RESEARCH - Humira in adults with RA receiving concomitant MTX

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Clin Ther. 2003 Jun;25(6):1700-21.

Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully

human anti-tumor necrosis factor-alpha monoclonal antibody, in adults

with rheumatoid arthritis receiving concomitant methotrexate: a pilot

study.

Weisman MH, Moreland LW, Furst DE, Weinblatt ME, Keystone EC, us HE,

Teoh LS, Velagapudi RB, Noertersheuser PA, Granneman GR, Fischkoff SA,

Chartash EK.

Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

weisman@...

BACKGROUND: Because traditional therapies for rheumatoid arthritis (RA)

such as methotrexate (MTX) do not produce an adequate response in many

patients, newer therapies that block the proinflammatory cytokine tumor

necrosis factor-alpha (TNF-alpha) are increasingly being used in

combination with MTX. OBJECTIVE: This study evaluated the efficacy,

pharmacokinetics, and safety profile of adalimumab, a fully human

anti-TNF alpha monoclonal antibody, when added to continuing MTX

therapy. METHODS: This Phase I, randomized, dose-titration study

consisted of a 4-week, double-blind, placebo-controlled treatment phase

and a 26-month, open-label continuation phase. Patients with RA who had

been taking stable doses of MTX (mean dose, 17 mg/wk) for > or =3 months

before enrollment with an inadequate response were randomly assigned to

receive 2 single doses of either adalimumab 0.25, 0.5, 1, 3, or 5 mg/kg

i.v. or placebo in the double-blind phase. In the open-label phase,

patients received treatment with 1 of the doses of adalimumab every

other week or monthly for 18 months; patients were then switched to

adalimumab 40 mg i.v. or SC every other week or monthly. The main

efficacy end point was 20% improvement in American College of

Rheumatology response criteria (ACR20). Other efficacy end points

included 50% (ACR50) and 70% improvements in ACR response criteria.

Pharmacokinetic parameters were analyzed for adalimumab and MTX during

both phases of the study. Serum adalimumab concentrations were analyzed

using a validated enzyme-linked immunosorbent assay relying on the

double-antigen principle. Peak and trough concentrations were determined

from observed concentration-time data, and a modeling approach was used

to estimate total serum clearance, mean apparent terminal half-life,

apparent volume of distribution at steady state, and area under the

concentration-time curve. RESULTS: Sixty patients entered the

double-blind phase, 45 receiving adalimumab and 15 receiving placebo; 1

placebo recipient chose not to continue into the open-label phase.

Overall, the study population included 47 (78.3%) women and 13 (21.7%)

men. The mean age was 52.9 years (range, 24-73 years), and the mean body

weight was 69.7 kg (range, 43-98 kg). ACR20 and ACR50 responses were

achieved on at least 1 assessment during the 4-week double-blind phase

by a respective 29 (64.4%) and 11 (24.4%) of 45 patients receiving

active treatment and by 4 (26.7%) and none of the 15 patients receiving

placebo. Responses to adalimumab were rapid, with 10 (22.2%) of 45

patients achieving an ACR20 response within 24 hours of dosing. Of 29

adalimumab recipients who had an ACR20 response, 18 (62.1%) had a

duration of response (time from first occurrence of a response to first

occurrence of a nonresponse) of 1 to 2 weeks, and 11 (37.9%) had a

duration of response of 3 to 13 weeks. The pharmacokinetic properties of

adalimumab appeared to be linear. The mean apparent terminal half-life

after a single intravenous dose of adalimumab ranged from 15 to 19 days

in the 5 dose groups. Repeated administration of adalimumab had no

statistically significant effect on the pharmacokinetics of MTX,

indicating that dose adjustment of MTX is not necessary. Adalimumab was

well tolerated, and there were no dose-related adverse events.

CONCLUSIONS: Among patients with active RA who had not had an adequate

response to MTX, addition of adalimumab to MTX achieved statistically

significant, long-term improvement compared with placebo plus MTX (P <

or = 0.05), as indicated by ACR responses at 26 months. The combination

was well tolerated. Adalimumab exhibited linear pharmacokinetics. In

this selected patient population, adalimumab's long half-life of 15 to

19 days supports every-other-week dosing. Coadministration of adalimumab

did not alter serum levels of MTX.

PMID: 12860493

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=12860493 & itool=iconabstr

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