title: Conversion from Prograf to Advagraf in adolescents with stable liver transplants: comparative pharmacokinetics and 1-year follow-up.
abstract: The recommended dose of Advagraf for conversion from Prograf is considered to be 1:1 on a milligram basis. However, the long-term equivalence of Prograf and Advagraf has been questioned. The relative bioavailability of Advagraf and Prograf was evaluated in a single-center, open-label study of Prograf-to-Advagraf conversion in 20 patients, ranging in age from 12 to 18 years, who had a stable liver transplant and were receiving Prograf. After the supervised administration of Prograf for 7 days, the patients were converted to Advagraf. On days 7 and 14, serial blood samples were obtained for tacrolimus determinations. The pharmacokinetic parameters were calculated with a noncompartmental approach, and the relative bioavailability of both formulations was calculated according to standard statistical methods. Polymorphisms in cytochrome P450 3A5 (rs776746), adenosine triphosphate-binding cassette B1 (rs1045642), POR*28 (rs1057868), and POR (rs2868177) were determined with standard methods. The clinical and analytical data from a 1-year follow-up period were collected for all patients 30, 90, 180, and 360 days after conversion. The mean ratios for Cmax and AUC0-24 were 96.9 (90% confidence interval = 85.37-110.19) and 100.1 (90% confidence interval = 90.8-112.1), respectively. No relationship was found between the patients' genotypes and the pharmacokinetic tacrolimus values. During the follow-up, biochemical parameters (aspartate aminotransferase, alanine aminotransferase, bilirubin, cystatin C, and creatinine) did not change significantly; 3 patients presented with relevant clinical events, but no event was considered to be related to tacrolimus. A decrease in tacrolimus blood levels and an increase in dose/level ratios were observed 3 and 6 months after conversion, but they returned to basal levels by month 12. In conclusion, conversion from Prograf to Advagraf with a 1:1 dose equivalence is appropriate as an initial guideline. Our 1-year follow-up showed a transient decrease in tacrolimus levels, so closer monitoring of tacrolimus levels may be required after conversion.
authors.affiliation: Clinical Pharmacology Service, La Paz University Hospital, Madrid, Spain; Department of Pharmacology, School of Medicine, Autonomous University of Madrid, Madrid, Spain.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Carcas-Sansuán
authors.forename: Loreto
authors.initials: L
authors.lastname: Hierro
authors.forename: Gonzalo N
authors.initials: GN
authors.lastname: Almeida-Paulo
authors.forename: Esteban
authors.initials: E
authors.lastname: Frauca
authors.forename: Hoi Yan
authors.initials: HY
authors.lastname: Tong
authors.forename: Carmen
authors.initials: C
authors.lastname: Díaz
authors.forename: Enrique
authors.initials: E
authors.lastname: Piñana
authors.forename: Jesús
authors.initials: J
authors.lastname: Frías-Iniesta
authors.forename: Paloma
authors.initials: P
authors.lastname: Jara
mesh_terms: D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001682:Biological Availability; D002648:Child; D003404:Creatinine / Q000097:blood; D055316:Cystatin C / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics; D017093:Liver Failure / Q000628:therapy*; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D055316:Cystatin C; D007166:Immunosuppressive Agents; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin; D016559:Tacrolimus