Adequacy of a hospital-wide standard dose of 7mg/kg bodyweight gentamicin sufficient to achieve an adequate prophylactic maximum serum concentration (Cmax) in burn patients undergoing surgical burn wound treatment.

INTRODUCTION: Pharmacokinetics of drugs can be significantly altered in burn patients. The aim of our study was to validate if the current hospital-wide standard dosage of 7mg/kg total bodyweight gentamicin is sufficient to achieve an adequate prophylactic Cmax (Cmax≥20mg/L). MATERIALS AND METHODS: A prospective observational cohort pharmacokinetic study was conducted in burn patients undergoing surgical burn wound treatment. RESULTS: 36/40 (90%) burn patients undergoing surgical burn wound treatment at Rotterdam Burn Centre (Maasstad Hospital), the Netherlands, achieved adequate prophylactic serum concentrations (Cmax≥20mg/L) after a single prophylactic intravenous dose of 7mg/kg total bodyweight gentamicin. Total Body Surface Area (TBSA) burned and total bodyweight were statistically significantly correlated with the Cmax, with correlation coefficients of -0.316, 0.443 and p values of 0.047, 0.004, respectively. Other covariates (age, time after injury, serum creatinine, dose, gender, intensive care admittance) were not statistically significantly correlated. Occurrence of postoperative infection was limited (n=1), no statistically significant difference was observed between patients with a therapeutic and patients with a subtherapeutic serum concentration. CONCLUSION: The current hospital-wide standard dosage of 7mg/kg total bodyweight is sufficient to achieve an adequate prophylactic Cmax in burn patients undergoing surgical burn wound treatment.

A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation.

Tacrolimus is a critical dose drug with a considerable intrapatient variability (IPV) in its pharmacokinetics. We investigated whether a high IPV in tacrolimus exposure is associated with adverse long-term renal transplantation outcomes. Tacrolimus IPV was calculated from predose concentrations measured between 6 and 12 months post-transplantation of 808 renal transplant recipients (RTRs) transplanted between 2000 and 2010. One hundred and eighty-eight (23.3%) patients reached the composite end point consisting of graft loss, late biopsy-proven rejection, transplant glomerulopathy, or doubling of serum creatinine concentration between month 12 and the last follow-up. The cumulative incidence of the composite end point was significantly higher in patients with high IPV than in patients with low IPV (hazard ratio: 1.41, 95% CI: 1.06-1.89; P = 0.019). After the adjustment for several factors, the higher incidence of the composite end point for RTRs with a high IPV remained statistically significant (hazard ratio: 1.42, 95% CI: 1.06-1.90; P = 0.019). Younger recipient age at transplantation, previous transplantation, worse graft function (at month 6 post-transplantation), and low mean tacrolimus concentration at 1 year post-transplantation were additional predictors for worse long-term transplant outcome. A high tacrolimus IPV is an independent risk factor for adverse kidney transplant outcomes that can be used as an easy monitoring tool to help identify high-risk RTRs.

High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation.

BACKGROUND: We hypothesized that a high within-patient variability in clearance of tacrolimus and mycophenolate mofetil (MMF) would put patients at risk for periods of over- or underimmunosuppression and would thus lead to long-term chronic allograft nephropathy and graft loss after transplantation. METHODS: From 297 patients transplanted between 1 January 2000 and 31 December 2004, the within-patient variability in clearance was calculated from tacrolimus whole-blood concentrations and mycophenolic acid (MPA) plasma concentrations drawn between 6 and 12 months post-transplantation. As a primary outcome, a composite end point consisting of graft loss, biopsy-proven chronic allograft nephropathy and 'doubling in plasma creatinine concentration in the period between t = 12 months post-transplantation and last follow-up' was used. RESULTS: In the study population of 297 patients, 34 patients reached the primary end point of graft failure. The within-patient variability in the clearance of tacrolimus and three other covariates are significant risk factors for reaching the composite end point of failure [P-values for intraindividual tacrolimus variability = 0.003, biopsy-proven acute rejection (BPAR) = 0.003, recipient age at transplantation = 0.005]. The mean tacrolimus concentration for controls [7.4 (+/- 2.9) ng/mL] and for failures [6.9 (+/- 2.5) ng/mL] was similar. Within-patient variability in the clearance of MPA was not related to reaching the composite end point of failure. CONCLUSIONS: This study shows a significant relationship between the high within-patient variability in the clearance of tacrolimus, but not for MPA, and long-term graft failure.