Plasma concentration and eGFR in preterm and term neonates receiving gentamicin or successive amikacin therapy.

BACKGROUND: Gentamicin and amikacin are aminoglycoside antibiotics which are renally excreted and known to be nephrotoxic. Estimate of glomerular filtration rate (eGFR) per body surface area is lower in neonates than in adults and exposure to these drugs could lead to more suppression in kidney function. The aim of this study was to determine maximum and minimum plasma concentrations (Cmax and Cmin), time to reach Cmin levels of gentamicin and amikacin, and to assess eGFR in preterm and term neonates. METHODS: Two groups of patients were recruited, 44 neonates receiving gentamicin (5 mg/kg/24 h) and 35 neonates receiving amikacin (15 mg/kg/24 h) by slow intravenous injection. Patients on amikacin had been on gentamicin before being switched to amikacin. Two blood samples were drawn for the determination of the maximum and minimum plasma concentration. Primary outcomes were determination of Cmax, Cmin, and the time it took to clear the aminoglycoside to a plasma concentration below the toxicity threshold (gentamicin: < 1 mcg/mL; amikacin: < 5 mcg/mL. RESULTS: Therapeutic range for Cmax of gentamicin (15-25 mcg/mL) or amikacin (30-40 mcg/mL) was achieved in only 27.3 and 2.9% of neonates, respectively. Percentage of neonates reaching plasma concentrations below the toxicity threshold within the 24-hour dosing interval was 72.7% for gentamicin and 97.1% for amikacin. Positive correlation between gentamicin clearance and postnatal age borderline statistical significance (p = 0.007), while the correlation between amikacin clearance and postnatal age was poor and not statistically significant (r2 = - 0.30, p = 0.971). CONCLUSION: Although eGFR decreased significantly as a function of postnatal age in neonates receiving amikacin, the majority (91.4%) of these neonates were able to clear the drug to < 5 mcg/mL within a 24-hour dosing interval.

Time of drug administration, CYP3A5 and ABCB1 genotypes, and analytical method influence tacrolimus pharmacokinetics: a population pharmacokinetic study.

Tacrolimus (TAC) pharmacokinetics are characterized by a very high variability that complicates its therapeutic use. The aims of this study were: 1) to identify and model the effect of demographic, clinical, and genetic factors and time of drug administration on TAC pharmacokinetic variability; and 2) to assess the influence of the analytical method by modeling the TAC blood concentrations measured simultaneously by microparticle enzyme immune assay (MEIA) and liquid chromatography-tandem mass spectroscopy. Data from 19 renal transplant candidates were analyzed. A total of 266 blood samples were analyzed for TAC by both techniques. Linear regression and Bland and Altman analyses were performed to compare TAC blood concentrations obtained with MEIA and liquid chromatography-tandem mass spectroscopy. A population pharmacokinetic analysis was performed. As expected, blood concentrations obtained by MEIA were higher than those obtained by liquid chromatography-tandem mass spectroscopy. A two-compartment model with first-order absorption and elimination best fit TAC blood concentrations. An exponential model was used to describe the interindividual and interoccasion variability and a mixed model was retained for the residual variability. A supplementary proportional term was necessary for the residual error in case of TAC blood concentrations determined by MEIA. The following covariates were retained in the final model: time of drug administration on the absorption rate constant and CYP3A5 and ABCB1 genotypes on the TAC apparent clearance. All parameter estimates had reliable values. The final model was found to be stable and generated parameters with good precision. The validation of the final model by bootstrapping (2000 bootstraps), case deletion diagnostics, crossvalidation, and visual predictive check (1000 simulated subjects) gave satisfactory results. This is the first population pharmacokinetic study confirming the chronopharmacokinetics of TAC and showing an effect of ABCB1 genotype and analytical method on TAC pharmacokinetics. These results may be helpful for TAC dose individualization.

A simultaneous d-optimal designed study for population pharmacokinetic analyses of mycophenolic Acid and tacrolimus early after renal transplantation.

Mycophenolic acid (MPA) and tacrolimus (TAC) are immunosuppressive agents used in combination with corticosteroids for the prevention of acute rejection after solid organ transplantation. Their pharmacokinetics (PK) show considerable unexplained intraindividual and interindividual variability, particularly in the early period after transplantation. The main objective of the present work was to design a study based on D-optimality to describe the PK of the 2 drugs with good precision and accuracy and to explain their variability by means of patients' demographics, biochemical test results, and physiological characteristics. Pharmacokinetic profiles of MPA and TAC were obtained from 65 stable adult renal allograft recipients on a single occasion (ie, day 15 after transplantation). A sampling schedule was estimated based on the D-optimality criterion with the POPED software, using parameter values from previously published studies on MPA and TAC modeling early after transplantation. Subsequently, a population PK model describing MPA and TAC concentrations was developed using nonlinear mixed-effects modeling. Optimal blood-sampling times for determination of MPA and TAC concentrations were estimated to be at 0 (predose) and at 0.24, 0.64, 0.98, 1.37, 2.38, and 11 hours after oral intake of mycophenolate and TAC. The PK of MPA and TAC were best described by a 2-compartment model with first-order elimination. For MPA, the absorption was best described by a transit compartment model, whereas first-order absorption with a lag time best described TAC transfer from the gastrointestinal tract. Parameters were estimated with good precision and accuracy. While hematocrit levels and CYP3A5 genetic polymorphism significantly influenced TAC clearance, the pharmaceutical formulation and MRP2 genetic polymorphism were retained as significant covariates on MPA absorption and elimination, respectively. The prospective use of the simultaneous D-optimal design approach for MPA and TAC has allowed good estimation of MPA and TAC PK parameters in the early period after transplantation characterized by a very high unexplained variability. The influence of some relevant covariates could be shown.