Use of a new gene variant test can greatly reduce the incidence of cutaneous adverse reactions to carbamazepine, a drug used in a broad range of neurologic disorders, a new study shows.
The study was conducted in Japanese patients, but the test should also be effective in US and European populations and may be warranted in routine clinical practice, the authors say.
The study was published online in JAMA Neurology on April 2.
The researchers, led by Taisei Mushiroda, PhD, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan, explain that cutaneous adverse drug reactions with carbamazepine are common and problematic, and the most severe — Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) — can be fatal.
A gene variant, HLA-B*15:02, found in the Han Chinese in China, Taiwan, and Hong Kong, and the Thai, Indian, and Malay populations and linked to these adverse reactions, has previously been identified, and genetic testing in these populations is now recommended before carbamazepine is prescribed.
The HLA-B*15:02 variant is not normally seen in Japanese, Korean, and white populations in the United States and Europe. More recently, a second variant — HLA-A*31:01 — linked to cutaneous adverse drug reactions with carbamazepine has been identified in these populations.
The current study is the first to proactively test for this gene variant and use it to guide treatment decisions.
For the study, neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for the HLA-A*31:01 gene variant and alternative drugs for those who tested positive for the variant.
Of the 1130 included patients tested, 198 (17.5%) were positive for HLA-A*31:01 and were given alternative medication.
Cutaneous adverse drug reactions occurred in 23 of the carbamazepine patients (2.0%), 4 of whom required hospitalization. No cases of SJS or TEN were seen.
The authors say the 2% figure for carbamazepine cutaneous reactions in this study compares favorably with that in historical controls, which ranges from 3.4% to 5.1%, thus representing a reduction of at least 40%.
They note that the frequency of the HLA-A*31:01 allele is 7% to 9% in Japanese, 5% in Korean, 2% in Chinese, 2% to 3% in European, and 1% in African populations.
Moreover, the variant has been associated with a full spectrum of carbamazepine-induced cutaneous reactions, and therefore “HLA-A*31:01 screening prior to prescribing carbamazepine would be useful for preventing many types of carbamazepine-induced cutaneous adverse drug reactions in a range of patient populations.”
Preemptive Strategies
Authors of an accompanying editorial write, “The study by Mushiroda et al provides initial data that preemptive strategies may allow for a more consistent approach to safely administer this commonly used medication.”
The editorialists note that while the study did not have the statistical power to definitively demonstrate complete avoidance of the high morbidity and mortality from forms of severe cutaneous adverse reactions (SJS/TEN), the absence of clinical cases was noted.
One of the editorialists, Howard L. McLeod, PharmD, Moffitt Cancer Center, Tampa, Florida, told Medscape Medical News, “This new gene test is not perfect. It doesn’t completely eliminate these adverse reactions, but it’s a lot better than we what we have at the moment, which is just hoping for the best.”
He explained that while the other variant — HLA-B*15:02 — is tested for in some Asian countries, the test is not used routinely in the United States and Europe. “This new variant is more commonly seen in the white population as well as the Japanese and thus makes routine testing much more feasible.”
“I think everyone considering taking carbamazepine should now be tested for both gene variants. It will be the same cost to test for the both of them as for one of them, so we might as well get all the information.”
The Japanese authors suggest a cost-effectiveness analysis may be necessary before testing becomes routine, adding that such an analysis has been conducted in the United Kingdom and found to be positive.
McLeod believes cost-effectiveness analyses in other systems would also be positive because these cutaneous adverse reactions can be very expensive to manage. “With the more severe reactions, patients have to be admitted to the burns unit, so the cost of care is very high.”
“From a patient safety standpoint, it makes complete sense to test everyone now. I would think in countries with nationalized health services it will become routine sooner as the money saved from not having to treat these ADRs [adverse drug reactions] will be immediately obvious to the system. It’s not so straightforward in the private system in the US. But I would think the main centers will do it now.”
He noted that although carbamazepine has been around for decades, it is still used widely, despite the problem with cutaneous reactions.
“It works in many different conditions, we are very familiar with it, and it has a low cost,” he said. “While its use in epilepsy has declined now as there are so many other options, it is still a popular choice for neuropathic pain, tinnitus, and bipolar disorder. However, there are alternatives, so if a patient is positive for one of these gene variants then there are generally other drugs that can be used.”
This study was supported by grants from the Project for Development of Innovative Research on Cancer Therapeutics and from the Tailor-made Medical Treatment Program (BioBank Japan Project) funded by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The authors and editorialists have disclosed no relevant financial relationships .
JAMA Neurol. Published online April 2, 2018. Abstract, Editorial
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