Pharmacokinetic-pharmacodynamic correlation of imipenem in pediatric burn patients using a bioanalytical liquid chromatographic method

Abstract

A bioanalytical method was developed and applied to quantify the free imipenem concentrations for pharmacokinetics and PK/PD correlation studies of the dose adjustments required to maintain antimicrobial effectiveness in pediatric burn patients. A reverse-phase Supelcosil LC18 column (250 x 4.6 mm 5 micra), binary mobile phase consisting of 0.01 M, pH 7.0 phosphate buffer and acetonitrile (99:1, v/v), flow rate of 0.8 mL/min, was applied. The method showed good absolute recovery (above 90%), good linearity (0.25-100.0 µg/mL, r 2 =0.999), good sensitivity (LLOQ: 0.25 µg/mL; LLOD: 0.12 µg/mL) and acceptable stability. Inter/intraday precision values were 7.3/5.9%, and mean accuracy was 92.9%. A bioanalytical method was applied to quantify free drug concentrations in children with burns. Six pediatric burn patients (median 7.0 years old, 27.5 kg), normal renal function, and 33% total burn surface area were prospectively investigated; inhalation injuries were present in 4/6 (67%) of the patients. Plasma monitoring and PK assessments were performed using a serial blood sample collection for each set, totaling 10 sets. The PK/PD target attained (40%T>MIC) for each minimum inhibitory concentration (MIC: 0.5, 1.0, 2.0, 4.0 mg/L) occurred at a percentage higher than 80% of the sets investigated and 100% after dose adjustment. In conclusion, the purification of plasma samples using an ultrafiltration technique followed by quantification of imipenem plasma measurements using the LC method is quite simple, useful, and requires small volumes for blood sampling. In addition, a small amount of plasma (0.25 mL) is needed to guarantee drug effectiveness in pediatric burn patients. There is also a low risk of neurotoxicity, which is important because pharmacokinetics are unpredictable in these critical patients with severe hospital infection. Finally, the PK/PD target was attained for imipenem in the control of sepsis in pediatric patients with burns.Uniterms: Imipenem/quantification. Antibiotics/dosage. Pediatric patients/burn/antibiotics use. High Performance Liquid Chromatography/quantitative analysis. Drug plasma monitoring. PK/PD.Desenvolveu-se e aplicou-se método bioanalítico para quantificar concentrações de imipenem livre para estudos de farmacocinética (PK) e de correlação PK/PD dos ajustes de dose requeridos para manter a efetividade antimicrobiana em pacientes pediátricos queimados. Utilizou-se coluna Supelcosil LC18 (250 x 4,6 mm 5 micra), fase móvel binária, consistindo de tampão fosfato 0,01M pH 7,0 e acetonitrila (99:1, v/v) e fluxo de 0,8 mL/min. O método mostrou boa recuperação absoluta (acima de 90%), boa linearidade (0,25-100,0 µg/mL, r 2 =0.999), boa sensibilidade (LLOQ: 0,25 µg/mL; LLOD: 0,12 µg/mL) e estabilidade aceitável. Os valores de precisão inter/intradia foram 7,3/5,9% e a exatidão média foi de 92,9%. O método bioanalítico foi aplicado para quantificar concentrações de fármaco livre em crianças com queimaduras, Seis pacientes pediátricos queimados (idade média de 7,0 anos, 27,5 kg), com função renal n...

Meropenem Pharmacokinetics in Children: Series of Cases

“…These pharmacokinetic variabilities may be associated with differences in age, physiological characteristics such as volume of distribution, biological half-life, renal clerance and clinical condition. 1,[4][5] To Santos et al, (2011) 5 in their study evaluating only one burned child, observed differences in pharmacokinetic parameters at two different moments of evaluation, indicating that these alterations in the parameters are related to clinical status, changes in the degree of hydration, serum protein concentrations, creatinine clearance, presence of lesions, mechanical ventilation and the use of vasoactive drugs. As in the study of Kongthavonsakul et al (2016) 4 the interindividual variability in relation to pharmacokinetic parameters did not occur due to age, but due to the physiological changes of the severe clinical picture, since many of these children had some organic dysfunction, indicating the need for therapeutic monitoring and dose individualization in populations pediatric patients.…”

“…Volume of distribution (eq.4). Vd=dose*(e -KT)/vale*(1-e -KT) [4] Antimicrobial clerance (eq.5) CL=Vd*Kel [5] The dose adjustment estimate for meropenem was performed using the equation suggested by Winter (2004)10 eq.6, maintaining an interval of 8 hours between doses, considering CIM of 1μg/mL and 4μg/mL, in 40 and 100% fT>CIM.…”

“…For the quantification of serum meropenem in plasma, a methodology developed and validated previously by Santos et al was used. (2011) 5 , considering the free fraction of 98%2 the final concentration was calculated for the free drug from this ratio.…”

“…[1][2][3][4] In Brazil, the monitoring and adjustment of doses of antibiotics in children is not routinely performed, and the lack of this service not only compromises care, but also information related to the antimicrobial resistance pattern in children, as resistance is not well defined to carbapenems and, if related to concentrations, dose, pharmacokinetics, among other factors. [4][5] Therefore, this study aimed to describe the pharmacokinetic/pharmacodynamic characteristics of meropenem in children in a pediatric hospital and to verify whether the plasma concentrations of meropenem were within the therapeutic range.…”

Vancomycin for Dialytic Therapy in Critically Ill Patients: Analysis of Its Reduction and the Factors Associated with Subtherapeutic Concentrations

“…Formulas utilized for the calculation of Vancomycin pharmacokinetic[18][19][20].Pharmacokinetic Formula Distribution Volume (L) VD = Vancomycin dose (mg)/concentration of vancomycin (mg/L) Dialytic Clearence of vancomycin (L/h) Cl vanco = (Initial-final concentration)/Initial concentration × QD/t Half-life time T 1 2 life = 0.693 × VD/Cl % reduction in vancomycin % red = (C pre HD-C final HD)/C pre HD) × 100 VD: Distribution volume. Cl vanco: Dialytic Clearence of vancomycin.…”