Steroid–tacrolimus drug–drug interaction and the effect of CYP3A genotypes

• DOI: 10.1111/bcp.16172
• Publication Date: 2024-07-12T10:59:12Z
• Authors: Abdelrahman Saqr; Mahmoud Al‐Kofahi; Moataz Mohamed; Casey Dorr; Rory P. Remmel; Guillaume Onyeaghala; William S. Oetting; Weihua Guan; Roslyn B. Mannon; Arthur J. Matas; Ajay Israni; Pamala A. Jacobson
• Keywords: CYP3A

Abstract Aims Tacrolimus, metabolized by CYP3A4 and CYP3A5 enzymes, is susceptible to drug–drug interactions (DDI). Steroids induce CYP3A genes increase tacrolimus clearance, but the effect variable. We hypothesized that extent of steroid–tacrolimus DDI differs CYP3A4/5 genotypes. Methods Kidney transplant recipients ( n = 2462) were classified number loss function alleles (LOF) CYP3A5*3 , *6 *7 CYP3A4*22 ) steroid use at each trough in first 6 months post‐transplant. A population pharmacokinetic analysis was performed nonlinear mixed‐effect modelling (NONMEM) stepwise covariate define significant covariates affecting clearance. stochastic simulation translated into a Shiny application with mrgsolve packages R. Results associated modestly higher (3%–11.8%) Patients 0‐LOF receiving steroids showed greatest (11.8%) clearance compared no steroids, whereas those 2‐LOFs had negligible (2.6%) presence steroids. Steroid increased 5% 10.3% patients 1‐LOF 3/4‐LOFs, respectively. Conclusions vary slightly genotype. This important individuals African ancestry who are more likely carry LOF alleles, may commonly receive treatment, will need doses.