Page 677 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 36 NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout 663

effective in lowering serum urate levels than was allopurinol at allowing for IV dosing every 2 weeks. Pegloticase should not be
a standard 300-mg daily dose. The urate-lowering effect was used for asymptomatic hyperuricemia.
comparable regardless of the pathogenic cause of hyperuricemia— 4. Adverse Effects: Gout flare can occur during treatment with
overproduction or underexcretion. pegloticase, especially during the first 3–6 months of treat-
3. Indications: Febuxostat is approved at doses of 40 or 80 mg for ment, requiring prophylaxis with NSAIDs or colchicine. Large
the treatment of chronic hyperuricemia in gout patients. numbers of patients show immune responses to pegloticase.
Although it appeared to be more effective then allopurinol as The presence of antipegloticase antibodies is associated with
urate-lowering therapy, the allopurinol dosing was limited to shortened circulating half-life, loss of response leading to a rise
300 mg/d, thus not reflecting the actual dosing regimens used in plasma urate levels, and a higher rate of infusion reactions
in clinical practice. At this time, the dose equivalence of and anaphylaxis. Anaphylaxis occurs in more than 6–15% of
allopurinol and febuxostat is unknown. patients receiving pegloticase. Monitoring of plasma uric acid
4. Adverse Effects: As with allopurinol, prophylactic treatment level, with rising level as an indicator of antibody production,
with colchicine or NSAIDs should be started at the beginning allows for safer administration and monitoring of efficacy. In
of therapy to avoid gout flares. The most frequent treatment- addition, other oral urate-lowering agents should be avoided
related adverse events are liver function abnormalities, diarrhea, in order not to mask the loss of pegloticase efficacy. Nephroli-
headache, and nausea. Febuxostat is well tolerated in patients thiasis, arthralgia, muscle spasm, headache, anemia, and nausea
with a history of allopurinol intolerance. There does not appear may occur. Other less frequent side effects noted include upper
to be an increased risk of cardiovascular events. respiratory tract infection, peripheral edema, urinary tract infec-
5. Dosage: The recommended starting dose of febuxostat is tion, and diarrhea. There is some concern for hemolytic anemia
40 mg daily. Because there was concern for cardiovascular in patients with glucose-6-phosphate dehydrogenase deficiency
events in the original phase 3 trials, the FDA approved only because of the formation of hydrogen peroxide by uricase; there-
40-mg and 80-mg dosing. No dose adjustment is necessary for fore, pegloticase should be avoided in these patients.
patients with renal impairment since it is highly metabolized
into an inactive metabolite by the liver.
GLUCOCORTICOIDS

Corticosteroids are sometimes used in the treatment of severe
PEGLOTICASE symptomatic gout, by intra-articular, systemic, or subcutaneous
routes, depending on the degree of pain and inflammation.
Pegloticase is the newest urate-lowering therapy to be approved for The most commonly used oral corticosteroid is prednisone.
the treatment of refractory chronic gout. The recommended oral dose is 30–50 mg/d for 1–2 days, tapered
1. Chemistry: Pegloticase is a recombinant mammalian uricase over 7–10 days. Intra-articular injection of 10 mg (small joints),
that is covalently attached to methoxy polyethylene glycol 30 mg (wrist, ankle, elbow), and 40 mg (knee) of triamcino-
(mPEG) to prolong the circulating half-life and diminish lone acetonide can be given if the patient is unable to take oral
immunogenic response. medications.
2. Pharmacokinetics and Dosage: The recommended dose for
pegloticase is 8 mg every 2 weeks administered as an intrave- INTERLEUKIN 1 INHIBITORS
nous infusion. It is a rapidly acting drug, achieving a peak
decline in uric acid level within 24–72 hours. The serum half- Drugs targeting the IL-1 pathway, such as anakinra, canakinumab,
life ranges from 6 to 14 days. Several studies have shown earlier and rilonacept, are used for the treatment of gout. Although the
clearance of PEG-uricase (mean of 11 days) due to antibody data are limited, these agents may provide a promising treatment
response when compared to PEG-uricase antibody-negative option for acute gout in patients with contraindications to, or who
subjects (mean of 16.1 days). are refractory to, traditional therapies like NSAIDs or colchicine.
3. Pharmacodynamics: Urate oxidase enzyme, absent in humans A recent study suggests that canakinumab, a fully human anti-
and some higher primates, converts uric acid to allantoin. This IL-1β monoclonal antibody, can provide rapid and sustained pain
product is highly soluble and can be easily eliminated by the relief at a dose of 150 mg subcutaneously. These medications are
kidney. Pegloticase has been shown to maintain low urate levels also being evaluated as therapies for prevention of gout flares while
for up to 21 days after a single dose at doses of 4–12 mg, initiating urate-lowering therapy.