Summary: Population pharmacokinetic parameter estimates were calculated from 725 routine plasma gentamicin concentrations obtained in 177 neonates of 24 to 42 weeks' gestational age in their first week of life. K el increases and V/W decreases with increasing gestational age. Almost identical results were obtained with iterative twostage Bayesian fitting (MW\PHARM 3.30) as with a non-parametric maximization algorithm (NPEM2). The effect of various covariates on drug disposition was investigated retrospectively using multiple regression analysis. Predictive power for K el increases with rising gestational age. For neonates Յ28.5 weeks and neonates >28.5 weeks and Յ30.9 weeks, the predictive power of the regression equation for K el was relatively low (r 2 respectively 0.270 and 0.364). Better predictivity was found for K el at gestational ages >30.9 weeks (r 2 ס 0.482), with gestational age, postnatal age, and Apgar score at 5 minutes being predictors. A very strong correlation existed between volume of distribution and weight (r 2 ס 0.83). Volume as a function of weight could be described with low predictivity by gestational age and to a lesser degree by Apgar score at 5 minutes (r 2 ס 0 .298)The developed models need appropriate prospective clinical validation.
The artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine. In an attempt to enhance the bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In part 1, the relative bioavailability of the two SDF variants was compared with that of the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In part 2, the pharmacokinetics of lumefantrine from both SDF variants were evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions. The bioavailability of lumefantrine from SDF variant 1 and variant 2 increased up to ∼48-fold and ∼24-fold, respectively, relative to that of the conventional formulation. Both variants demonstrated a positive food effect and a less than proportional increase in exposure between the 480-mg and 960-mg doses. Most adverse events (AEs) were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant 2. No clinically significant treatment-emergent changes in vital signs, electrocardiograms, or laboratory blood assessments were noted. The solid dispersion formulation enhances the lumefantrine bioavailability to a significant extent, and SDF variant 1 is superior to SDF variant 2.
Single-dose kinetics of mexiletine (MEX) was studied in six healthy subjects after three different formulations. The respective doses were 200 mg (intravenous infusion), 400 mg (two conventional capsules), and 432 mg (sustained-release dosage forms). By a three-compartment open model with lag time the kinetic parameters of the drug were calculated from the experimental plasma level data. The mathematical analysis of the processes of distribution and elimination was restricted to the intravenous data only, and the resulting transfer constants were introduced into the evaluations of the oral experiments. With this procedure one common value for the plasma t 1/2 of elimination was obtained (t 1/2 gamma = 6.34 +/- 1.5 hr). Mean values for the total volume of distribution (Vdtot) and the total body clearance (Cltot) were 5.5 l/kg and 10.3 ml/min/kg. After capsules, peak plasma concentrations (Cmax = 0.77 microgram/ml) were reached after 2.2 hr. and the sustained-release form built up a flat maximum of concentration (Cmax = 0.34 microgram/ml) after 9.2 hr. Mexiletine is highly bioavailable, almost identical for the two oral formulations: 87.3% (capsule) and 78.7% (slow release). Under physiologic urinary pH1 7.5% to 9.2% of the dose was excreted unchanged by the kidneys.
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