Aim: Coagulation factor XI (FXI) plays a crucial role in the intrinsic coagulation pathway, and inhibitors targeting it may mitigate the risk of hemorrhage compared to anticoagulants currently on the market. SKB336, a novel selective inhibitor of FXI/FXIa, has been shown to prolong the activated partial thromboplastin time (APTT) in in-vitro and in-vivo studies. This study aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of SKB336 in healthy subjects. Methods: In this randomized, single-blinded, placebo-controlled, and dose-escalation phase I study, 60 healthy subjects were allocated to six cohorts (0.1 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.25 mg/kg, 2.5 mg/kg, and 4 mg/kg) and received SKB336 injection or placebo in a 4:1 ratio. The safety, tolerability, pharmacokinetics, and immunogenicity were measured up to 85 days post-dose. Exploratory analysis consisted of FXI activity and APTT. Results: SKB336 was well tolerated in all six cohorts, without any hemorrhagic events, reported deaths, or serious adverse events. No significant dose-dependent correlation was observed with the incidence of adverse events. Dose-dependent increases in the Cmax and AUC were observed. The mean t1/2 was 21.3–33.5 days, indicating a potential monthly dosing frequency. The maximum inhibition rate of FXI activity for all six cohorts reached 0, 17%, 28%, 48%, 54%, and 59%, respectively. The maximum APTT ratio to baseline reached 1.09-, 1.26-, 1.47-, 1.77, 1.91-, and 2.00-fold, respectively. Conclusion: SKB336 was generally tolerated, without any bleeding events in healthy volunteers. Besides, SKB336 presented a persistent dose-dependent prolongation of APTT and duration of FXI inhibition.

Thiopurines are a class of immunosuppressant and anti-neoplastic agents. They are widely used in the treatment of inflammatory bowel disease, hematological malignancies, and autoimmune diseases, but can cause significant toxicity. Inherited gene mutations are now recognized as independent risk factors for severe adverse drug reactions to thiopurines even at tenfold dose reductions. We present a case of thiopurine toxicity resulting in severe myelosuppression, hepatotoxicity, and alopecia in an individual with homozygous *3/*3 loss-of-function alleles in the NUDT15 gene. Our case highlights important differences in gene mutation frequencies between races that can help guide pharmacogenomic testing.

A document by Andreas Bonertz. Click on the document to view its contents.

Aim: Genetic susceptibility has been identified in idiosyncratic drug-induced liver injury, a potentially severe adverse reaction towards drugs, herbal products and dietary supplements. Drug-induced liver injury epigenetic signatures could help explain genetic regulatory mechanisms behind this disease and might provide disease biomarkers. This systematic review aims to analyse all available information on epigenetic risk association studies, as well as to include additional information on receiver operating characteristic analyses in idiosyncratic drug-induced liver injury when present. Methods: The main inclusion criteria were population studies on idiosyncratic drug-induced liver injury with significant risk association between drug-induced liver injury and an epigenetic regulation mechanism. Results: Out of the seven included articles six were focused on DNA methylation and one on long non-coding RNA. All of the studies were on drug-induced liver injury due to anti-tuberculosis drugs and came from Asia. CpG site methylation in the CYP2D6 (Odds ratio:9.19, 95% confidence interval:3.62-25.89, p-value:0.001) and NAT2 (Odds ratio:8.37, 95% confidence interval:2.39-29.32, p-value:0.001) promoters conferred the highest risk. Regarding the potential of epigenetic signatures as biomarkers, LINE-1 and ALU transposable elements hypomethylation levels showed an area under the curve value of 0.94, indicating their potential as biomarkers. Conclusions: The majority of the studies were on DNA methylation and hepatotoxicity due to anti-tuberculosis drugs, with all of them coming from Asia where tuberculosis is a public health burden. While this is an area that requires further research, the results of this systematic analysis suggest the potential of epigenetic regulation as a new diagnostic and therapeutic target.