Jessica Gadsby, Amy Page, Dipesh Patel, Damini Amin, Jorge Jesus-Silva, Hussain Mulla
PK modeling supports risk-stratified protocol selection. Sirolimus dosing should be based on age, hematocrit, and tacrolimus requirements. Abbreviated Overlap with sirolimus loading is preferred for higher immunological-risk patients, and Standard Overlap for routine conversion. Laboratory monitoring preconversion and postconversion is necessary in clinical practice.
BACKGROUND: Tacrolimus is central to kidney transplant immunosuppression but causes toxicity. Optimal conversion regimens to sirolimus are unclear, and therapeutic drug monitoring is retrospective. We used pharmacokinetic (PK) modeling to identify conversion strategies to minimize under- or over-immunosuppression.
METHODS: Adult kidney transplant recipients converted from tacrolimus to sirolimus at a single center (March 2007-January 2024) were reviewed. Demographics, conversion regimens, and therapeutic drug monitoring concentrations were collected. PK models were developed, conversion strategies were simulated using a combined tacrolimus-sirolimus range of 8.5-11.6 ng/mL, and relationships between drug exposure and laboratory outcomes were analyzed.
RESULTS: Forty-five recipients underwent conversion. The most common approach halved tacrolimus for 5-7 days during sirolimus initiation. Tacrolimus and sirolimus clearance declined with age (-1.65% and -0.95% year-1, respectively). Sirolimus clearance fell with increasing hematocrit (-4.1% per percentage point). Tacrolimus dose predicted sirolimus needs (r = 0.62, P < 0.001). Higher combined exposure was associated with alanine transaminase elevation (r = 0.54, P = 0.004). Mean glomerular filtration rate rose by 4.6 mL·min-1·1.73 m-2 after conversion (P < 0.001); white cell and platelet counts fell by 13.9% and 19.2%, respectively. Simulations favored Abbreviated Overlap with a sirolimus loading dose, achieving the greatest time within range (48.2% versus 40.2% for Standard Overlap). Immediate Switch without a loading dose resulted in 67.5% of the transition period below 8.5 ng/mL.
CONCLUSIONS: PK modeling supports risk-stratified protocol selection. Sirolimus dosing should be based on age, hematocrit, and tacrolimus requirements. Abbreviated Overlap with sirolimus loading is preferred for higher immunological-risk patients, and Standard Overlap for routine conversion. Laboratory monitoring preconversion and postconversion is necessary in clinical practice.