Population pharmacokinetic models of tacrolimus in paediatric solid organ transplant recipients: A systematic review.

AIMS: This study aimed to provide up-to-date information on paediatric population pharmacokinetic models of tacrolimus and to identify factors influencing tacrolimus pharmacokinetic variability. METHODS: Systematic searches in the Web of Science, PubMed, Scopus, Science Direct, Cochrane, EMBASE databases and reference lists of articles were conducted from inception to March 2023. All population pharmacokinetic studies of tacrolimus using nonlinear mixed-effect modelling in paediatric solid organ transplant patients were included. RESULTS: Of the 21 studies reviewed, 62% developed from liver transplant recipients and 33% from kidney transplant recipients. Most studies used a 1-compartment model to describe tacrolimus pharmacokinetics. Body weight was a significant predictor for tacrolimus volume of distribution (Vd/F). The estimated Vd/F for 1-compartment models ranged from 20 to 1890 L, whereas the peripheral volume of distribution (Vp/F) for 2-compartment models was between 290 and 1520 L. Body weight, days post-transplant, CYP3A5 genotype or haematocrit were frequently reported as significant predictors of tacrolimus clearance. The estimated apparent clearance values range between 0.12 and 2.18 L/h/kg, with inter-individual variability from 13.5 to 110.0%. Only 29% of the studies assessed the generalizability of the models with external validation. CONCLUSION: This review highlights the potential factors, modelling approaches and validation methods that impact tacrolimus pharmacokinetics in a paediatric population. The clinician could predict tacrolimus clearance based on body weight, CYP3A5 genotype, days post-transplant or haematocrit. Further research is required to determine the relationship between pharmacogenetics and tacrolimus pharmacodynamics in paediatric patients and confirm the applicability of nonlinear kinetics in this population.

A systematic review of population pharmacokinetic analyses of digoxin in the paediatric population.

This is a PROSPERO registered systematic review (CRD42018105207), conducted to summarize the available knowledge regarding the population pharmacokinetics of digoxin in paediatrics and to identify the sources of variability in its disposition. PubMed, ISI Web of Science, SCOPUS and Science Direct databases were searched from inception to January 2019. All paediatric population pharmacokinetic studies of digoxin that utilized the nonlinear mixed-effect modelling approach were incorporated in this review, and data were synthesized descriptively. After application of the inclusion-exclusion criteria 8 studies were included. Most studies described digoxin pharmacokinetics as a 1-compartment model with only 1 study describing its pharmacokinetics as 2-compartments. Age was an important predictor of clearance in studies involving neonates or infants, other predictors of clearance were weight, height, serum creatinine, coadministration of spironolactone and presence of congestive heart failure. Congestive heart failure was also associated with an increased volume of distribution in 1 study. The estimated value of apparent clearance in a typical individual standardized by mean weight ranged between 0.24 and 0.56 L/h/kg, the interindividual variability in clearance ranged between 7.0 and 35.1%. Half of the studies evaluated the performance of their developed models via external evaluation. In conclusion, substantial predictors of digoxin pharmacokinetics in the paediatric population in addition to model characteristics and evaluation techniques are presented. For clinicians, clearance could be predicted using age especially in neonates or infants, weight, height, serum creatinine, coadministration of medications and disease status. For future researchers, designing pharmacokinetic studies that allow 2-compartment modelling and linking pharmacokinetics with pharmacodynamics is recommended.

Pharmacokinetic characteristics and microbiologic appropriateness of cefazolin for perioperative antibiotic prophylaxis in elective cardiac surgery.

OBJECTIVE: Adequate levels of perioperative antibiotic prophylaxis are essential for prevention of surgical site infections. We examined pharmacokinetic details of 2 g cefazolin administered during induction of anesthesia with repeat dosing shortly after initiation of cardiopulmonary bypass (CPB) in cardiac surgery. METHODS: To identify the microbiologic flora targeted with prophylaxis, pre-, and postoperative swabs were taken from sternal skin. Blood samples for measurement of cefazolin were obtained in 24 patients. Drug levels were used for population pharmacokinetic modeling using Nonmem software (Icon Development Solutions, San Antonio, Tex). RESULTS: More than 90% of bacteria on sternal skin were sensitive to cefazolin, indicating minimal inhibitory concentrations <8 mg/L. All serum levels of cefazolin were above 8 mg/L and might thus effectively prevent infection. Pharmacokinetic modeling in a 1-compartment model predicted a population mean clearance (CL) of 5.23 L/h and a volume of distribution (Vd) of 15.8 L. CPB increased Vd from 14.4 L to 22.1 L with a consecutive reduction to 18 L after the end of extracorporeal circulation. The final model implemented interindividual variability on CL and Vd, incorporating the covariates CPB and albumin on Vd and creatinine clearance on CL. Goodness-of-fit calculations showed that this model adequately describes the data derived from our clinical cohort. CONCLUSIONS: Two grams of cefazolin at induction of anesthesia with a repeat dose after initiation of CPB ensures adequate drug levels to target a majority of pathogens of surgical site infections. Pharmacokinetic modeling demonstrated a significant influence of CPB on the volume of distribution and elimination of cefazolin. Other influences on pharmacokinetic parameters were albumin, protein, and creatinine clearance.