How Genes Affect Clozapine Levels and Doses

Genes play a big role in how the body handles medicines. One gene, NFIB, has a specific change (rs28379954 T>C) that can affect how much clozapine, a medicine used for treatment-resistant schizophrenia, is in the blood. People with this change need higher doses to feel the medicine's effects. This study looked at 285 patients taking clozapine. It found that people with the CT version of the NFIB gene needed 25% more clozapine to reach the same blood levels as those with the TT version. Interestingly, the way the body breaks down clozapine into metabolites was similar between both groups. This suggests that the difference in blood levels is not due to changes in how the body metabolizes the drug. The study also looked at how NFIB affects the expression of transporters in the intestines. These transporters help move clozapine into and out of cells. In lab-grown cells, increasing NFIB levels led to a decrease in the expression of two important transporters, ABCB1 and ABCG2. This could explain why people with the CT version of NFIB have lower clozapine levels. However, more research is needed to fully understand this process. In summary, the NFIB gene variant rs28379954 T>C leads to lower clozapine levels in the blood. This means people with this gene variant need higher doses to achieve the same therapeutic effect. The study suggests that this is due to changes in the expression of intestinal transporters, rather than changes in how the body metabolizes the drug. This information could help doctors tailor clozapine doses to individual patients based on their genetic makeup.