3 results for Allegaert, K

  • Tramadol and O-Desmethyl Tramadol Clearance Maturation and Disposition in Humans: A Pooled Pharmacokinetic Study

    Allegaert, K; Holford, Nicholas; Anderson, Brian; Holford, S; Stuber, F; Rochette, A; Troc??niz, IF; Beier, H; de Hoon, JN; Pedersen, RS; Stamer, U (2015-02)

    Journal article
    The University of Auckland Library

    BACKGROUND AND OBJECTIVES: We aimed to study the impact of size, maturation and cytochrome P450 2D6 (CYP2D6) genotype activity score as predictors of intravenous tramadol disposition. METHODS: Tramadol and O-desmethyl tramadol (M1) observations in 295 human subjects (postmenstrual age 25 weeks to 84.8 years, weight 0.5-186 kg) were pooled. A population pharmacokinetic analysis was performed using a two-compartment model for tramadol and two additional M1 compartments. Covariate analysis included weight, age, sex, disease characteristics (healthy subject or patient) and CYP2D6 genotype activity. A sigmoid maturation model was used to describe age-related changes in tramadol clearance (CLPO), M1 formation clearance (CLPM) and M1 elimination clearance (CLMO). A phenotype-based mixture model was used to identify CLPM polymorphism. RESULTS: Differences in clearances were largely accounted for by maturation and size. The time to reach 50 % of adult clearance (TM50) values was used to describe maturation. CLPM (TM50 39.8 weeks) and CLPO (TM50 39.1 weeks) displayed fast maturation, while CLMO matured slower, similar to glomerular filtration rate (TM50 47 weeks). The phenotype-based mixture model identified a slow and a faster metabolizer group. Slow metabolizers comprised 9.8 % of subjects with 19.4 % of faster metabolizer CLPM. Low CYP2D6 genotype activity was associated with lower (25 %) than faster metabolizer CLPM, but only 32 % of those with low genotype activity were in the slow metabolizer group. CONCLUSIONS: Maturation and size are key predictors of variability. A two-group polymorphism was identified based on phenotypic M1 formation clearance. Maturation of tramadol elimination occurs early (50 % of adult value at term gestation).

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  • Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance

    Anderson, Brian; Allegaert, K; van den Anker, JN; Cossey, V; Holford, Nicholas (2007)

    Journal article
    The University of Auckland Library

    Aim To identify and quantify factors describing the variability of vancomycin clearance in premature neonates. Methods Population pharmacokinetics were estimated (NONMEM) in 214 neonates [postmenstrual age (PMA) 30.4 weeks, range 24???34 weeks; postnatal age 11.9 days, range 1???27 days; weight 1.30 kg, range 0.42???2.6 kg] using therapeutic drug monitoring data. Covariate analysis included weight, PMA, serum creatinine, use of inotropes or ibuprofen, positive blood culture and respiratory support. A one-compartment linear disposition model with zero order input and ???rst-order elimination was used to describe the data (604 observations). Results The population estimate for volume of distribution (V) was 39 l 70 kg ???1 (coef???cient of variation 19.4%). Clearance (CL) increased from 0.897 l h ???1 70 kg ???1 at 24 weeks PMA to 2.02 l h ???1 70 kg ???1 by 34 weeks PMA. The between-subject variability for CL was 18.6% and the between-occasion variability was 12.2%. The use of ibuprofen reduced clearance, but this effect was attributable to reduced renal function. Overall, 82% of the variability of CL was predictable. Size explained 49.8%, PMA 18.2% and renal function 14.1%. The use of a variable slope sigmoidal model to describe the relationship between clearance and PMA predicted an adult clearance of 3.79 l h ???1 70 kg ???1 (95% con???dence interval 2.76, 4.98). Conclusions Size, renal function and PMA are the major contributors to clearance variability in premature neonates. The small (18%) unexplained variability in clearance suggests target concentration intervention is unnecessary if size, age and renal function are used to predict the dose. Extrapolation to an adult clearance from neonatal data is possible using allometric size models and a function describing clearance maturation.

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  • The paracetamol concentration-effect relation in neonates

    Allegaert, K; Naulaers, G; Vanhaesebrouck, S; Anderson, Brian (2013-01)

    Journal article
    The University of Auckland Library

    Summary Objectives We suggested a loading dose (20 mg??kg -1 ) followed by 10 mg??kg -1 q6h of intravenous (IV) paracetamol to achieve an effect compartment concentration of 11 mg??l -1 in neonates. Since there are no pharmacodynamic data to support such an effect compartment concentration, pain scores collected in neonates treated with an IV paracetamol loading dose (20 mg??kg -1 ) were used to validate this effect compartment concentration. Methods Pain scores (Leuven Neonatal Pain Score, LNPS, 0-14) before and 0.5, 1, 2, 3, 4, 5, and 6 h after IV paracetamol loading dose administration in neonates to whom IV paracetamol was administered as single analgesic (PARANEO, www.clinicaltrials.gov, NCT00969176) were collected. Trends were analyzed using repeated measures anova. An E max model with a delayed response compartment was fitted to data using population modeling. Results Nineteen of 60 neonates included in the PARANEO study received monotherapy with IV paracetamol to treat mild to moderate pain (e.g., alprostadil administration, delivery related trauma). Using repeated measures anova, there was a trend (P = 0.02) for lower pain scores within 30 min after administration, with a slight increase in pain scores from 5 to 6 h. An E max model had a maximum effect of 4.15 pain units, an EC 50 of 2.07 mg??l -1 . Equilibration halftime (T 1/2 keo) was 1.58 h. Conclusion Intravenous paracetamol is effective for moderate pain. An effect compartment concentration of 10 mg??l -1 (loading dose of 20 mg??kg -1 ) is associated with a pain score reduction of 3.4 LNPS units. This analysis suggests a similar paracetamol effect compartment concentration in neonates compared to children. ?? 2012 Blackwell Publishing Ltd.

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