Pharmacoepidemiology and pharmacogenetics of serious adverse drug reactions

Abstract

Serious adverse drug reactions (SADRs) are one of the major causes of morbidity and mortality, posing significant burdens on patients as well as the health care system. Studies on SADRs are limited due to its rare occurrence. Large population-based databases may overcome this challenge by providing adequate samples to examine the pharmacoepidemiology of SADRs. On the other hand, genetic predisposition were observed in SADRs and pharmacogenetic tests have demonstrated its effectiveness to prevent SADRs. However, only few pharmacogenetic tests are available, urging the need for more pharmacogenetic studies.

This thesis particularly studied two SADRs – Steven-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) and drug-induced agranulocytosis (DIAG). The aim of the thesis is to investigate the epidemiology of SJS/TEN and DIAG in Hong Kong with the use of large population-based database, and determine the genetic susceptibility of these two SDARs in Chinese population. The epidemiological studies were conducted using data from the Hong Kong Clinical Data Analysis and Reporting System. The cases of TEN in two teaching hospitals were reviewed while all cases of DIAG in Hong Kong were evaluated. Genome-wide association studies were performed to investigate the pharmacogenetics of the SADRs.

The epidemiological studies reported a very low incidence rate but high mortality of TEN in Hong Kong, which is consistent with other populations. In contrary, the incidence rate and mortality of DIAG in Hong Kong were relatively lower than other populations. The two SADRs shared some common drug aetiology. Anticonvulsants, allopurinol and antibiotics are the most common implicated drugs in TEN, whereas antithyroid drugs, anticonvulsants and antibiotics are the most common in DIAG.

In the pharmacogenetic studies, no significant SNP was found in SJS/TEN but an interesting HLA class I marker, HLA-A*03:01, showed a significant association with SJS/TEN, suggesting a role of this allele in developing SJS/TEN. On the other hand, a significant SNP which is in complete linkage equilibrium with HLA-B*03:02:01 was found in carbimazole /methimazole-induced agranulocytosis. HLA-B*03:02:01 demonstrated potential clinical utility in preventing agranulocytosis.

The findings in this thesis broaden the understanding of the pharmacoepidemiology of SADRs in Hong Kong, which may help healthcare provider to direct future planning on the management of the two SADRs. The genetic markers discovered in this thesis provides insights in preventing the SADRs by using pharmacogenetic screening. Further studies are encouraged to confirm the findings. In addition, the thesis demonstrated a great value of using large healthcare database to study SADRs.