Tacrolimus pharmacokinetic drug interactions: effect of prednisone, mycophenolic acid or sirolimus.
This study was conducted to evaluate time-dependent pharmacokinetic changes and drug interactions over the first 6 months after transplantation in kidney transplant recipients receiving tacrolimus (TAC), prednisone (PRED) and mycophenolate mofetil (MMF) or sirolimus (SRL). Pharmacokinetic assessments were carried out at day 7 and months 1, 3, and 6 in kidney transplant recipients receiving TAC plus PRED with either MMF (2 g/day, n = 13) or SRL (15 mg loading dose, 5 mg for 7 days followed by 2 mg/day, n = 12). There were no differences in the main demographic characteristics or in mean PRED doses during the first 6 months after transplant. From day 7 to month 6, there was a 65% increase in TAC dose corrected exposure (dose corrected area under the curve; AUC) in patients receiving MMF (P = 0.005) and a 59% increase in TAC dose corrected exposure in patients receiving SRL (P = 0.008). From day 7 to month 6, there was a 72% increase in mycophenolate dose corrected exposure (P = 0.001) and a 65% increase in SRL dose corrected exposure (P = 0.008). TAC dose corrected exposure was 23% lower in patients receiving SRL compared with MMF (P = 0.012) on average over the study period. PRED dose reduction was associated with increase in TAC (in patients receiving SRL, P = 0.040) and mycophenolic acid (MPA) (P = 0.070) drug exposures. Tercile distribution of TAC drug exposure showed a positive correlation with mean SRL exposures (P = 0.016). Conversely, tercile distribution of SRL drug exposure showed a positive correlation with mean TAC exposures (P = 0.004). Time-dependent increases in TAC, MPA and SRL drug exposures occur up to 6 months after transplantation. Drug-to-drug interactions indicate that intense therapeutic drug monitoring is required to avoid under- or over-immunosuppression.
Park
Sung-In
SI
Nephrology Division, Hospital do Rim e Hipertensão, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Felipe
Claudia R
CR
Pinheiro-Machado
Paula G
PG
Garcia
Riberto
R
Fernandes
Fernanda B
FB
Casarini
Dulce E
DE
Tedesco-Silva
Helio
H
Medina-Pestana
Jose O
JO
D000328:Adult; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D011241:Prednisone / Q000008:administration & dosage / Q000494:pharmacology; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D011241:Prednisone; D020123:Sirolimus; D016559:Tacrolimus