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Peripheral Volume (peripheral + volume)
Selected AbstractsPharmacokinetics and analgesic effects of intravenous propacetamol vs rectal paracetamol in children after major craniofacial surgeryPEDIATRIC ANESTHESIA, Issue 7 2008SANDRA A. PRINS MD PhD Summary Background:, The pharmacokinetics and analgesic effects of intravenous and rectal paracetamol were compared in nonventilated infants after craniofacial surgery in a double-blind placebo controlled study. Methods:, During surgery all infants (6 months,2 years) received a rectal loading dose of 40 mg·kg,1 paracetamol 2 h before anticipated extubation. On admittance to the pediatric surgical ICU, the children were randomized to receive either a 15 min intravenous infusion of 40 mg·kg,1 propacetamol, a prodrug of paracetamol, or 20 mg·kg,1 paracetamol rectally every 6 h. A population pharmacokinetic analysis of the paracetamol plasma concentration time-profiles was undertaken using nonlinear mixed effects models. The visual analogue scale (VAS) (score 0,10 cm) and COMFORT Behavior scale (score 6,30) were used to monitor analgesia in the 24-h period following surgery. Results:, Twelve infants received intravenous propacetamol and 14 paracetamol suppositories. Paracetamol pharmacokinetics were described according to a two-compartmental model with linear disposition. Pharmacokinetic parameters were standardized to a 70 kg person using allometric ,1/4 power' models. Parameter estimates were: absorption half-life from the rectum 4.6 h, propacetamol hydrolysis half-life 0.028 h, clearance 12 l·h,1·70 kg,1, intercompartmental clearance 116 l·h,1·70 kg,1, central and peripheral volume of distribution 7.9 and 44 l·70 kg,1, respectively. During the 24-h study period 22 infants exhibited VAS scores <4 cm, which was considered a cutoff point. On single occasions four patients, two in each group, exhibited a VAS score ,4 cm. Nine patients in the rectal treatment group and three patients in the intravenous treatment group received midazolam for COMFORT-B scores exceeding 17 (P < 0.05). Conclusions:, Intravenous propacetamol proved to be more effective than rectal paracetamol in infants after craniofacial surgery. Midazolam was more frequently administered to patients receiving paracetamol suppositories, indicating that these children experienced more distress, possibly caused by pain. [source] Clonidine disposition in children: a population analysisPEDIATRIC ANESTHESIA, Issue 6 2007AL Potts Background:, There are few data describing clonidine population pharmacokinetics in children (0,15 years) despite common use. Current paediatric data, described in terms of elimination half-life or Cmax and Tmax, poorly explain variability in drug responses among individuals representative of those in whom the drug will be used clinically. Methods:, Published data from four studies investigating clonidine PK after intravenous, rectal and epidural administration (n = 42) were combined with an open-label study undertaken to examine the pharmacokinetics of IV clonidine 1,2 ,g·kg,1 bolus in children after cardiac surgery (n = 30, EC approval granted). A population pharmacokinetic analysis of clonidine time-concentration profiles (380 observations) was undertaken using nonlinear mixed effects modelling. Estimates were standardised to a 70 kg adult using allometric size models. Results:, Children had a mean age of four (SD 3.6 years, range 1 week,14 years) year and weight 17.8 (SD 12.6, range 2.8,60 kg). A two compartment disposition model with first order elimination was superior to a one compartment model. Population parameter estimates (between subject variability) were clearance (CL) 14 (CV 28.3%) 1 h,1·70 kg,1, central volume of distribution (V1) 56.7 (67.5%) l·70 kg,1, inter-compartment clearance (Q) 143 (19.1%) l h,1 70 kg,1 and peripheral volume of distribution (V2) 123 (72.8%) l.70kg,1. Clearance at birth was 4.7 l·h,1·70kg,1 and matured with a half-time of 25.5 weeks to reach 85% adult rate by 1 year of age. The volumes of distribution, but not clearance, were increased after cardiac surgery (V1 180%, V2 117%). There was a lag time of 2.6 (CV 64%) min before absorption began in the rectum. The absorption half-life from the epidural space was slower than that from the rectum 1.04 (CV31%) h vs 0.28 (CV24%) h. The relative bioavailability of epidural and rectal clonidine was unity (F = 1). Conclusions:, Clearance in neonates is approximately one third that described in adults, consistent with immature clearance pathways. Maintenance dosing, which is a function of clearance, should be reduced in neonates and infants when using a target concentration approach. [source] Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2008Qing Ma Abstract The combination of efavirenz with HIV-1 protease inhibitors (PI) results in complex interactions secondary to mixed induction and inhibition of oxidative metabolism. ACTG A5043 was a prospective, open-label, controlled, two-period, multiple-dose study with 55 healthy volunteers. The objective of the present study was to evaluate the potential pharmacokinetic interaction between efavirenz and dual PIs. The subjects received a daily dose of 600,mg efavirenz for 10 days with amprenavir 600,mg twice daily added at day 11 and were randomized to receive nelfinavir, indinavir, ritonavir, saquinavir, or no second PI on days 15,21. Intensive pharmacokinetic studies were conducted on day 14 and 21. Efavirenz plasma concentrations were fit to candidate models using weighted non-linear regression. The disposition of efavirenz was described by a linear two-compartment model with first order absorption following a fitted lag time. Apparent clearance (CLt/F), volume of distribution at steady state (Vss/F), inter-compartmental clearance, and the central and peripheral volume of distribution were estimated. The mean CLt/F and Vss/F of efavirenz were 0.126,l/h/kg and 4.412,l/kg, respectively. Both AUC and CLt/F of efavirenz remained unchanged after 7 days of dual PI dosing. The mean Vss/F of efavirenz increased an average of 89% across arms, ranging from 52% (nelfinavir) to 115% (indinavir) relative to efavirenz with amprenavir alone. Increases were also observed in Vp/F after the addition of nelfinavir, indinavir, ritonavir and saquinavir by 85%, 170%, 162% and 111%, respectively. In conclusion, concomitant administration of dual PIs is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2B6 substrates in general or oral efavirenz specifically. Copyright © 2007 John Wiley & Sons, Ltd. [source] Simultaneous fitting of R- and S-ibuprofen plasma concentrations after oral administration of the racemateBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2001Jörn Lötsch Aims, To assess the pharmacokinetic equivalence of two different formulations of ibuprofen lysinate with special focus on the expected effects. Methods, Sixteen healthy volunteers received cross-over ibuprofen lysinate as either one tablet of 400 mg (,test') or two tablets of 200 mg (,reference'). Ibuprofen plasma concentrations were followed up for 10 h. Bioequivalence was assessed by standard noncompartmental methods. Ibuprofen plasma concentrations were fitted with a model that took bioinversion of R- to S-ibuprofen into account. Results, Peak plasma concentrations of R- and S-ibuprofen were 18.1 and 20 µg ml,1 (test), and 18.2 and 20 µg ml,1 (reference). Areas under the plasma concentration vs time curves were 39.7 and 67.5 µg ml,1 h (test), and 41.1 and 68.2 µg ml,1 h (reference). Clearance of R-ibuprofen was 5.2 (test) and 5 l h,1 (reference). A specific plasma concentration was reached with the test formulation about 5 min later than with the reference. Parameters from compartmental modelling were (given for R-and then for S-ibuprofen): body clearance: 4.9 and 4.64 l h,1, central volume of distribution: 2.8 and 4.1 l, intercompartment clearance: 5.1 and 5.45 l h,1, peripheral volume of distribution: 4.1 and 5.2 l. The absorption rate constant was 1.52 h,1, and the test but not the reference formulation had a lag time of 0.1 h. Simulations showed similarity between formulations of the expected effects except for a calculated delay of 6 min with the test formulation. Conclusions, Ibuprofen formulations were bioequivalent. The pharmacokinetic model may serve as a basis for future pharmacokinetic/pharmacodynamic calculations after administration of racemic ibuprofen. [source] | ||||||||||