Population pharmacokinetic analysis of ropivacaine and its metabolite 2′,6′- pipecoloxylidide from pooled data in neonates, infants, and children L. Aarons,

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Presentation transcript:

Population pharmacokinetic analysis of ropivacaine and its metabolite 2′,6′- pipecoloxylidide from pooled data in neonates, infants, and children L. Aarons, B. Sadler, M. Pitsiu, J. Sjövall, J. Henriksson, V. Molnár British Journal of Anaesthesia Volume 107, Issue 3, Pages 409-424 (September 2011) DOI: 10.1093/bja/aer154 Copyright © 2011 The Author(s) Terms and Conditions

Fig 1 Schematic representation of the combined pharmokinetic model for ropivacaine and PPX. Ro_Input, the zero-order ropivacaine administration; ka, the first-order ropivacaine absorption rate constant; C_Ro, the total concentration of ropivacaine; R_Ro, the binding model for ropivacaine; Cu_Ro, the unbound concentration of ropivacaine; k20_Ro and k23_Ro represent the elimination of ropivacaine partitioned in two first-order processes, with k23_Ro=fm, the fraction of ropivacaine metabolized into PPX and k20_Ro=1−fm, the fraction of ropivacaine eliminated by other processes; C_PPX, the total concentration of PPX; R_PPX, the binding model for PPX; Cu_PPX, the unbound concentration of PPX; k30_PPX, the first-order elimination rate constant for PPX, all of which is assumed to be excreted in urine with no subsequent metabolism; Ae_PPX, the amount of PPX in urine. British Journal of Anaesthesia 2011 107, 409-424DOI: (10.1093/bja/aer154) Copyright © 2011 The Author(s) Terms and Conditions

Fig 2 Effects of body weight and age on ropivacaine unbound clearance and volume of distribution. CLu/F, unbound ropivacaine clearance; Vu/F, unbound ropivacaine volume of distribution. Bands for post-natal age correspond to gestational age minus 40 (± 5) weeks. (a) Effect of body weight on CLu/F; (b) maturation of CLu/F with gestational age; and (c) maturation of Vu/F with gestational age. British Journal of Anaesthesia 2011 107, 409-424DOI: (10.1093/bja/aer154) Copyright © 2011 The Author(s) Terms and Conditions

Fig 3 Individual half-life estimates of ropivacaine (a) and PPX (b) by age group. t½, half-life. British Journal of Anaesthesia 2011 107, 409-424DOI: (10.1093/bja/aer154) Copyright © 2011 The Author(s) Terms and Conditions

Fig 4 VPC of epidural bolus+continuous epidural infusion median profile and 90% PI superimposed on ropivacaine observed unbound and total plasma concentrations for the 0–1 month and 1–12 yr age groups. (a) Unbound ropivacaine in the 0–1 month group; (b) total ropivacaine in the 0–1 month group: median age 2 days, median weight 3.3 kg, median dose 1.54 mg kg−1 single caudal bolus plus 72 h continuous infusion 0.19 mg kg−1 h−1. (c) Unbound ropivacaine in 1–12 yr; (d) total ropivacaine in 1–12 yr: median age 4.5 yr, median weight 18.0 kg, median dose 2.00 mg kg−1 single caudal bolus plus 72 h continuous infusion 0.40 mg kg−1 h−1. British Journal of Anaesthesia 2011 107, 409-424DOI: (10.1093/bja/aer154) Copyright © 2011 The Author(s) Terms and Conditions

Fig 5 Effects of body weight and age on PPX unbound clearance and body weight on PPX unbound volume of distribution. CLu/F, unbound PPX clearance; Vu/F, unbound PPX volume of distribution. Bands for post-natal age correspond to gestational age minus 40 (± 5) weeks. (a) Effect of body weight on CLu/F; (b) maturation of CLu/F with gestational age; and (c) effect of body weight on Vu/F. British Journal of Anaesthesia 2011 107, 409-424DOI: (10.1093/bja/aer154) Copyright © 2011 The Author(s) Terms and Conditions

Fig 6 VPC of epidural bolus+continuous epidural infusion median profile and 90% PI superimposed on PPX observed unbound (Cu) and total (C) plasma concentrations for the 0–1 month and 1–12 yr age groups. mgEq, milligrams equivalent to ropivacaine free base. (a) Unbound PPX in the 0–1 month group; (b) total PPX in the 0–1 month group: median age 2 days, median weight 3.3 kg, median dose 1.54 mg kg−1 single caudal bolus plus 72 h continuous infusion 0.19 mg kg−1 h−1. (c) Unbound PPX in 1–12 yr; (d) total PPX in 1–12 yr: median age 4.5 yr, median weight 18.0 kg, median dose 2.00 mg kg−1 single caudal bolus plus 72 h continuous infusion 0.40 mg kg−1 h−1. British Journal of Anaesthesia 2011 107, 409-424DOI: (10.1093/bja/aer154) Copyright © 2011 The Author(s) Terms and Conditions

Fig 7 Estimated individual unbound ropivacaine clearance (litre h−1) in the present paediatric population compared with that in adults assessed after postoperative epidural infusion (mg h−1)7 and single i.v. doses to volunteers (mg)33 [mean (sd)]. CLu/F, unbound clearance. British Journal of Anaesthesia 2011 107, 409-424DOI: (10.1093/bja/aer154) Copyright © 2011 The Author(s) Terms and Conditions