Background

Human antithrombin (hAT) is commonly used to prevent artery thrombosis in early stage of liver transplantation (LT).

Objectives

We describe baseline AT activity level and pharmacokinetic (PK) profile of hAT in early stage of paediatric LT and then simulate appropriate dosing regimens.

Methods

We analyzed 22 children who received hAT with an empirical dosing of 50 U kg^-1. Measured AT activity levels were analyzed using a non-linear mixed effect modeling approach. Dosing regimens were simulated to obtain AT activity levels between 70 to 120 U dl^-1 throughout the dosing interval.

Results

Baseline AT activity level was 39 (19-68) U dl^-1. The relationships for endogenous production rate (q); constant of endogenous production recovery (Kq); clearance (CL) and volume of distribution (V) were:

q_i(t) = q0_pop x(1-fq0.e^-Kqi*t) x (BW_i/70)^0.75; Kq_i = Kq_pop x (LM_i/315)^1.47 where ; fq0, baseline fraction of endogenous production at recovery; BW, bodyweight; LM, liver mass

CL_i = CL_pop x (BW_i/70)^0.75 x (1+drain outflow_i/13)^0.04 , V_i = V_pop x (BW_i/70)¹

Figure: The solid and dashed lines depict the overall AT activity levels after hAT administration and the endogenous AT contribution. For a patient weighing 10 kg, the 3 {liver graft weight in g/drain outflow rate in ml.h^-1} scenarii are 150/100, 200/50 and 300/10 denoted by the green, blue and red curves

Conclusion

The best scheme to attain the target of 70 to 120 U dl^-1 required highest dosing regimens via an extended infusion of 3 hours for the youngest children with a low LM and high abdominal drain losses

Background

Usual dosing regimens of meropenem could lead to the suboptimal exposure in critically ill children

Objectives

We aimed to develop a meropenem population pharmacokinetic model and simulate dosing regimens in order to optimize patient exposure

Methods

Meropenem PK was investigated using a non linear mixed-effect modeling approach. Meropenem concentration was quantified by high performance liquid chromatography. Estimated glomerular filtration rate (eGFR) was estimated by the Schwartz formula

Results

Forty patients with a total of 121 samples were included. Eleven patients received continuous replacement renal therapy (CRRT). Concentration-time courses were best described by a two-compartment model with first order elimination. Bodyweight (BW), eGFR and CRRT were significant covariates inluencing clearance (CL), inter compartment clearance (Q) and central/peripheral volume of distribution (V1/V2):

V1_i= V1_pop x (BW/70)¹, Q_i = Q_popx (BW/70)^0.75, V2_i = V2_pop x(BW/70)¹ , CL_i= (CL_pop x (BW/70)^0.75) x (eGFR/151)^0.355) for patients without CRRT and CL_i = (CL_pop x (BW/70)^0.75) x 0.8 for patients with CRRT.

Probability of target attainment (PTA) obtained from 400 simulations for a target defined as 100% time > MIC (100% fT _{> MIC}): dotted blue: 20mg/kg every 8 hours as a 20-min infusion, dotted red: 40mg/kg every 8 hours as a 20-min infusion, dotted dark green: 20 mg/kg every 8 hours as a 3-hour infusion, blue: 60 mg/kg per day as a continuous infusion, red: 120 mg/kg per day as a continuous infusion.

Conclusion

Meropenem continuous infusion allows te reach the 100% fT _{> MIC} target in critically ill children with normal or increased renal clearance and those needed CRRT.