (1.6) 35.B (23.7) B.9 (B.1)

Maini et al. 1999

At week 30 ACR50 ACR70

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) |g/ml

At week 40

Wolbink et al. 2006

ACR20 58%

ACR50 37%

Kavanaugh et al. 2000


At week 1

Gottlieb et al. 2003

5 mg/kg

Week0, 2, 6 then every 8weeks

*2/9 patients had levels <0.1

and 46



















61 %

Crohn's disease

10 mg/kg Every 8 weeks


7.9 |g/ml

Maintenance of remission

Rutgeerts et al. 1999


10.0 |g/ml

At week 44


8.1 |g/ml

Placebo 35%


8.0 |g/ml

IFX 60%

week 6 or 4 weeks following the second infusion. The from 26 % to 31 %, and the ACR70 response from 8 % to total response rate was maintained at week 30 between 18% across all dose groups with no apparent dose 50 % and 60 %. The ACR50 response at week 30 ranged response (Table 2.1) (Maini et al. 1998).

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