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Aims: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment., Methods: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400-600 mg*h/L was used as target range., Results: Sixteen patients received vancomycin (median gestational age: 41 [range: 38-42] weeks, postnatal age: 4.4 [2.5-5.5] days, birth weight: 3.5 [2.3-4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20-0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment., Conclusion: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Pharmacokinetic/pharmacodynamic target attainment of ceftriaxone is compromised in intensive care unit (ICU) patients and non-ICU hospitalized patients in Beira, Mozambique. Whether this also accounts for non-ICU patients in a high-income setting is unknown. We therefore assessed the probability of target attainment (PTA) of the currently recommended dosing regimen of 2 g every 24 h (q24h) in this patient group., Methods: We performed a multicentre population pharmacokinetic study in hospitalized non-ICU adult patients empirically treated with intravenous ceftriaxone. During both the acute phase of infection (i.e. first 24 h of treatment) and convalescence, a maximum of 4 random blood samples were obtained per patient for ceftriaxone total and unbound concentration measurements. PTA was calculated using NONMEM and was defined as the percentage of patients of which the unbound ceftriaxone concentration exceeded the minimum inhibitory concentration (MIC) for >50% of the first dosing interval of 24 h. Monte Carlo simulations were performed to determine PTA for different estimated glomerular filtration rates (eGFR; CKD-EPI) and MICs. PTA >90% was considered adequate., Results: Forty-one patients provided 252 ceftriaxone total and 253 unbound concentrations. The median eGFR was 65 mL/min/1.73 m 2 (5th to 95th percentile 36-122). With the recommended dose of 2 g q24h, PTA >90% was achieved for bacteria with an MIC ≤2 mg/L. Simulations showed that PTA was insufficient for an MIC of 4 mg/L in case the eGFR was 122 mL/min/1.73 m 2 (PTA 56.9%) and for an MIC of 8 mg/L regardless of eGFR., Conclusion: The PTA of 2 g q24h ceftriaxone dosing is adequate for common pathogens during the acute phase of infection in non-ICU patients., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: To explore the optimal data sampling scheme and the pharmacokinetic (PK) target exposure on which dose computation is based in the model-based therapeutic drug monitoring (TDM) practice of vancomycin in intensive care (ICU) patients., Methods: We simulated concentration data for 1 day following four sampling schemes, C min , C max + C min , C max + C mid-interval + C min , and rich sampling where a sample was drawn every hour within a dose interval. The datasets were used for Bayesian estimation to obtain PK parameters, which were used to compute the doses for the next day based on five PK target exposures: AUC 24 = 400, 500, and 600 mg·h/L and C min = 15 and 20 mg/L. We then simulated data for the next day, adopting the computed doses, and repeated the above procedure for 7 days. Thereafter, we calculated the percentage error and the normalized root mean square error (NRMSE) of estimated against "true" PK parameters, and the percentage of optimal treatment (POT), defined as the percentage of patients who met 400 ≤ AUC 24 ≤ 600 mg·h/L and C min ≤ 20 mg/L., Results: PK parameters were unbiasedly estimated in all investigated scenarios and the 6-day average NRMSE were 32.5%/38.5% (CL/V, where CL is clearance and V is volume of distribution) in the trough sampling scheme and 27.3%/26.5% (CL/V) in the rich sampling scheme. Regarding POT, the sampling scheme had marginal influence, while target exposure showed clear impacts that the maximum POT of 71.5% was reached when doses were computed based on AUC 24 = 500 mg·h/L., Conclusions: For model-based TDM of vancomycin in ICU patients, sampling more frequently than taking only trough samples adds no value and dosing based on AUC 24 = 500 mg·h/L lead to the best POT., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Pharmacokinetic studies of the immunosuppressive compound mycophenolic acid (MPA) have shown a structural decrease in clearance (CL) over time after renal transplantation. The aim of this study was to characterize the time-dependent CL of MPA by means of a population pharmacokinetic meta-analysis, and to test whether it can be described by covariate effects., Methods: One thousand eight hundred and ninety-four MPA concentration-time profiles from 468 renal transplant patients (range 1-9 profiles per patient) were analyzed retrospectively by nonlinear mixed effect modelling. Sampling occasions ranged from day 1-10 years after transplantation., Results: The pharmacokinetics of MPA were described by a two-compartment model with time-lagged first order absorption, and a first-order term for time-dependent CL. The model predicted the mean CL to decrease from 35 l h(-1) (CV = 44%) in the first week after transplantation to 17 l h(-1) (CV = 38%) after 6 months. In a covariate model without a term for time-dependent CL, changes during the first 6 months after transplantation in creatinine clearance from 19 to 71 ml min(-1), in albumin concentration from 35 to 40 g l(-1), in haemoglobin from 9.7 to 12 g dl(-1) and in cyclosporin predose concentration from 225 to 100 ng ml(-1) corresponded with a decrease of CL from 32 to 19 l h(-1). Creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration explained, respectively, 19%, 12%, 4% and 3% of the within-patient variability in MPA CL., Conclusions: By monitoring creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration, changes in MPA exposure over time can be predicted. Such information can be used to optimize therapy with mycophenolate mofetil.