TABLE 1.
Summary of clinical studies investigating blood, PBMC and allograft tacrolimus concentrations and their associations with clinical outcomes or ex-vivo pharmacodynamic assessments.
| Study transplant type | Time post-transplant | Maintenance immuno-suppresion | Analytical methods and sample collection times | Interacting drugs | Main clinical outcomes or ex vivo pharmacodynamic outcomes |
|---|---|---|---|---|---|
| A. Clinical Outcomes | |||||
| Sandborn et al. (1995)Adult Liver (n = 17) | Up to 8 weeks | Tac, steroid | Plasma and graft tissue: IA (non-specific)C0 | Not stated | Prospective observational studyBased on protocol and for-cause biopsies, liver [Tac] significantly lower in rejectors compared to non-rejectors. No difference in plasma [Tac] |
| Capron et al. (2007)Adult Liver (n = 146) | Day 7 | Tac ± steroid | Blood: IA (non-specific) graft tissue: LC-MS/MSC0 | Ceased by day 7 | Prospective observational studyBased on day 7 protocol biopsies, liver [Tac] 30 pg/mg cut-off (sensitivity 89%, specificity 98%) predicts clinically significant rejection |
| Capron et al. (2012)Adult Liver (n = 90) | Day 7 | Tac | Blood: IAPBMC and graft tissue: LC-MS/MSC0 | Excluded | Prospective observational studyBased on day 7 protocol biopsies, significant association between severity of rejection and C0PBMC or C0Liver. No relationship with C0Blood |
| Rayar et al. (2018)Adult Liver (n = 41) | Days 1–7 | Tac, MPA, steroid | Blood and PBMC: LC-MS/MSC0 | Not stated | Prospective observational studyNo significant independent associations of C0PBMC with measures of graft function |
| Han et al. (2016)Adult Kidney (n = 214) | SS up to 14 years | Tac, MPA, steroid | Blood and PBMC: LC-MS/MSC0 | Excluded | Prospective observational PK-ex vivo PD study. Retrospective analysis of rejection and tacrolimus-induced nephrotoxicity. No significant association between C0PBMC and history of acute rejection or nephrotoxicity in first 6 months post-transplant |
| Francke et al. (2020)Adult Kidney (n = 175) | 3, 6 and 12 months | Tac, MPA, steroid | Blood: IAPBMC: LC-MS/MSC0 | Excluded up to 3 months. Unclear for >3 months | Prospective observational PK study. Retrospective analysis of rejection and tacrolimus-induced nephrotoxicity. Based on for-cause biopsies, no association between the 3-month C0PBMC or C0Blood and rejection within the first 3 months post-transplant. Similarly, no associations with clinically defined nephrotoxicity or new onset diabetes mellitus within the first 3 months post-transplant |
| Zhang et al. (2020)Adult Kidney (n = 52) | 3 months and 1 year | Tac, MPA, steroid | Blood: IA graft tissue: LC-MS/MSC0 | Not stated | Prospective observational studyBased on protocol biopsies, no association between renal [Tac] and subclinical acute rejection at either 3 months or 1 year |
| Sallustio et al. (2021)Adult Kidney (n = 132) | SS 15 (8–80)7 days | Tac, MPA, steroid | Blood and graft tissue: LC-MS/MSC0 | Not excluded | Prospective observational studyBased on protocol and for-cause biopsies, no association between renal [Tac] and rejection. C0Blood, dose and acute nephrotoxicity were associated with renal [Tac] |
| B. Ex-vivo Pharmacodynamic Assessments | |||||
| Lemaitre et al. (2015)Adult Liver (n = 10) | Days 1 and 7 | Tac, MPA, steroid | Blood and PBMC: LC-MS/MSCmax, C12 and AUC | Anti-retrovirals excluded | Prospective observational studyOn day 1 changes in CNA mirrored those in blood and PBMC [Tac]. No correlations between AUCCNA and either AUCBlood or AUCPBMC. |
| Tron et al. (2020)Adult Liver (n = 32) | SSDay 7–10 | Tac, MPA, steroid | Blood and PBMC: LC-MS/MSC0, Cmax and AUC | Excluded | Prospective observational studyNo correlation between AUCCNA and either AUCBlood or AUCPBMC. Significant association between maximal inhibition of CAN and either log AUCPBMC or log AUCBlood |
| Han et al. (2016)Adult Kidney (n = 214) | SS up to 14 years | Tac, MPA, steroid | Blood and PBMC: LC-MS/MSC0 | Excluded | Prospective observational studyIn sub-group (n = 39), both C0PBMC and C0Blood associated with ex vivo measures of T-cell activation |
| Fontova et al. (2021)Adult Kidney (n = 25) | SS > 6 months a.m. and p.m. dose | Tac, MPA, steroid | Blood and PBMC: LC-MS/MSCmax, C12 and AUC | Excluded | Prospective observational studySignificant correlation between blood [Tac] and CNA over a 24 h (a.m. plus p.m.) dosing interval. Correlation between PBMC [Tac] and CNA not investigated |
Tac = tacrolimus, [Tac] = tacrolimus concentration, MPA = mycophenolic acid, SS = steady state, CNA = calcineurin activity, PK = pharmacokinetic, PD = pharmacodynamic.