Tacrolimus dose adjustment is not necessary in dose to dose conversion from a twice daily to a prolonged release once daily dose form

Abstract

Twice daily TAC (BID TAC) and prolonged released once daily dose tacrolimus (OD TAC) have different pharmacokinetic (PK) profiles in kidney transplant (KT) recipients. Precise dose adjustment recommendations when converting from BID TAC to OD TAC remain inconclusive. A single center, PK study was conducted in stable KT recipients taking constant doses of TAC, mycophenolic acid, and prednisolone. The area under the concentration-time curve (AUC) 0-24 and C_trough were measured before and 4 weeks after 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment. A 90% confidence interval (CI) of geometric mean ratio (GMR) of OD TAC/BID TAC within the range of 0.9-1.11 was utilized to indicate equivalence of the narrow therapeutic index drugs. The roles of CYP3A5 genotypic polymorphism on PK parameters were also assessed. There were 20 patients with median time since transplantation of 18 months. The mean of CKD-EPI eGFR was 60.7 ± 16.43 mL/min/1.73 m². The median total daily TAC dose of 0.058 mg/kg/day. The geometric means (%CV) of AUC_0-24 of OD and BID TAC were 205.16 (36.4%) and 210.3 (32.5%) ng/mL × h, respectively, with a GMR of 0.98 (90%CI 0.91-1.04). The geometric means (%CV) of C_trough of OD TAC and BID TAC were 5.43 (33.1%) and 6.09 (34.6%) ng/mL, respectively. The GMR of C_trough was 0.89 (90%CI 0.82-0.98), which was below 0.9. The newly calculated target C_trough level of OD TAC was 4.8-6.2 ng/mL. The best abbreviated AUC_0-24 was AUC = 0.97(C0) + 5.79(C6) + 18.97(C12) - 4.26. The GMR AUC_0-24 was within the range of 0.9-1.11 irrespective of CYP3A5 genotypic polymorphism while the GMR of C_trough was below 0.9 only in the CYP3A5 expressor patients. The 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment provided similar AUC_0-24 regardless of CYP3A5 genotypic polymorphism. However, the C_trough was lower in the CYP3A5 expressor group. Therefore, it is not necessary to routinely increase the OD TAC dose after conversion.Trial registration: Thai Clinical Trials Registry (TCTR20210715002).