Development of an Optimized Pharmacokinetic Model of Dexmedetomidine Using Target-controlled Infusion in Healthy Volunteers

Abstract

Using target-controlled infusion in healthy volunteers, the pharmacokinetics of dexmedetomidine were best described by a three-compartment allometric model. Apart from weight, no other covariates were identified.

Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine

“…For a complete overview, the reader is redirected to Table 1. Most of these models were derived from a small group of postoperative ICU patients (median sample size 21, range 8–40) [22, 32, 38–41] or healthy volunteers (median sample size 17, range 10–24) [21, 26, 29, 42]. In addition, Välitalo et al [24] developed a PopPK model from three phase III trials in which a prolonged dexmedetomidine dosing regimen was evaluated in critically ill patients (sample size 527).…”

“…This is because of a lack of an effect of TBW on V 1 and V 2 and an inhibition of DMED CL as a function of fat mass. However, the authors found that during surgery the DMED V 1 is significantly lower (20.8%) which, according to the authors, is likely the result of the concomitant use of other anestheticsHannivoort (2015) [42]HV18 × 2 sessions14 a samples during ( n  = 7) and after ( n  = 7) DMED infusion300 min20–70 years (range)51–110 kg (range)9 were male, 9 were femaleAge-stratified cohorts (18–34/35–54/55–72 years)TCI (based on the model from Dyck et al) targeting 1, 2, 3, 4, 6, and 8 ng/mL 10 min after a short (20 s) bolus infusion at 6 µg/kg/hAge, WGT, HGT, BMI, sex3-compartment model with weight as a covariate on clearance, Q 2 , Q 3 , V 1 , V 2 , and V 3 The authors found no systematic difference in V 1 between a volunteer’s first or second session. Nevertheless, the magnitude of the IOV far exceeds the magnitude of the IIV for DMED V 1 Kuang (2016) [41]Chinese patients under spinal anesthesia19 young/16 elderly15 a/v during ( n  = 5) and after ( n  = 10) DMED infusion600 min33 vs. 69 years71 vs. 54 kg172 vs. 158 cmALT 49 vs.20 U/LMale:female7:12 vs. 15:13.0 µg/kg/h for 10 min followed by 0.5 µg/kg/h for 50 min Maximum measured DMED concentration is approximately 1.7 ng/mLAge, WGT, HGT, sex, BMI, AST, ALT, creatinine clearance3-compartment model with ALT as a covariate on clearance, age on V 1 and weight on V 2

ALB albumin, ALT alanine transaminase, AST aspartate transaminase, BMI body mass index, BSA body surface area, CL clearance, C max maximum plasma concentration, CO cardiac output, C ss plasma concentration at steady state, ELS extended least squares, FAT fat mass, FFM fat-free mass, HGT height, HV healthy volunteers, IC 50 half maximal inhibitory concentration, IIV inter-individual variability, I max maximal inhibition, IOV inter-occasion variability, LBM lean body mass, N number of subjects, PK pharmacokinetic, Q inter-compartmental clearance, SVR systemic vascular resistance, TBW total body weight, TCI target-controlled infusion, V apparent volume of distribution, WGT weight

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“…Target-controlled infusion (TCI) was used in several studies to target a specific, predicted dexmedetomidine plasma concentration [38] or a sequence of plasma concentrations according to a “step-up” dosing design [21, 26, 42]. Dexmedetomidine plasma targets ranged from 0.49 to 8 ng/mL.…”

“…Four investigators [21, 26, 39, 42] found that a three-compartment PK model best described dexmedetomidine PK and the analysis by Välitalo et al reported a one-compartment PK model as their final PK model. To describe the observed variability in dexmedetomidine pharmacokinetics across and within subjects, different covariate models have been suggested.…”

“…To describe the observed variability in dexmedetomidine pharmacokinetics across and within subjects, different covariate models have been suggested. The central and/or peripheral volumes of distribution ( V 1 , V 2 , V 3 ) were found to correlate with a subject’s age [29, 41], body weight [41, 42], fat free mass [40], serum albumin level [24, 32] and/or whether or not a subject was undergoing surgery [40]. The elimination and/or distributional clearance (CL, Q 2 , Q 3 ) was found to vary significantly according to height [21, 39], body weight [24, 42], or fat (free) mass [40], age [32], cardiac output [26, 32], plasma albumin level [29] and/or alanine aminotransferase activity [41].…”