1 Star2 Stars3 Stars4 Stars5 Stars (No Ratings Yet)
blankLoading...

Bortezomib

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

BortezomibSynonyms: Bortezomib; LDP-341; PS-341
BAN: Bortezomib
USAN: Bortezomib
INN: Bortezomib [rINN (en)]
INN: Bortezomib [rINN (es)]
INN: Bortézomib [rINN (fr)]
INN: Bortezomibum [rINN (la)]
INN: Бортезомиб [rINN (ru)]
Chemical name: N-((1S)-1-Benzyl-2-{[(1R)-1-(dihydroxyboranyl)-3-methylbutyl]amino}-2-oxoethyl)pyrazinecarboxamide; {(1R)-3-Methyl-1-[(2S)-3-phenyl-2-(pyrazin-2-carboxamido)propanamido]butyl}boronic acid;
Molecular formula: C19H25BN4O4 =384.2
CAS: 179324-69-7
ATC code: L01XX32

Adverse Effects, Treatment, and Precautions

For a general outline see Antineoplastics.

The most common adverse effects of bortezomib include haematological toxicities (especially transient thrombocytopenia), decreased appetite, gastrointestinal disturbances, peripheral neuropathy, fatigue, fever, dyspnoea, rash, and myalgia. Complete blood counts including platelet counts should be monitored and therapy withheld or given at reduced doses if necessary. Peripheral neuropathy may also be dose-limiting.

Other common adverse effects include hyperglycaemia, hypokalaemia, insomnia, anxiety, confusion, depression, blurred vision, eye pain, dizziness, dysgeusia, tremor, epistaxis, cough, rhinorrhoea, pruritus, arthralgia, oedema, and orthostatic hypotension. Tumour lysis syndrome, hypersensitivity, and seizures have been reported. Tachycardia, arrhythmias, palpitations, angina pectoris, and myocardial infarction have occurred. Congestive heart failure may be exacerbated and pulmonary oedema has been reported. There have been rare reports of acute respiratory distress syndrome, some of them fatal.

Renal impairment is common in patients with multiple myeloma and acute renal failure has developed in patients on bortezomib. Licensed product information in the UK considers that patients with compromised renal function should be monitored, and dose reductions considered if needed although in the United States of America this is considered unnecessary. Hepatotoxicity which may be reversible, has included increases in liver enzyme values, hyperbilirubinaemia, and acute liver failure; bortezomib should be used with caution in hepatic impairment.

The impact of proteasome inhibition by bortezomib on disorders associated with protein accumulation such as amyloidosis is unknown and caution is advised in these patients.

Effects on the nervous system

Treatment with bortezomib is often associated with peripheral neuropathy, mainly sensory, although cases of motor neuropathy have been reported. Results from an analysis found that the peripheral neuropathy associated with bortezomib seemed to be cumulative and dose-related, and increased in prevalence through the first 5 treatment cycles. Prolonged bortezomib exposure beyond this time did not seem to increase the incidence or severity of neuropathy. Development of neuropathy appeared to be independent of the previous neuro-toxic therapy. In most patients, neuropathic pain resolved or improved after dose modification or upon completion of therapy.

Effects on the skin

In 3 studies of bortezomib in patients with non-Hodgkin’s lymphoma, 26 of 140 patients developed an erythematous maculopapular rash. Six patients underwent biopsy; all cases revealed a small vessel necrotising vasculitis. Although some patients had dosage reductions implemented or therapy interrupted upon development ofthe rash, others were treated continuously without dose reduction, with no apparent adverse clinical consequences. Infact, analysis ofthe data supported a strong relationship between bortezomib-associated cutaneous vasculitis and a positive clinical response in patient with non-Hodgkin’s lymphoma. A macular brown-red eruption developed in a patient at the site of bortezomib infusions; abundant venous flushing was given from the fourth infusion, and the eruption did not recur, although hyperpigmentation persisted for several months.

Interactions

Bortezomib is metabolised in the liver via the cytochrome P450 isoenzymes CYP3A4, CYP2C19, and CYP1A2; CYP2D6 and CYP2C9 are also thought to play minor roles. Consequently, patients should be monitored closely when bortezomib is used with other drugs that induce or inhibit these isoenzymes. Hypoglycaemia and hyperglycaemia have occurred in diabetic patients receiving oral antidiabetics who were given bortezomib. Caution may be required if bortezomib is used with drugs that are associated with peripheral neuropathy or hypotension.

Pharmacokinetics

After a single intravenous dose of bortezomib, plasma concentrations decline in a biphasic manner; a distribution phase with a half-life of less than 10 minutes is followed by a terminal elimination phase of about 5 to 15 hours. After multiple doses, clearance decreases and there is an increase in the terminal elimination phase. Protein binding has been reported to be over 80%. In-vitro studies indicate that bortezomib is primarily oxidatively metabolised via the cytochrome P450 isoenzymes CYP3A4, CYP2C19, and CYP1A2; minor metabolism via CYP2D6 and CYP2C9 also occurs. The major metabolic pathway is deboronation to inactive metabolites.

Uses and Administration

Bortezomib is an inhibitor of the 26S proteasome, a large protein complex in cells that is responsible for breaking down regulatory proteins of the cell cycle. Such inhibition disrupts tumour cell turnover and induces apoptosis. Bortezomib is used for the treatment of multiple myeloma in patients who have failed at least one previous therapy. In the United States of America (US and USA), it is also used similarly for mantle cell lymphoma in patients given at least one previous therapy. Bortezomib is given in initial doses of 1.3 mg/m intravenously on days 1, 4, 8, and 11 of a 21-day cycle.

At least 72 hours should elapse between consecutive doses of bortezomib. In the UK, licensed product information recommends that patients with a confirmed complete response should receive 2 additional cycles of bortezomib, and that those who respond but do not achieve complete remission receive a total of 8 cycles. In the USA, extended therapy of more than 8 cycles may be given, either on the standard schedule recommended above, or on a maintenance schedule of one dose weekly for 4 weeks (days 1,8, 15, and 22 of a 35-day cycle).

The dose should be reduced, or treatment withdrawn, according to toxicity particularly when peripheral neuropathy, neuropathic pain, and haematological toxicity occur.

Proprietary Preparations

Argentina: Velcade;

Australia: Velcade;

Belgium: Velcade;

Canada: Velcade;

Chile: Velcade;

Czech Republic: Velcade;

Denmark: Velcade;

Finland: Velcade;

France: Velcade;

Germany; Velcade;

Greece: Velcade;

Hong Kong; Velcade;

Hungary: Velcade;

Indonesia: Velcade;

Israel: Velcade;

Italy: Velcade;

Malaysia: Velcade;

Mexico: Velcade;

The Netherlands: Velcade;

Norway: Velcade;

New Zealand: Velcade;

Philippines: Velcade;

Poland: Velcade;

Portugal: Velcade;

Russia: Velcade:

Singapore: Velcade;

Spain: Velcade;

Sweden: Velcade;

Switzerland: Velcade;

Thailand: Velcade;

United Kingdom (UK): Velcade;

United States of America (US and USA): Velcade;

Venezuela: Velcade.

Leave a Reply

  Subscribe  
Notify of