A physiological approach to renal clearance : from premature neonates to adults

Aims We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. Methods Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. Results This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin). Conclusions GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention

Rapid and Simultaneous Quantification of Levetiracetam and Its Carboxylic Metabolite in Human Plasma by Liquid Chromatography Tandem Mass Spectrometry

<div><p>A simple liquid chromatography tandem mass spectrometry method was developed and validated according to the guidelines of the US Food and Drug Administration and the European Medicines Agency for a simultaneous quantification of levetiracetam (LEV) and its metabolite, UCB L057 in the plasma of patients. A 0.050 mL plasma sample was prepared by a simple and direct protein precipitation with 0.450 mL acetonitrile (ACN) containing 1 µg/mL of internal standard (IS, diphenhydramine), then vortex mixed and centrifuged. A 0.100 mL of the clear supernatant was diluted with 0.400 mL water and well mixed. A 0.010 mL of the resultant solution was injected into an Agilent Zorbax SB-C18 (2.1 mm×100 mm, 3.5 µm) column with an isocratic elution at 0.5 mL/min using a mixture of 0.1% formic acid in water and ACN (40∶60 v/v). Detection was performed using an AB Sciex API 3000 triple quadrupole mass spectrometer, equipped with a Turbo Ion Spray source, operating in a positive mode: LEV at transition 171.1>154.1, UCB L057 at 172.5>126.1, and IS at 256.3>167.3; with an assay run time of 2 minutes. The lower limit of quantification (LLOQ) for both LEV and UCB L057 was validated at 0.5 µg/mL, while their lower limit of detection (LOD) was 0.25 µg/mL. The calibration curves were linear between 0.5 and 100 µg/mL for both analytes. The inaccuracy and imprecision of both intra-assay and inter-assay were less than 10%. Matrix effects were consistent between sources of plasma and the recoveries of all compounds were between 100% and 110%. Stability was established under various storage and processing conditions. The carryovers from both LEV and UCB L057 were less than 6% of the LLOQ and 0.13% of the IS. This assay method has been successfully applied to a population pharmacokinetic study of LEV in patients with epilepsy.</p></div

Recovery and matrix effects for each analyte.

<p><i>QCLOQ is QC at LLOQ concentration, QCL is QC at low concentration, QCM is QC at medium concentration and QCH is QC at high concentration. LEV is levetiracetam and UCB L057 is its carboxylic metabolite. CV is coefficient of variation and is expressed in percentage (%).</i></p><p>Recovery and matrix effects for each analyte.</p

Representative semi-log plots of plasma concentrations of LEV (○) and UCB L057 (•) versus time after last dose of 6 patients with epilepsy on maintenance dose of oral LEV.

<p>Representative semi-log plots of plasma concentrations of LEV (○) and UCB L057 (•) versus time after last dose of 6 patients with epilepsy on maintenance dose of oral LEV.</p

Molecular structures of (A) Levetiracetam (molecular weight 170.2), (B) Etiracetam carboxylic acid (molecular weight 171.2) and (C) Diphenhydramine (molecular weight 255.4).

<p>Molecular structures of (A) Levetiracetam (molecular weight 170.2), (B) Etiracetam carboxylic acid (molecular weight 171.2) and (C) Diphenhydramine (molecular weight 255.4).</p

Mean and standard error of mean (SEM) of the ratio percent of plasma concentrations of UCB L057/LEV at various dosing regimens.

<p>Mean and standard error of mean (SEM) of the ratio percent of plasma concentrations of UCB L057/LEV at various dosing regimens.</p

Stability study for each analyte.

<p><i>QCLOQ is QC at LLOQ concentration, QCL is QC at low concentration, QCM is QC at medium concentration and QCH is QC at high concentration. LEV is levetiracetam and UCB L057 is its carboxylic metabolite. CV is coefficient of variation and is expressed in percentage (%).RT is room temperature. The presented data in this table are calculated as % deviation (% CV).</i></p><p><i>*Analytes and IS are spiked into reagent at 1∶50 dilution ratio.</i></p><p>Stability study for each analyte.</p

Optimized mass spectrometer voltage settings including MS/MS transitions for all analytes evaluated.

<p>DP  =  declustering potential, FP  =  focusing potential, CE  =  collision energy, CXP  =  collision cell exit potential and EP  =  entrance potential.</p><p>Optimized mass spectrometer voltage settings including MS/MS transitions for all analytes evaluated.</p