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Pharmacokinetics and Pharmacodynamics of Once-daily Prolonged-release Tacrolimus in Liver Transplant Recipients
- Source :
- Clinical Therapeutics, Clinical Therapeutics, Elsevier, 2019, 41 (5), pp.882-896.e3. ⟨10.1016/j.clinthera.2019.03.006⟩, Clinical Therapeutics, 2019, 41 (5), pp.882-896.e3. ⟨10.1016/j.clinthera.2019.03.006⟩
- Publication Year :
- 2019
- Publisher :
- HAL CCSD, 2019.
-
Abstract
- Purpose Limited published data are available regarding the pharmacokinetic (PK) and pharmacodynamic (PD) variables of prolonged-release tacrolimus (PRT) after liver transplantations. The goal of this study was to compare the PK and PD profiles of PRT in early and stable liver transplant recipients by developing a population PK model of PRT and investigating the profile of calcineurin activity (CNA) in the peripheral blood mononuclear cells. Methods A conversion from BID immediate-release tacrolimus (IRT) to once-daily PRT based on a one-to-one daily dose was performed at day 7 (D7) and D90 posttransplantation in groups A (n = 12) and B (n = 12), respectively. Extensive PK samplings, including whole-blood tacrolimus (TAC) concentration, and CNA assessments were performed at D14 and D104 in groups A and B, respectively. TAC concentration–time data (N = 221) were analyzed by using nonlinear mixed effects modeling. Findings A 2-compartment model with linear elimination and a delayed first-order absorption characterized by 2 transit compartments best described the PK data. Model-predicted dose-normalized (6.0 mg/d) area under the TAC concentration–time curve over the dosing interval in groups A and B was similar (geometric mean, 235.6 ng/mL · h [95% CI, 139.6–598.7] vs 224.6 ng/mL · h [95% CI, 117.6–421.5], respectively; P = 0.94). Area under the CNA versus time curve over the dosing interval did not differ between groups (4897 [3437] and 4079 [1008] pmol/min/106 cells; P = 0.50). In group A, trough CNA at D14 posttransplantation was statistically higher than that measured just before the switch to PRT (ie, D7 posttransplantation) (198 [92] vs 124 [72] pmol/min/106cells, n = 8; P = 0.048); no statistical difference in TAC concentration was observed (P = 0.11). In group B, no statistical difference between D90 and D104 was observed in either trough CNA (149 [78] vs 172 [82] pmol/min/106 cells, n = 6; P = 0.18) or TAC (P = 0.17) concentration. No graft rejection was observed in either of the groups. Implications This study suggests that one-to-one dosage conversion to once-daily PRT during the early posttransplantation period could result in significant CNA variations but without causing graft rejection. Further investigations in larger cohorts are warranted to confirm these results. ClinicalTrials.gov identifier: NCT02105155 .
- Subjects :
- Male
medicine.medical_specialty
medicine.medical_treatment
Population
Urology
prolonged-release tacrolimus
02 engineering and technology
030204 cardiovascular system & hematology
Liver transplantation
Peripheral blood mononuclear cell
Models, Biological
Drug Administration Schedule
Tacrolimus
03 medical and health sciences
020210 optoelectronics & photonics
0302 clinical medicine
Pharmacokinetics
0202 electrical engineering, electronic engineering, information engineering
medicine
Humans
Pharmacology (medical)
Prospective Studies
education
Pharmacology
education.field_of_study
liver transplantation
business.industry
calcineurin activity
[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy
Middle Aged
Calcineurin activity
Pharmacodynamics
[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Leukocytes, Mononuclear
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Female
Geometric mean
[SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy
business
pharmacokinetics
Immunosuppressive Agents
Subjects
Details
- Language :
- English
- ISSN :
- 01492918
- Database :
- OpenAIRE
- Journal :
- Clinical Therapeutics, Clinical Therapeutics, Elsevier, 2019, 41 (5), pp.882-896.e3. ⟨10.1016/j.clinthera.2019.03.006⟩, Clinical Therapeutics, 2019, 41 (5), pp.882-896.e3. ⟨10.1016/j.clinthera.2019.03.006⟩
- Accession number :
- edsair.doi.dedup.....b76f19b31686af28a7d6590096286893