Riberto Garcia

The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring.

Abstract: The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring. We sought to determine the influence of ethnic miscegenation on tacrolimus pharmacokinetics and trough concentrations during the first 6 months after transplantation.

Mycophenolate mofetil vs. sirolimus in kidney transplant recipients receiving tacrolimus‐based immunosuppressive regimen

Abstract:  Mycophenolate mofetil (MMF) and sirolimus (SRL) are effective immunosuppressive drugs with distinct safety profile.

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.

Circadian and time‐dependent variability in tacrolimus pharmacokinetics

Tacrolimus (TAC) is considered a critical dose drug. The purpose of our study was to investigate circadian and time‐dependent changes in TAC pharmacokinetics over the first year after kidney transplantation. Pharmacokinetic (PK) studies were performed in 26 recipients of first living donor kidney transplants at day 7 after morning (a.m.) and evening (p.m.) doses of TAC. Additional serial PK studies were carried out in nine patients at month 6 (M6) and month 12 (M12). Blood samples were collected before 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 h after TAC administration. Demographics, TAC and adjunctive immunosuppressive doses, hematology, and biochemistry were recorded in each PK study. Mean age was 37 years, body mass index 23 kg/m2, 58% males, and 85% Caucasian. Higher AUC (231.4 vs. 220 ng·h/mL, P = 0.06) and Cmax (34.1 ± 12.6 vs. 24.4 ± 9.8 ng/mL, P < 0.001), and lower Tmax (1.6 ± 0.8 vs. 2.7 ± 2.0 h, P = 0.05) values were observed comparing a.m. and p.m. administrations. Comparing D7, M6 and M12, there was a significant increase in dose‐normalized AUC (31.4 ± 22.2 vs. 50.1 ± 33 vs. 39.2 ± 24.4 ng·h/mL/mg, P = 0.005), Cmax (4.4 ± 2.4 vs. 7.8 ± 3.5 vs. 6.0 ± 3.3 ng/mL/mg, P < 0.001) and Tmax (1.6 ± 1.1 vs. 1.7 ± 0.4 vs. 1.8 ± 0.8 h, P = 0.006), respectively. Over the first year the intraindividual variability of dose‐normalized AUC, Cmax and C0 were 82%, 72%, and 90%, respectively. No significant changes were observed comparing inter‐individual variability of dose‐normalized AUC (21%, 24%, 33%), Cmax (46%, 45%, 55%), C0 (49%, 83%, 81%) at D7, M6 and M12, respectively. We observed a good correlation between a.m. and p.m. TAC AUC (r2 = 0.90) and C0 (r2 = 0.88). Tacrolimus pharmacokinetics display circadian variation suggesting a slower and delayed absorption phase at nighttime. Tacrolimus also showed time‐dependent PK changes, suggesting an improvement in absorption during the first 6 months. Despite circadian variation we observed good correlations between a.m. and p.m. TAC AUC (r2 = 0.90) and C0 (r2 = 0.88) and between C0 and total daily TAC exposure (a.m. + p.m. AUC) suggesting that trough‐guided therapeutic monitoring is still a reliable and simple strategy to optimize the clinical use of TAC.

An open‐label randomized trial of the safety and efficacy of sirolimus vs. azathioprine in living related renal allograft recipients receiving cyclosporine and prednisone combination

Abstract:  Background:  The ability of sirolimus (SRL), in combination with reduced exposure of cyclosporine, was investigated to prevent acute rejection and associated side effects.

Concentration-controlled use of sirolimus associated with reduced exposure of cyclosporine in black recipients of primarily living renal allograft donors : 12-month results

Abstract:  Aim:  This study was designed to identify optimal therapeutic sirolimus (SRL) concentrations in black kidney transplant recipients on reduced cyclosporine (CsA) exposure and prednisone.

Cyclosporine and sirolimus pharmacokinetics and drug-to-drug interactions in kidney transplant recipients

This study was conducted to evaluate the pharmacokinetics (pk) and drug interactions between cyclosporine (CsA) and sirolimus (SRL) in kidney transplant recipients. The morning (a.m.) and evening (p.m.) pk of CsA (4–5 mg/kg/dose) and SRL (2 mg, n = 20; 5 mg, n = 33) were evaluated on day 7 (n = 53). CsA showed circadian variation when comparing a.m. and p.m. administration [AUC: 8066 vs. 6699, P < 0.001 (CI 970.9; 1763.6); C0: 272 vs. 245, P = 0.007 (CI 7.5; 46.1)]. SRL showed dose‐proportional pk. Significant and drug‐to‐drug concentration‐dependent pk interactions were observed within a narrow concentration range for both drugs. A fivefold increase in SRL AUC (from a mean of 130 to 538 ng h/mL) was associated with a 25% increase in mean a.m. CsA AUC [7021 to 8811 ng h/mL, P = 0.037, CI (−3461.2; −118.9)] and with a 42% increase in mean p.m. CsA AUC [5386–7639, P = 0.024, CI (−4164.4; −340.7)]. A twofold increase in a.m. CsA AUC (from 5860 to 10 974 ng h/mL) was associated with a 70% increase in mean SRL AUC [223 to 380 ng h/mL, P = 0.0026, CI (−291.7; −22.8)]. A twofold increase in p.m. CsA AUC (from 4573 to 9692 ng h/mL) was associated with a 63% increase in mean SRL AUC [246 to 400 ng h/mL, P = 0.032, CI (−290.7; −16.6)]. CSA shows circadian pk regardless of sirolimus dose or blood concentration. Significant drug‐to‐drug interactions occur within narrow blood drug concentrations. The magnitude of the effect of CsA on SRL blood concentration is higher than that of SRL on CsA blood concentrations. These findings emphasize the need for therapeutic drug monitoring using this drug combination.

Randomized crossover study to assess the inter- and intrasubject variability of morning mycophenolic acid concentrations from enteric-coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients

Tedesco‐Silva H, Felipe CR, Park SI, Pinheiro‐Machado PG, Garcia R, Slade A, Schmouder R, Medina‐Pestana JO. Randomized crossover study to assess the inter‐ and intrasubject variability of morning mycophenolic acid concentrations from enteric‐coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients.
Clin Transplant 2010: 24: E116–E123.
© 2009 John Wiley & Sons A/S.