Dexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia

Table 1

Comparison of dexmedetomidine pharmacokinetics in 7 neonates with HIE undergoing TH to literature data in normothermic, non-HIE neonates.

	Subject #							Present	Chrysostomou [15]	Greenberg [13]	Potts [28]
	1	2	3	4	5	6	7	Mean ± SD or median (range)
Subject characteristics
Gestational age (wks; days)	39 5 d	41 5 d	37 3 d	40 4 d	40 6 d	38 0 d	39 0 d	39.6 ± 1.4	39.1 ± 1.6	39 (27–40)	NR
Postnatal age (d, wks, or yrs)								1.7 ± 0.5 d	2.23 ± 1.60 wks	6.14 (0.57–29) wks	3.8 (0.02–14) yrs
Body weight (kg)	3.83	3.47	2.41	3.84	3.08	4.13	3.81	3.51 ± 0.54	3.40 ± 0.60	4.02 (2.00–6.00)	16.1 (3.1–58.9)
Time from birth to TH (h)	4.55	4.78	4.60	8.50	3.65	5.78	4.7	5.22 ± 1.57	NA	NA	NA
Dexmedetomidine dosing
Time from TH to infusion start (h)	4	9.7	16.2	12.5	5.5	23.7	20.7	13.19 ± 7.44	NA	NA	NA
Duration of infusion (h)	74.0	68.3	61.8	65.5	72.5	54.3	57.3	64.8 ± 6.9	6–24	Variable	Bolus or 8 h inf.
Maintenance infusion rate (μg/kg/h)	0.4	0.4	0.4	0.4	0.4	0.4	0.4	0.4	0.2	0.5–2.5 (max)	0.4 (under age 1 yr)
Nominal infused dose (μg/kg)	24.1	25.9	18.5	25.9	14.2	21.4	22.6	21.8 ± 3.9	NR	NR	NR
Corrected infused dose (μg/kg)	22.8	25.0	17.8	24.9	13.5	19.8	21.1	20.7 ± 3.8	NA	NA	NA
Descriptive PK parameters
Cmax (pg/mL)	929	562	501	523	295	517	433	537 ± 180	968 ± 1011^a	304 ± 49^b,	670 ± 128^b
Tmax (h)	48.0	24.0	24.0	24.0	0.2	48.3	48.3	31.0 ± 16.8	NR	End of infusion	End of infusion
AUC0–∞ (ng/mL·h)	47.4	32.3	25.5	26.0	19.5	26.4	21.8	28.4 ± 8.6	NR	NR	NR
CL (L/h/kg)	0.480	0.775	0.699	0.958	0.694	0.752	0.968	0.761 ± 0.155	0.907 ± 0.502	1.23 ± 0.08	0.548 ± 0.032
MRT (h)	4.05	11.4	4.73	2.64	6.85	11.3	6.79	6.84 ± 3.20	4.26 ± 3.90	1.24 ± 0.09	3.28 ± 0.19
Vss (L/kg)	1.95	8.88	3.31	2.53	4.75	8.54	6.57	5.22 ± 2.62	4.57 ± 4.26	1.51^c,†	1.79^d,†

Abbreviations: NR, not reported; NA, not applicable or available; TH, therapeutic hypothermia (33.5°C); PK, pharmacokinetics; C_max, maximum observed plasma concentration; T_max, time of C_max; AUC_0–∞, area under the plasma concentration-time curve from time 0 to infinity; CL, clearance based upon the infused dose corrected for sorptive loss; MRT, mean residence time; V_ss, steady-state distribution volume. Note that, for all the pharmacokinetic parameters, estimates presented in the Potts et al. and Greenberg et al. columns are mean ± SD for the 7 normothermic counterparts predicted based upon the reported population pharmacokinetic models. ^aExtrapolated from an infusion rate of 0.2 μg/kg/h, i.e., multiplying reported mean ± SD by 2. ^bAverage of simulations for normothermic counterparts to each of our 7 cooled newborns without HIE at the maximum infusion rate of 0.4 μg/kg/h. ^cGreenberg et al. were only able to provide the population mean estimate of distribution volume because of insufficient data in the initial accumulation or washout phases of DEX infusion, i.e., no modeling of interindividual variation. ^dDistribution volume was scaled to body weight; hence, volume per kg did not differ between the normothermic counterparts. for a 2-tailed, 2-sample t-test between reported values for normothermic, non-HIE newborns and presently observed values for cooled newborns with HIE. for a 2-tailed, 2-sample t-test between reported values for normothermic, non-HIE newborns and presently observed values for cooled newborns with HIE. for a 2-tailed, one-sample t-test between the reported fixed value for normothermic, non-HIE newborns and presently observed values for cooled newborns with HIE.