Comparative Analysis of Ampicillin Plasma and Dried Blood Spot Pharmacokinetics in Neonates

Abstract

Background: Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated.

Methods: An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches.

Results: A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CONCPlasma (eCONCPlasma) was derived using (CONCDBS - 3.223)/0.51. The median bias and geometric mean ratio improved to -11% and 0.88 (Wilcoxon signed-rank test, P < 0.001), respectively, when comparing eCONCPlasma to CONCPlasma. Furthermore, using pop-PK modeling, the median bias (interquartile range) for clearance and individual predicted concentrations improved to 8% (-11 to 50) and -8% (-34 to 11), respectively, when eCONCPlasma was used.

Conclusions: After transformation, DBS sampling accurately predicted ampicillin exposure in neonates.

Conflict of interest statement

Disclosures: The other authors have no potential conflicts of interest.

Figures

Figure 1. Relationship between plasma and DBS concentrations

Relationship between plasma and DBS concentrations: A) concentration (log scale) vs. time; solid and dashed lines represent plasma and dried blood spot linear trends, respectively; and B) linear regression (solid line represents mean [CONCDBS] = 3.223 + 0.51 * [CONCplasma] and dashed line 95% CI; R2=0.902 [slope 0.51 with 95% CI = 0.444 − 0.577]) Abbreviations: CI = confidence interval; DBS = dried blood spot

Figure 1. Relationship between plasma and DBS concentrations

Relationship between plasma and DBS concentrations: A) concentration (log scale) vs. time; solid and dashed lines represent plasma and dried blood spot linear trends, respectively; and B) linear regression (solid line represents mean [CONCDBS] = 3.223 + 0.51 * [CONCplasma] and dashed line 95% CI; R2=0.902 [slope 0.51 with 95% CI = 0.444 − 0.577]) Abbreviations: CI = confidence interval; DBS = dried blood spot

Figure 2. Bland-Altman plots

Bland-Altman plots of A) plasma concentrations and DBS (the solid black line denotes the mean ratio of 0.58 and dashed lines 95% CI) and B) estimated plasma (derived from dried blood spot [DBS]) and plasma concentrations (the solid black line denotes the mean ratio of 0.79 and dashed lines 95% CI; estimated plasma concentrations were calculated using the equation [CONCDBS − 3.223] / 0.51 that was derived from simple linear regression). Abbreviations: CI = confidence interval; DBS = dried blood spot

Figure 2. Bland-Altman plots

Bland-Altman plots of A) plasma concentrations and DBS (the solid black line denotes the mean ratio of 0.58 and dashed lines 95% CI) and B) estimated plasma (derived from dried blood spot [DBS]) and plasma concentrations (the solid black line denotes the mean ratio of 0.79 and dashed lines 95% CI; estimated plasma concentrations were calculated using the equation [CONCDBS − 3.223] / 0.51 that was derived from simple linear regression). Abbreviations: CI = confidence interval; DBS = dried blood spot