Page 669 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 36 NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout 655

contain an F region, found on a complete antibody, and does Golimumab
c
not fix complement or cause antibody-dependent cell-mediated
cytotoxicity in vitro. 1. Mechanism of Action: Golimumab is a human monoclonal
2. Pharmacokinetics: Certolizumab is given subcutaneously and antibody with a high affinity for soluble and membrane-bound
has a half-life of 14 days. Methotrexate decreases the appear- TNF-α. Golimumab effectively neutralizes the inflammatory
ance of anti-certolizumab antibodies. The usual dose for RA is effects produced by TNF-α seen in diseases such as RA.
400 mg initially and at weeks 2 and 4, followed by 200 mg 2. Pharmacokinetics: Golimumab is administered subcutane-
every other week, or 400 mg every 4 weeks. ously and has a half-life of approximately 14 days. Concomi-
3. Indications: Certolizumab is indicated for the treatment of tant use with methotrexate increases golimumab serum levels
adults with moderately to severely active RA. It can be used as and decreases anti-golimumab antibodies. The recommended
monotherapy or in combination with nonbiologic DMARDs. dose for the treatment of RA, PsA, and AS is 50 mg given every
Additionally, certolizumab is approved in adult patients with 4 weeks. A higher dose of golimumab is used for the treatment
Crohn’s disease, active PsA, and active AS. The certolizumab of ulcerative colitis as follows: 200 mg initially at week
head-to-head TNFi trial, Exxelerate (NCT01500278), was 0 followed by 100 mg at week 2 and every 4 weeks thereafter.
a multicenter, single-blind, 24-month, randomized, parallel- 3. Indications: Golimumab with methotrexate is indicated for
group trial in moderate to severe MTX-incomplete-responder the treatment of moderately to severely active RA in adult
RA patients, comparing adalimumab + MTX to certolizumab patients. It is also indicated for the treatment of PsA and AS
+ MTX. ACR20 responses at 3 months and achievement of and moderate to severe ulcerative colitis.
low disease activity at 2 years were numerically comparable for
both protocols. Although putatively a 24-month trial, patients Infliximab
could switch from one regimen to the other at 3 months, con-
founding comparability beyond that time frame. Not surpris- 1. Mechanism of Action: Infliximab (Figure 36–4) is a chimeric
ingly, given this confounding, the primary goal of certolizumab (25% mouse, 75% human) IgG monoclonal antibody that
1
+ MTX superiority was not met. Patients were switched without binds with high affinity to soluble and possibly membrane-
washout so blood levels of TNFis as a group could be expected bound TNF-α. Its mechanism of action probably is the same
to be very high during the switchover. Interestingly, no serious as that of adalimumab.
infectious events occurred during the switch-over period. 2. Pharmacokinetics: Infliximab is given as an intravenous infu-
sion with “induction” at 0, 2, and 6 weeks and maintenance
Etanercept every 8 weeks thereafter. Dosing is 3–10 mg/kg, and the usual
dose is 3–5 mg/kg every 8 weeks. There is a relationship
1. Mechanism of Action: Etanercept is a recombinant fusion between serum concentration and effect, although individual
protein consisting of two soluble TNF p75 receptor moieties clearances vary markedly. The terminal half-life is 9–12 days
linked to the F portion of human IgG (Figure 36–4); it binds without accumulation after repeated dosing at the recom-
c
1
TNF-α molecules and also inhibits lymphotoxin α. mended interval of 8 weeks. After intermittent therapy, inflix-
2. Pharmacokinetics: Etanercept is given subcutaneously as imab elicits human antichimeric antibodies in up to 62% of
25 mg twice weekly or 50 mg weekly. In psoriasis, 50 mg is patients. Concurrent therapy with methotrexate markedly
given twice weekly for 12 weeks and then is followed by 50 mg decreases the prevalence of human antichimeric antibodies.
weekly. The drug is slowly absorbed, with peak concentration 3. Indications: Infliximab is approved for use in RA, AS, PsA,
72 hours after drug administration. Etanercept has a mean Crohn’s disease, ulcerative colitis, pediatric inflammatory
serum elimination half-life of 4.5 days. A recent study demon- bowel disease, and psoriasis. It is being used off-label in other
strated a reduction of radiographic progression with the use of diseases, including granulomatosis with polyangiitis (Wegener’s
50 mg of etanercept weekly. granulomatosis), giant cell arteritis, Behçet’s disease, uveitis,
3. Indications: Etanercept is approved for the treatment of RA, and sarcoidosis. In RA, infliximab plus methotrexate decreases
juvenile chronic arthritis, psoriasis, PsA, and AS. It can be the rate of formation of new erosions. Although it is recom-
used as monotherapy, although over 70% of patients taking mended that methotrexate be used in conjunction with inflix-
etanercept are also using methotrexate. Etanercept decreases imab, a number of other nonbiologic csDMARDs, including
the rate of formation of new erosions relative to methotrex- antimalarials, azathioprine, leflunomide, and cyclosporine, can
ate alone. It is also being used in other rheumatic syndromes be used as background therapy for this drug. Infliximab is also
such as scleroderma, granulomatosis with polyangiitis (Wegener’s used as monotherapy.
granulomatosis), giant cell arteritis, Behçet’s disease, uveitis,
and sarcoidosis. However, a comparative study of ustekinumab Adverse Effects of TNF-`-Blocking Agents
(an IL-12 and IL-23 blocker) and etanercept concluded that
ustekinumab at a dose of 45 or 90 mg was superior to high- TNF-α–blocking agents have multiple adverse effects in common.
dose etanercept (50 mg twice weekly) over a 12-week period in The risk of bacterial infections and macrophage-dependent infec-
patients with psoriasis. tion (including tuberculosis, fungal, and other opportunistic