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Abstract

Aims: To describe the pharmacokinetics (PK) and concentration-related effects of dobutamine in critically ill neonates in the first days of life, using nonlinear mixed effects modelling. Methods: Dosing, plasma concentration and haemodynamic monitoring data from a dose-escalation study were analysed with a simultaneous population PK and pharmacodynamic (PD) model. Neonates receiving continuous infusion of dobutamine 5-20 μg kg-1 min-1 were included. Left ventricular ejection fraction (LVEF) and cardiac output of right and left ventricle (RVO, LVO) were measured on echocardiography; heart rate (HR), mean arterial pressure (MAP), peripheral arterial oxygen saturation and cerebral regional oxygen saturation were recorded from patient monitors. Results: 28 neonates with median (range) gestational age of 30.4 (22.7 - 41.0) weeks and birth weight (BW) of 1618 (465 - 4380) g were included. PK data was adequately described by one-compartmental linear structural model. Dobutamine clearance (CL) was described by allometric scaling on BW with sigmoidal maturation function of postmenstrual age (PMA). The final population PK model parameter mean typical value (standard error) estimates, standardised to median BW of 1618 g, were 41.2 (44.5) l h-1 for CL and 5.29 (0.821) l for volume of distribution, which shared a common between subject variability of 29(17.2) %. The relationship between dobutamine concentration and RVO/LVEF was described by linear model, between concentration and LVO/HR/MAP/cerebral fractional tissue oxygen extraction by sigmoidal Emax model. Conclusions: In postnatal transitional period PK of dobutamine was described by one-compartmental linear model, CL related to BW and PMA. A concentration-response relationship with haemodynamic variables has been established.
ORIGINAL ARTICLE
Population pharmacokinetics and pharmacodynamics of
dobutamine in neonates on the first days of life
Maarja Hallik
1
| Mari-Liis Ilmoja
2
| Joseph F. Standing
3
| Hiie Soeorg
4
|
Tiiu Jalas
2
| Maila Raidmäe
2
| Karin Uibo
2
| Kristel Köbas
5
| Margit Sõnajalg
5
|
Kalev Takkis
6
|R
uta Veigure
7
| Karin Kipper
6,7
| Joel Starkopf
1,8
|
Tuuli Metsvaht
8,9
1
Department of Anaesthesiology and Intensive
Care, Institute of Clinical Medicine, University
of Tartu, Tartu, Estonia
2
Clinic of Paediatrics, Tallinn Children's
Hospital, Tallinn, Estonia
3
Inflammation, Infection and Rheumatology
section, Great Ormond Street Institute of Child
Health, University College London, London,
UK
4
Department of Microbiology, Institute of
Biomedicine and Translational Medicine,
University of Tartu, Tartu, Estonia
5
Clinic of Paediatrics, Tartu University
Hospital, Tartu, Estonia
6
Analytical Services International, St George's
University of London, Cranmer Terrace,
London, UK
7
Institute of Chemistry, University of Tartu,
Tartu, Estonia
8
Clinic of Anaesthesiology and Intensive Care,
Tartu University Hospital, Tartu, Estonia
9
Department of Paediatrics, Institute of
Clinical Medicine, University of Tartu, Tartu,
Estonia
Correspondence
Maarja Hallik, Department of Anaesthesiology
and Intensive Care, Institute of Clinical
Medicine, University of Tartu, L. Puusepa 8 -
G1. 209, 50406, Tartu, Estonia.
Email: maarja.hallik@gmail.com
Funding information
Eesti Teadusagentuur, Grant/Award Number:
PUT1197
Aims: To describe the pharmacokinetics (PK) and concentration-related effects of
dobutamine in critically ill neonates in the first days of life, using nonlinear mixed
effects modelling.
Methods: Dosing, plasma concentration and haemodynamic monitoring data from
a dose-escalation study were analysed with a simultaneous population PK and
pharmacodynamic model. Neonates receiving continuous infusion of dobutamine
520 μgkg
1
min
1
were included. Left ventricular ejection fraction (LVEF) and
cardiac output of right and left ventricle (RVO, LVO) were measured on echocar-
diography; heart rate (HR), mean arterial pressure (MAP), peripheral arterial oxy-
gen saturation and cerebral regional oxygen saturation were recorded from
patient monitors.
Results: Twenty-eight neonates with median (range) gestational age of 30.4 (22.7
41.0) weeks and birth weight (BW) of 1618 (4654380) g were included. PK data
were adequately described by 1-compartmental linear structural model. Dobutamine
clearance (CL) was described by allometric scaling on BW with sigmoidal maturation
function of postmenstrual age (PMA). The final population PK model parameter mean
typical value (standard error) estimates, standardised to median BW of 1618 g, were
41.2 (44.5) L h
1
for CL and 5.29 (0.821) L for volume of distribution, which shared a
common between subject variability of 29% (17.2%). The relationship between dobu-
tamine concentration and RVO/LVEF was described by linear model, between con-
centration and LVO/HR/MAP/cerebral fractional tissue oxygen extraction by
sigmoidal E
max
model.
Conclusion: In the postnatal transitional period, PK of dobutamine was described by
a 1-compartmental linear model, CL related to BW and PMA. A concentration
response relationship with haemodynamic variables has been established.
The authors confirm that the PI for this paper is Maarja Hallik and that she had direct clinical
responsibility for patients.
EU Clinical Trials Register number 2015-004836-36.
Received: 23 July 2019 Revised: 5 September 2019 Accepted: 26 September 2019
DOI: 10.1111/bcp.14146
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society
318 Br J Clin Pharmacol. 2020;86:318328.wileyonlinelibrary.com/journal/bcp
KEYWORDS
cardiovascular pharmacology, intensive care, neonatology, NONMEM, pharmacokinetic
pharmacodynamic
1|INTRODUCTION
Dobutamine is a β
1
-adrenoceptor (AR) agonist catecholamine,
designed to increase cardiac output (CO) without evoking vasocon-
striction or tachycardia.
1
In critically ill neonates, inotropic therapy
with dobutamine is often used because of low blood pressure (BP),
signs of low organ perfusion, or CO measured at echocardiography.
2
Early administration of dobutamine to preterm infants during the first
days of life has been found to stabilise transitional circulation.
3-6
The pharmacokinetics (PK) of dobutamine in the paediatric popu-
lation is described in children rather than neonates.
7-13
Except for 1,
10
the studies indicate first-order elimination kinetics within the dose
range of 2.510 μgkg
1
min
1
for neonates and 2.5
17.5 μgkg
1
min
1
for infants and children. Plasma clearance (CL) rate
is widely variable.
7-13
The only study describing PK of dobutamine in
neonates, reported mean (standard deviation) CL of 90 (38) mL
min
1
kg
1
with variability independent of gestation and birth weight
(BW).
13
However, the sample size was small and postmenstrual age
(PMA), a potentially better marker for maturation of elimination pro-
cesses, was not explored.
13
In the dose range of 2.5 to
7.5 μgkg
1
min
1
the elimination of dobutamine was linear
13
but as
doses rise above this range the kinetics may become nonlinear.
10
Studies on pharmacodynamic (PD) effect of cardiac performance
have mostly assessed doseresponse relationship in doses up to
10 μgkg
1
min
1
.
13,14
CO increases at low doses, but heart rate (HR)
or BP require larger doses to be affected.
13,14
However, such associa-
tions have not been consistently found
15
that may be in part due to
wide variation in CL, requiring simultaneous analysis of actual plasma
concentrations and response. Considering the immaturity of the car-
diovascular system in neonates, a plateau of the effect on CO and BP
at doses of 7.510 μgkg
1
min
1
in children
9
may not occur in neo-
nates and thus PKPD in larger doses needs to be studied.
We aimed to describe the PK and PD of dobutamine in simulta-
neous PKPD modelling in critically ill preterm and term neonates
treated with dobutamine in doses of 520 μgkg
1
min
1
on clinical
indication in the first days of life.
2|METHODS
The study was approved by the Ethics Committee of the University of
Tartu and registered at the EU Clinical Trials Register under number
2015004836-36.
A prospective 2-centre study was performed in Tallinn Children's
Hospital, Tallinn, Estonia and Tartu University Hospital, Tartu, Estonia.
All neonates hospitalized to NICU within the first 72 h of life from
April 2016 to December 2017 were screened for eligibility. We
included neonates who needed inotropic therapy according to the
decision of the treating physician (based on echocardiographic assess-
ment, cerebral regional oxygen saturation (rScO
2
), mean arterial blood
pressure (MAP), acidbase balance, serum lactate and capillary refill
time), and had arterial catheter and/or central venous catheter in
place on clinical indication. Study exclusion criteria were congenital
malformations with potential impact on haemodynamic (HD) response
to inotropic therapy (congenital heart disease), congenital hydrops,
other unresolved cause of low blood flow (air leak), known metabolic
disease, situations where the treating physician considered a different
vasoactive treatment necessary or dobutamine contraindicated and
hypersensitivity to dobutamine or any other component of the study
medication. Written informed consent was signed by parents or
guardians before study inclusion.
2.1 |Study drug administration and PK sampling
Dobutamine 12.5 mg mL
1
concentrate for solution for infusion
(Dobutamine Claris, Claris Lifesciences Limited, UK) was diluted with
0.9% NaCl to a concentration of 1.25 mg mL
1
within 20 min before
administration. Study medication infusion was started immediately
What is already known about this subject
Dobutamine clearance has high interindividual variability
in neonates and children.
Individual plasma concentrations are linearly related to
the doses, with increasing uncertainty at higher levels.
Concentrationeffect relationship is described in neo-
nates with dose range of 2.57.5 μgkg
1
min
1
.
What this study adds
Describes pharmacokinetics and pharmacodynamics of
dobutamine in postnatal transitional period using popula-
tion nonlinear mixed effects modelling.
For clearance 62% of between subject variability is
related to birth weight and postmenstrual age.
Dobutamine effects to central haemodynamic parameters
and cerebral fractional tissue oxygen extraction are con-
centration related.
HALLIK ET AL.319
after the first echocardiographic assessment at a dose of
5μgkg
1
min
1
and raised by 5 μgkg
1
min
1
approximately every
30 min to a maximum of 20 μgkg
1
min
1
. Dose change times were
recorded with the precision of the nearest minute. Individual dose
escalation maximum was decided based on echocardiographic and
clinical findings. Dose-limiting effects of the study medication were (i)
persistent tachycardia (HR >200 min
1
in preterm and >180 min
1
in
term neonates) or arrhythmias; (ii) no additional effect of the last dose
increase; or (iii) sufficient effect of the last dose. To ensure adequate
intravascular volume, all neonates received a bolus of 10 mL kg
1
of
normal saline over 10 min, unless any fluid bolus was already received
within 4 h prior to study inclusion. Further cardiovascular support
with volume bolus and inotropes other than study medication was
provided on the decision of the treating physician without any restric-
tions in the study protocol.
Blood samples of 0.3 mL were collected from an indwelling arte-
rial line into Na-heparin vials 1530 min after every dobutamine dose
change and 15 min after termination of dobutamine infusion. It was
difficult to predict elimination half-life of dobutamine in the study
population, so PK and PD sampling times were balanced against clini-
cal feasibility to reach desired cardiovascular effects within a reason-
able time frame. Actual blood collection time was recorded to the
nearest minute. Blood was centrifuged immediately, and plasma
stored at 80C (up to 12 h storage at 20C was accepted). Dobu-
tamine concentrations were measured by ultra-high-performance liq-
uid chromatography coupled to tandem mass spectrometry. The
within- and between-run accuracy (coefficient of variability) was 95
99% (47%) and 94102% (35%), respectively, lower limit of quanti-
fication (LLOQ) 0.97 μgL
1
.
16
All concentrations below LLOQ were
included into the analysis with the value of 0.5 μgL
1
.
17
2.2 |Patient monitoring
Echocardiography was performed before the start of treatment and
approximately 2030 min after each dose escalation, and left ventric-
ular ejection fraction (LVEF) and CO of right and left ventricle (RVO,
LVO) were measured.
18
Patent ductus arteriosus diameter was mea-
sured by 2D imaging at the narrowest point. Intra- and interobserver
variability was assessed according to a recent recommendation.
19
HR, BP, peripheral arterial oxygen saturation (SaO
2
) and rScO
2
were monitored continuously and recorded with 2.5-s intervals by
BedBase software (University Medical Center Utrecht, the Nether-
lands). Demographic data, birth history, Score for Neonatal Acute
Physiology Perinatal Extension (SNAPPE II),
20
therapeutic interven-
tions and laboratory data were collected from hospital records. All
neonates were monitored for adverse events for 7 days after the end
of treatment with study medication.
2.3 |PKPD analysis
PKPD modelling was undertaken with nonlinear mixed-effects soft-
ware NONMEM version 7.3 (ICON Development Solutions, MD,
USA). The first-order conditional estimation method with interaction
was used. Dobutamine concentrationtime courses were analysed by
a 1-compartment PK models with first-order elimination, Michaelis
Menten (M-M) elimination and elimination by parallel first-order and
M-M processes was also tested.
CL and volume of distribution (V) were allometrically scaled to
population median BW and a maturation function, describing the mat-
uration of dobutamine CL with PMA was applied (Equation 1, Equa-
tion 2):
CLi=θCL BWi
Wst

0:75
PMAHill
i
PMAHill
50 +PMAHill
i
ð1Þ
Vi=θVBWi
Wst
 ð2Þ
where CL
i
and V
i
are the individual predicted values for CL and V, θ
CL
and θ
V
typical values for CL and V, BW
i
and PMA
i
are the patient's
individual BW and PMA, W
st
is the population median BW, Hill is the
sigmoidicity coefficient and PMA
50
is the PMA when the maturation
of the dobutamine CL reaches 50% of adult values.
21
PMA
50
and Hill's
coefficient for the maturation function of dobutamine CL were esti-
mated from PK data.
In covariate analysis parameterization of PK model with postnatal
age, antenatal glucocorticoid hormone administration,
coadministration of dopamine, blood haemoglobin and albumin con-
centration, patent ductus arteriosus diameter, baseline LVEF and
baseline RVO was tested.
Models were compared by objective function value (OFV), for a
nested model a parameter was added if their inclusion resulted in
improvement of OFV value >3.84 (P<.05 by likelihood ratio test for 1
degree of freedom).
Simultaneous PKPD modelling was undertaken with HD parame-
ters as PD effect, using the final linear PK structural model with Hill
coefficient and PMA
50
fixed to values estimated from PK data
(Table 2). HR, MAP, SaO
2
and rScO
2
data recorded during a 15 min
period (5 min before and 10 min after each dose change) were
selected and averaged over 1 min. Cerebral fractional tissue oxygen
extraction (cFTOE) was calculated as a ratio: (SaO
2
rScO
2
)/SaO
2
.
Adding an effect compartment with a first-order equilibration rate
constant (k
eo
) to the final PK structural model was tested with for HR,
MAP and cFTOE PKPD models, assuming that the amount of drug dis-
tributing into the effect compartment does not influence the overall
PK (Equation 3):
δCe
δt=keo Ckeo Ceð3Þ
where C is the plasma concentration, C
e
is the effect compartment
concentration and k
eo
is the equilibration rate constant between
effect and observed (plasma) compartments.
Baseline HD parameter values were estimated. Changes in HD
parameter values were explored using linear (Equation 4), E
max
(Equa-
tion 5) and sigmoidal E
max
(Equation 6) models:
320 HALLIK ET AL.
Eij =E0,i+SLiCij ð4Þ
Eij =E0,i+Emax,iE0,i
ðÞ
Cij
EC50,i+Cij
 ð5Þ
Eij =E0,i+Emax,iE0,i
ðÞ
Cγ
ij
ECγ
50,i+Cγ
ij
 ð6Þ
where E
ij
is the j-th observed HD parameter value at the
corresponding plasma or effect compartment concentration (C
ij
)of
the i-th individual, E
0,i
represents the estimated baseline value, SL
i
is
the slope of the linear relationship between E
ij
and C
ij
for the i-th indi-
vidual, E
max
,
i
is the estimated maximum HD parameter value for the i-
th individual, and EC
50,i
represents the concentration at half-maximal
effect for the i-th individual, γdescribes the steepness of concentra-
tioneffect relationship.
Between subject variability (BSV) was estimated for most of the
PK and PD model parameters using exponential variance model,
assuming log-normal parameter distribution. Individual estimates for
BSV for CL and V were highly correlated (r= 1.0), so a shared BSV
was used with an estimated scale factor applied for V. The residual
unexplained variability was explored to be described by additive, pro-
portional, or combined additive and proportional error models. The
residual error was estimated separately for the PK and PD
observations.
To assess the goodness of fit (GOF) of the models, population
and individual predicted vs. observed dobutamine concentration and
PD effect measurements, absolute value of individual weighted resid-
uals vs individual predictions, and conditional weighted residual error
vs time plots were used. A prediction-corrected visual predictive
check (VPC) was constructed and a nonparametric bootstrap with
1,000 replicates was undertaken, with software Perl speaks NON-
MEM
22
and R Version 3.6.0.
23
2.4 |Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to
corresponding entries in http://www.guidetopharmacology.org, the
common portal for data from the IUPHAR/BPS Guide to
PHARMACOLOGY.
3|RESULTS
Thirty-one neonates were recruited and data from 28 of them were
included in the final analysis. The reason for omission was therapeutic
hypothermia, considered to possibly affect the PK of dobutamine, in
2, and withdrawal of parental consent in 1 case. Demographic and
clinical data of the study patients are presented in Table 1. The main
underlying diagnoses were respiratory distress syndrome (14), early
onset neonatal sepsis defined as clinical and laboratory signs of
infection with antibacterial therapy for more than 3 days (8, none
were culture positive), perinatal asphyxia (2), meconium aspiration (2)
and foeto-foetal transfusion syndrome (2).
The maximal dobutamine dose was 10, 15 and 20 μgkg
1
min
1
in 1, 17 and 10 patients, respectively, median (range) infusion duration
3.5 (1.417.7) days. A total of 119 dobutamine plasma concentrations
were collected, in 2 samples dobutamine was not detected and in 9
TABLE 1 Demographic and clinical data of the study population.
Data are presented as median (range) or count (percent of the
population), if not stated differently
Patient characteristics (n= 28) Values
Demographic data
GA at birth (weeks) 30.4 (22.741.0)
GA <28 weeks 7 (25%)
GA 2832 weeks 9 (32%)
GA 3237 weeks 7 (25%)
GA >37 weeks 5 (18%)
Sex, male 18 (64%)
Birth weight, g 1618 (4654380)
Age at recruitment (h) 6 (228)
Birth history
Multiple birth 6 (21%)
Small for GA 2(7%)
Born from caesarean section 22(79%)
SNAPPE II score 16 (389)
Apgar score at 507(18)
Antenatal glucocorticoids (% of
neonates born <34 weeks of GA)
15 (71%)
Laboratory data at recruitment
Haemoglobin, g/L 163 (117203)
Albumin, g/L 27.7 (21.641.3)
pH 7.327 (7.1377.536)
HCO
3
, mmol/L 19.1 (15.224.9)
Concomitant medications
Dopamine 5 (18%)
Caffeine 5 (18%)
Opiates 6 (21%)
Sedatives 5 (18%)
Nitric oxide inhalation 1 (4%)
Ventilation support at recruitment
Invasive ventilation/FiO
2
23 (82%)/0.30(0.211)
Noninvasive ventilation or nasal
CPAP/FiO
2
5 (18%)/0.25(0.210.6)
Circulatory status at recruitment
RVO (mL/kg/min) 136 (75306)
LVO (mL/kg/min) 128 (71338)
LVEF (%) 64 (5179)
GA, gestational age; SNAPPE II, Score for Neonatal Acute Physiology
Perinatal Extension; RVO, right ventricular cardiac output; LVO, left
ventricular cardiac output; LVEF, left ventricular ejection fraction
HALLIK ET AL.321
samples dobutamine concentration remained below LLOQ. The maxi-
mum measured concentration was 330 μgL
1
. The doseconcentra-
tion graph is shown in Figure 1.
Intra- and interobserver variability for RVO, LVO and LVEF mea-
surements (mean ± SD) did not exceed 5 ± 5% and 12 ± 10%,
respectively.
3.1 |Dobutamine PK and PD
The PK data were described by 1-compartmental linear structural
model with proportional error model for residual variability. M-M elim-
ination did not improve fit to the observed data, combining M-M pro-
cess parallel to linear elimination in PK model resulted only in slightly
better fit (ΔOFV = 10). Therefore, to avoid over-parameterization, a
linear PK model was carried forward to PKPD modelling. Adding allo-
metric weight scaling and CL maturation function significantly
improved model fit (ΔOFV = 26 and 15, respectively) and lowered
BSV by 62%, without further improvement by other covariates.
The final linear PK model parameter estimates are presented in
Table 2, basic GOF plots in Figure 2 and prediction-corrected VPC in
Figure 3.
Concentration-related changes in RVO and LVEF were best
described with linear PD models and in LVO with a sigmoidal E
max
model (Table 3). Continuously measured HD parameters were best
described with a sigmoidal E
max
model with effect compartment
equilibration rate constant with mean effect time (k
eo-1
60 min) of
9 min for HR and without effect compartment equilibration rate
constant for MAP and cFTOE (Table 3). Final PKPD model parame-
ter estimates for RVO, LVO and LVEF are presented in Table 4
and for HR, MAP and cFTOE in Table 5. The observed lower mean
EC
50
estimates (2553 μgL
1
) and steep concentrationeffect rela-
tionship (γof 3.413.5) for HR, MAP and cFTOE indicate that
these changes take place at lower dobutamine concentrations. In
contrast, linearity of concentration-effect relationship within the
studied concentration range for RVO, LVEF and mean EC
50
esti-
mate of 117 μgL
1
for LVO suggest improvement of cardiac func-
tion throughout the studied dose range. Prediction-corrected VPC
plots for PD observations are presented in Figure 4, GOF plots of
effect predictions in Supporting information Figures S1S6 and
bootstrap analysis results in Supporting information Table S1.
Residual variability was best described with proportional error
model, remaining >50% in PK observations and between 520% in
PD observations.
TABLE 2 The linear pharmacokinetic model mean (standard error, SE) parameter estimates
Parameters Fixed effect θ(SE) BSV (SE)
a
Shrinkage
CL (L h
1
1618-g
1
) 41.2 (44.5) 29% (17.2%) 17%
V (L 1618-g
1
) 5.29 (0.821) 29% (17.2%) 17%
Shared BSV scale factor 1.34 (0.373) - -
Hill 2.67 (1.90) NE NE
PMA
50
(weeks) 37.4 (30.6) NE NE
Residual error (proportional) 0.581 (0.229) - 5%
θ, population typical parameter value; NE, not estimated; BSV, between subject variability;
a
presented as coefficient of variation, calculated as: (square root of ω
2
)100%; CL, clearance; V, volume of distribution; Hill, the sigmoidicity coefficient of
maturation of CL; PMA
50
, the PMA when the maturation of the CL reaches 50% of adult values
FIGURE 1 Measured dobutamine plasma
concentrations at different continuous infusion
rates. The connected observation points
represent the same patient
322 HALLIK ET AL.
FIGURE 2 Basic goodness-of-fit plots of the final linear pharmacokinetic model: (A) observed vs population predicted dobutamine plasma
concentrations (C); (B) observed vs individual predicted dobutamine plasma concentrations (C); (C) absolute value of individual weighted residuals
(|iWRES|) vs individual predictions; (D) conditional weighted residuals (CWRES) over time (log-scale)
FIGURE 3 Prediction-corrected visual
predictive check (VPC) of 1000 simulated
concentrationtime datasets from the final linear
pharmacokinetic model. Open circles represent
the observations, solid line the 50
th
, dashed lines
the 2.5
th
and 97.5
th
percentiles, shaded areas the
95% confidence intervals of the corresponding
predicted dobutamine concentrations
TABLE 3 Objective function values of tested pharmacokineticpharmacodynamic models
PD model structure RVO LVO LVEF HR HR + K
EO
MAP MAP+K
EO
cFTOE cFTOE+K
EO
Linear 1849 1806 1451 7655 7598 5418 5418 5080 5108
E
max
1847 1801 1451 7654 7513 5240 5145 5288 5139
Sigmoidal E
max
1847 1797 1451 7457 7411 5076 5101 5567 5152
RVO, right ventricular cardiac output; LVO, left ventricular cardiac output; LVEF, left ventricular ejection fraction; HR, heart rate; K
EO
, equilibration rate
constant between effect- and observed (plasma) compartment, indicating that effect compartment was added to the model; MAP, mean arterial blood
pressure; cFTOE, cerebral fractional oxygen extraction; underlined objective function values indicate the final models.
HALLIK ET AL.323
3.2 |Clinical outcome
Twenty-one serious adverse events in 14 patients were observed dur-
ing the study period. Four patients died of gastric perforation (1),
necrotising enterocolitis with intestinal perforation (1) or pulmonary
intestinal emphysema (2) combined with haemolysis and pulmonary
hypertension in 1 case. Deterioration of respiratory status requiring
intubation with invasive ventilation and intestinal perforation
occurred in 2 patients each, 1 patient had ileus as a complication of
surgery for anal atresia. None of the aforementioned serious adverse
events were considered to be related to dobutamine.
Twenty-seven patients had cerebral ultrasonography performed
within the follow-up period, intraventricular haemorrhage grade IIIIV
occurred in 2, grade I-II in 4, periventricular leucomalacia in 3 and
other intracranial pathologies in 3 patients.
4|DISCUSSION
The present study describes for the first time dobutamine population
PK and PD in critically ill neonates during the postnatal transitional
period. The main findings were that: (i) within the clinically relevant
dose range, dobutamine PK was well described by 1-compartment lin-
ear model; (ii) PK BSV was related to BW and PMA; (iii) the changes in
RVO, LVO, LVEF, HR, MAP and cFTOE were concentration related
and described by linear or sigmoidal E
max
models.
4.1 |Dobutamine PK
Dobutamine is metabolized predominantly through plasma catechol-
O-methyltransferase and sulfoconjugation, with renal elimination of
inactive metabolites and small extent of unchanged dobutamine.
11,24
TABLE 4 Final pharmacokineticpharmacodynamic (PKPD) model mean (standard error, SE) parameter estimates for right and left ventricular
cardiac output (RVO; LVO) and left ventricular ejection fraction (LVEF)
Model and parameters Fixed effect θ(SE) BSV (SE)
a
Shrinkage
PKPD model for RVO effect
CL (L h
1
1618-g
1
) 41.0 (3.15) 27% (18.7%) 18%
V (L 1618-g
1
) 5.31 (0.753) 27% (18.7%) 18%
Shared BSV scale factor 1.50 (0.479) - -
E
0
(mL kg
1
min
1
) 151 (12.8) 41% (22.2%) 3%
SL 0.214 (0.067) NE NE
Pharmacokinetic residual error (proportional) 0.583 (0.052) - 8%
Pharmacodynamic residual error (proportional) 0.184 (0.014) - 8%
PKPD model for LVO effect
CL (L h
1
1618-g
1
) 40.7 (3.03) 25% (17.5%) 21%
V (L 1618-g
1
) 5.14 (0.726) 25% (17.5%) 21%
Shared BSV scale factor 1.33(0.490) - -
E
0
(mL kg
1
min
1
) 131 (9.64) 36% (19.8%) 3%
γ2.82 (1.25) NE NE
EC
50
(μgL
1
) 117 (37.0) NE NE
E
max
(mL kg
1
min
1
) 157 (21.8) 44% (39.7%) 29%
Pharmacokinetic residual error (proportional) 0.589 (0.053) - 11%
Pharmacodynamic residual error (proportional) 0.167 (0.015) - 11%
PKPD model for LVEF effect
CL (L h
1
1618-g
1
) 41.2(3.22) 28% (19.3%) 17%
V (L 1618-g
1
) 5.26(0.753) 28% (19.3%) 17%
Shared BSV scale factor 1.38(0.434) - -
E
0
(%) 63.5 (1.46) 9% (5.6%) 10%
SL 0.0285 (0.0145) NE NE
Pharmacokinetic residual error (proportional) 0.580 (0.051) - 7%
Pharmacodynamic residual error (proportional) 0.098 (0.007) - 7%
θ, population typical parameter value; NE, not estimated; BSV, between subject variability;
a
presented as coefficient of variation, calculated as: (square root of ω
2
)100%; CL, clearance; V, volume of distribution; E
0
, estimated baseline value of PD
parameter; SL is the slope of the linear relationship between effect and concentration; γ, steepness of concentrationeffect relationship; EC
50
,
concentration at half-maximal effect; E
max
, estimated maximum value of PD parameter
324 HALLIK ET AL.
In previous paediatric studies an extremely wide BSV in dobutamine
plasma CL has been noticed
7,9
and explained by variation in
sulfoconjugation and renal function.
11
Maturation of these elimination
processes is not well understood. In the present study, the variation in
CL was well described with allometric scaling to population median
BW with power coefficient of 0.75 and exponential E
max
maturation
function with estimation of PMA
50
and Hill coefficient from PK
data.
21
The estimated mean parameter values of 37.4 weeks for
PMA
50
and 2.67 for Hill coefficient are similar to those identified for
CL maturation in other drugs in neonates.
21
This approach yielded a
shared BSV coefficient of 29% for CL and V, which is notably smaller
than described earlier for dobutamine CL.
There is 1 study reporting highly variable V of dobutamine with a
mean (range) of 1.14 (0.095.65) L kg
1
in paediatric patients aged
1 month to 16 years,
12
the mean value being higher than reported in
adults (0.202 L kg
1
).
25
The typical value for V of 5.29 L 1618-g
1
or
3.27 L kg
1
in the present study population is even higher than the
paediatric study.
12
Higher V of a water-soluble agents in neonates in
their first days of life can be explained by significantly higher total
body water content, which undergoes major reduction (accompanied
TABLE 5 Final pharmacokineticpharmacodynamic (PKPD) model mean (standard error, SE) parameter estimates for heart rate (HR), mean
arterial blood pressure (MAP) and cerebral fractional tissue oxygen extraction (cFTOE)
Model and parameters Fixed effect θ(SE) BSV (SE)
a
Shrinkage
PKPD model for HR effect
CL (L h
1
1618-g
1
) 42.3 (3.22) 27% (18.0%) 15%
V (L 1618-g
1
) 5.42 (0.766) 27% (18.0%) 15%
Shared BSV scale factor 1.72 (0.421) - -
E
0
(min
1
) 138 (4.2) 15% (8.1%) 4%
γ3.36 (0.326) NE NE
K
E0
(h
1
) 6.59 (2.18) NE NE
EC
50
(μgL
1
) 39.2 (5.56) 50% (32.2%) 21%
E
max
(min
1
) 172 (2.5) 5% (3.1%) 28%
Pharmacokinetic residual error (proportional) 0.590 (0.052) - 3%
Pharmacodynamic residual error (proportional) 0.051 (0.001) - 3%
PKPD model for MAP effect
CL (L h
1
1618-g
1
) 37.2 (2.88) 24% (16.6%) 4%
V (L 1618-g
1
) 4.88 (0.958) 24% (16.6%) 4%
Shared BSV scale factor 3.62 (0.760) - -
E
0
(mmHg) 39.7 (1.75) 22% (11.8%) 2%
γ13.5 (2.94) NE NE
EC
50
(μgL
1
) 25.4 (2.00) NE NE
E
max
(mmHg) 41.9 (2.19) 26% (13.9%) 4%
Pharmacokinetic residual error (proportional) 0.675 (0.062) - 2%
Pharmacodynamic residual error (proportional) 0.065 (0.001) - 2%
PKPD model for cFTOE effect
CL (L h
1
1618-g
1
) 37.2 (3.61) 35% (21.5%) 9%
V (L 1618-g
1
) 4.80 (0.993) 35% (21.5%) 9%
Shared BSV scale factor 2.42 (0.333) - -
E
0
0.227 (0.023) 50% (26.8%) 2%
γ3.65 (0.573) NE NE
EC
50
(μgL
1
) 52.9 (7.26) NE NE
E
max
0.206 (0.027) 60% (36.2%) 9%
Pharmacokinetic residual error (proportional) 0.653 (0.061) - 2%
Pharmacodynamic residual error (proportional) 0.181 (0.004) - 2%
θ, population typical parameter value; NE, not estimated; BSV, between subject variability;
a
presented as coefficient of variation, calculated as: (square root of ω
2
)100%; CL, clearance; V, volume of distribution; E
0
, estimated baseline value of PD
parameter; SL is the slope of the linear relationship between effect and concentration; γ, steepness of concentration-effect relationship; K
E0
, the
equilibration rate constant between effect- and observed (plasma) compartments; EC
50
, concentration at half-maximal effect; E
max
, the estimated
maximum value of PD parameter
HALLIK ET AL.325
by proportional weight loss) within the first 34 days of life,
26,27
as
also described for milrinone.
28
4.2 |Dobutamine PD
Dobutamine is known to increase HR and CO in neonates, whereas
the effect of BP varies from no effect to minor increase.
7-9,13,14,29
According to our results, these effects occur at different concentra-
tion. The effect on MAP and HR can be observed at relatively low
concentrations, with maximum effect reached within concentrations
of 50 and 80 μgL
1
, respectively. The increase of mean HR from 138
to 172 min
1
is in accordance with previous studies.
7-9,13,29
The
increase rather than decrease of MAP in response to dobutamine is
potentially explained by developmental differences in vascular α- and
β- AR expression. During early development cardiovascular α-AR
expression is upregulated while maturation of β-AR lags behind,
30
pre-
term neonates are likely to respond to dobutamine with attenuated
decreases in systemic vascular resistance and thus with more pro-
nounced increase in BP.
6
The additional effect on CO can be achieved with higher doses at
least up to concentration of 200 μgL
1
. The improvement of CO
FIGURE 4 Prediction-corrected visual predictive check (VPC) of 1000 simulated effecttime datasets from the final pharmacokinetic
pharmacodynamic models. Circles represent the observations, solid line the 50th, dashed lines the 2.5th and 97.5th percentiles, shaded areas the
95% CIs of the corresponding model predicted haemodynamic parameter values: (A) right ventricular cardiac output (RVO); (B) left ventricular
cardiac output (LVO); (C) left ventricular ejection fraction (LVEF); (D) heart rate (HR); (E) mean arterial blood pressure (MAP); (F) cerebral fractional
tissue oxygen extraction fraction (cFTOE)
326 HALLIK ET AL.
beyond maximum HR effect implicates the role of improved myocar-
dial function and/or decreased systemic vascular resistance. Further
increase in CO with dobutamine infusion rates 1020 μgkg
1
min
1
has
also been shown in critically ill children.
8
Although with limited efficacy, dobutamine has also been shown
to increase superior vena cava flow, which is considered to reflect
cerebral blood flow.
29,31
The present study describes dobutamine
effect to cFTOE, as a surrogate for cerebral blood flow. Decrease in
cFTOE with dobutamine may refer to increase in cerebral blood flow.
The aim of neonatal circulatory management is to prevent cere-
bral hypoperfusion particular in preterm neonates where the cerebral
autoregulation may be absent. Although the role of inotropes in pre-
vention of prematurity-related brain injury has been difficult to estab-
lish, there is some evidence that early administration of dobutamine
may be relatively safe. In a foetal sheep hypoxia-induced brain injury
model, dobutamine pretreatment decreased neuroinflammation in the
white matter and caudate and did not exacerbate cerebral injury or
inflammation in the sham group.
4
In a neonatal study dobutamine was
found to be associated with greater increase in systemic blood flow,
reduced rates of severe periventricular/intraventricular haemorrhage
and fewer disabilities at age 3 years, but combined rates of death or
disability similar, compared with infants treated with dopamine.
29,32
The rate of serious cerebral complications in our study patients born
before 32 weeks of gestation (2/16 for intraventricular haemorrhage
IIIIV and 2/16 for periventricular leucomalacia) was comparable to
that described in previous studies in extremely and very preterm
infants receiving early dobutamine treatment.
29,31
The present PKPD analysis included most of the well described
effects of dobutamine.
33
Describing population HD effect of dobu-
tamine as a function of concentration gives the confidence that at the
dose range of 520 μgkg
1
min
1
the medication is effective.
4.3 |Limitations of the study
The limited number of patents, and limited PK sampling, did not
yield informative data on V (hence BSV could not be separately esti-
mated for CL and V). As the smallest neonate weighed <500 g, only
35 plasma samples could be taken for research purposes, although
an analytical micro-method for plasma sample volumes of 20 μL
was developed.
16
Having only a few PK samples >200 μgL
1
in the
dataset, we may not have been able to capture this end sufficiently.
The relatively small number of patients limited the covariate analy-
sis. Although adding postnatal age, concomitant medications, sever-
ity of illness/status in covariate analysis did not improve PK model
fit in our study, a larger and more variable study sample may be
needed to draw firm conclusions.
34
In neonatal PK studies, an
important limitation/source of residual error is drug administration
accuracy. Dilution of the formula, low infusion rates and large dead
space may lead to discrepancy between the prescribed and actual
infusion rates, resulting in PK observation residual error of >50%.
Nevertheless, this considerably homogenous neonatal study popula-
tion allowed us to model PK of dobutamine, describing the
maturation of CL with PMA, and rich PD effect sampling allowed
identification of relationships between concentration and HD effects
with acceptable accuracy. Moreover, this study was conducted in
real-life conditions, e.g. critically ill neonates on their first days of
life, with all related challenges.
In conclusion, within the clinically relevant dose range, dobu-
tamine PK in neonates is linear. BSV of dobutamine CL is partly
explained by PMA and BW. Dobutamine effects on HD parameters as
CO, LVEF, HR, MAP and cFTOE are concentration related during the
period of transitional circulation. High BSV of the PD response sug-
gests need for individual dose titration rather than targeting specific
dosing regimen in neonates receiving dobutamine for stabilization of
transitional circulation.
ACKNOWLEDGEMENTS
The study was funded by the Estonian Research Council (PUT1197).
MH received support from the University of Tartu Foundation (Pro-
fessor Lembit Allikmets' and Heino Kruse's foundations).
The authors have no conflicts of interest to declare.
CONTRIBUTORS
M.H. conceived the study, participated in its design, collected,
analysed the data and drafted the manuscript. M.-L.I. conceived the
study, collected the data and was involved in revision of the manu-
script. J.F.S. supervised the data analysis process and revised the man-
uscript. H.S. participated in data analysis and revision of the
manuscript. T.J., M.R., K.U., K.K. and M.S. collected the data and were
involved in revising the manuscript. K.T., R.V. and K.K. supported the
work with liquid chromatographymass spectrometry quantification
of dobutamine. J.S. participated in study design process and critically
revised the manuscript. T.M. conceived the study, participated in its
design and drafted the manuscript. All authors read and approved the
final manuscript.
DATA AVAILABILTY STATEMENT
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
ORCID
Maarja Hallik https://orcid.org/0000-0001-9703-0158
Joseph F. Standing https://orcid.org/0000-0002-4561-7173
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SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section at the end of this article.
How to cite this article: Hallik M, Ilmoja M-L, Standing JF,
et al. Population pharmacokinetics and pharmacodynamics of
dobutamine in neonates on the first days of life. Br J Clin
Pharmacol. 2020;86:318328. https://doi.org/10.1111/bcp.
14146
328 HALLIK ET AL.
... Full details of the study can be found elsewhere. 17 Briefly, neonates hospitalised to NICU within the first 72 hours of life and needing inotropic therapy were studied. Written informed consent for genetic analysis was signed by parents or guardians separately from the main dobutamine PKPD study consent before study inclusion. ...
... Monitoring and recording of heart rate (HR) and mean arterial pressure (MAP) were started before dobutamine infusion and continued throughout the treatment period, left ventricular ejection fraction (LVEF), left and right ventricular cardiac output (LVO, RVO) were measured before and repeatedly during the dobutamine treatment. 17 The effect of SNPs on haemodynamic parameters (HR, MAP, LVEF, LVO and RVO) was analysed with linear mixed−effects models separately for each SNP. The model building process was started with full model including gestational age (GA), Score for Neonatal Acute Physiology Perinatal Extension (SNAPPE-II) 18 , age at recruitment, antenatal glucocorticoid administration (only if GA <34 weeks), exposure to dobutamine measured as the area under the time-plasma concentration curve (AUC) calculated according to the published dobutamine population pharmacokinetic model using empirical Bayes estimates of pharmacokinetic parameters in each neonate, and interaction between AUC and SNP as fixed effects and random intercept and random slope of AUC for each neonate. ...
... The model building process was started with full model including gestational age (GA), Score for Neonatal Acute Physiology Perinatal Extension (SNAPPE-II) 18 , age at recruitment, antenatal glucocorticoid administration (only if GA <34 weeks), exposure to dobutamine measured as the area under the time-plasma concentration curve (AUC) calculated according to the published dobutamine population pharmacokinetic model using empirical Bayes estimates of pharmacokinetic parameters in each neonate, and interaction between AUC and SNP as fixed effects and random intercept and random slope of AUC for each neonate. 17 Stepwise backward elimination was used to retain only statistically significant effects into model. Autocorrelation structure of order 1 with time after dose (in minutes) as covariate was used in models for HR and MAP. ...
Preprint
Aim: To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the hemodynamic response to dobutamine in critically ill neonates. Methods: Alleles in the known genetic single nucleotide polymorphisms in β1 and β2 adrenoceptor (AR) genes and Gs protein α-subunit gene (GNAS) possibly affecting inotropic effect were identified in patients of neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were used to describe the effect of genetic polymorphisms to heart rate (HR), left ventricular output (LVO) and right ventricular output (RVO) during dobutamine treatment. Results: 26 neonates (5 term, 21 preterm) were studied. Dobutamine plasma concentration and exposure time respective HR (adjusted to gestational age) is dependent on β1-AR Arg389Gly polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3 (15.8 – 60.7) bpm per AUC of 100 mg·h, p=0.0005. LVO (adjusted to antenatal glucocorticoid administration and illness severity) and RVO (adjusted to gestational age and illness severity) is dependent on GNAS c.393C>T polymorphism so that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes LVO and RVO increase with dobutamine treatment, 24.5 (6.2 – 42.9) mL kg-1 min-1 per AUC of 100 mg·h, p=0.0116 and 33.2 (12.1 – 54.3) mL kg-1 min-1 per AUC of 100 mg·h, p=0.0025, respectively. Conclusion: In critically ill neonates, β1-AR Arg389Gly and GNAS c.393C>T polymorphisms may play a role in the haemodynamic response to dobutamine during the first hours and days of life.
... More systems-focused PK/PD modelling attempts to take into consideration the evident non-stationarity of biological systems, across multiple temporal ranges. The continual temporal flux of physiological systems may be influenced by a variety of interconnected factors such as circadian rhythms (Al-Kofahi et al., 2020) systemic aging/ maturation stage (Anderson et al., 2020;Hallik et al., 2020;Nishikawa et al., 2020;Stader et al., 2020) or even dynamic epigenetic modifications (Fisel et al., 2016;Wu et al., 2015;Zhang et al., 2017a,b). In addition, temporal fluxes may also result themselves from the actual drug introduction itself. ...
Chapter
Systems pharmacology is a recently developed scientific field concerning the appreciation of novel therapeutic networks that enables biomedical scientists to understand the actions of medicinal agents in a multidimensional mechanistic manner. A thorough appreciation of systems pharmacology requires the synergistic integration of multiple disciplines including, receptor biology, network theory, high-dimensionality data acquisition and advanced informatics deconvolution. Appreciating pharmacological signaling pathways at a systemic network level holds the promise that this practice can improve the efficiency of therapeutic development. This advancement is associated with the ability of systems pharmacology to generate a highly nuanced and quantitative appreciation of simultaneous medicinal signaling across multiple physiological domains. Implicit in this process is the potential benefit that multi-level systems medication, as opposed to agents with a limited therapeutic scope, can engender upon disease networks. In this article we shall outline the benefits of this data and biology convergence for both therapeutic discovery, refinement and precision targeting.
... 28 Our mean observed weight-normalised clearance is consistent with the model recently developed by Hallik et al. in neonates. 29 Indeed, when incorporating the mean gestational age and body weight of our patients within their equation for dobutamine clearance calculation, the obtained calculated value of 8.67 l/h/kg is very close to our mean observed value of 9.43 l/h/kg. ...
Article
Dobutamine is particularly suited to treatment of haemodynamic insufficiency caused by increased peripheral vascular resistance and myocardial dysfunction in the preterm infant. Knowledge of the elimination half-life is essential to estimate the steady state when its efficacy/safety can be evaluated. Analysis of pharmacokinetic data in ten preterm newborns treated with a new neonatal formulation of dobutamine (IMP) after screening for haemodynamic insufficiency within the first 72 h from birth. Blood samples were withdrawn at the end of IMP infusion and at a random time after the end of infusion (5 min, 15 min, 45 min, 2 h and 6 h). IMP concentration in each sample was measured by ultra-high performance liquid chromatography with electrochemical detection. Median duration of IMP infusion was 37.7 h (IQR 21.2). Calculated IMP half-life ranged between 3.06 and 36.1 min (median 10.6 min), leading to a time to reach the steady-state concentration between 15 min and >2 h. Adverse events were not related to IMP. The wide variability in dobutamine metabolism in preterm infants requires awareness about the risk of under- or overtreatment. A delay of up to 3 h might be required before drawing blood samples to evaluate the effective dose. Small trials suggest dobutamine as the optimal drug in the preterm infant with haemodynamic insufficiency after birth. Age-related differences in drug pharmacokinetics may result in suboptimal treatments. The lack of formal studies in preterms results in inadequate data on efficacy and safety. This study provides data on the variability of the elimination half-life of dobutamine in the very preterm infant during transitional circulation. There is a wide variation in the time to reach the plasma concentration corresponding to steady state, the moment when its efficacy/safety can be reliably evaluated. This information is crucial for planning future trials on cardiovascular support.
Article
Aim: To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the hemodynamic response to dobutamine in critically ill neonates. Methods: Alleles in the known genetic single nucleotide polymorphisms in β1 and β2 adrenoceptor (AR) genes and Gs protein α-subunit gene (GNAS) possibly affecting inotropic effect were identified in patients of neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were used to describe the effect of genetic polymorphisms to heart rate (HR), left ventricular output (LVO) and right ventricular output (RVO) during dobutamine treatment. Results: 26 neonates (5 term, 21 preterm) were studied. Dobutamine plasma concentration and exposure time respective HR (adjusted to gestational age) is dependent on β1-AR Arg389Gly polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3 (15.8 - 60.7) bpm per AUC of 100 μg L-1 h, p=0.0008. LVO (adjusted to antenatal glucocorticoid administration and illness severity) and RVO (adjusted to gestational age and illness severity) is dependent on GNAS c.393C>T polymorphism so that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes LVO and RVO increase with dobutamine treatment, 24.5 (6.2 - 42.9) mL kg-1 min-1 per AUC of 100 μg L-1 h, p=0.0095 and 33.2 (12.1 - 54.3) mL kg-1 min-1 per AUC of 100 μg L-1 h, p=0.0025, respectively. Conclusion: In critically ill neonates, β1-AR Arg389Gly and GNAS c.393C>T polymorphisms may play a role in the haemodynamic response to dobutamine during the first hours and days of life.
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Pharmacokinetics and -dynamics show important changes throughout childhood. Studies on the different maturational processes that influence developmental pharmacology have been used to create population PK/PD models that can yield individualized pediatric drug dosages. These models were subsequently translated to semi-physiologically or physiology-based PK (PBPK) models that support predictions in pediatric patient cohorts and other special populations. Although these translational efforts are crucial, these models should be further improved towards individual patient predictions by including knowledge on non-maturational covariates. These efforts are needed to ultimately get to systems pharmacology models for children. These models take developmental changes relating to the pediatric dynamical system into account but also other aspects that may be of importance such as abnormal body composition, pharmacogenetics, critical illness and inflammatory status.
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Aim(s): When different models for weight and age are used in paediatric pharmacokinetic studies it is difficult to compare parameters between studies or perform model-based meta-analysis. This study aimed to compare published models with the proposed standard (allometric weight(0.75) and sigmoidal maturation function). Methods: A systematic literature search was undertaken to identify published clearance (CL) reports for gentamicin and midazolam and all published models for scaling clearance in children. Each model was fitted to the CL values for gentamicin and midazolam, and the results compared with the standard model (allometric weight exponent of 0.75, along with a sigmoidal maturation function estimating the time in weeks of postmenstrual age to reach half the mature value and a shape parameter). For comparison we also looked at allometric size models with no age effect, the influence of estimating the allometric exponent in the standard model and, for gentamicin, using a fixed allometric exponent of 0.632 as per a study on glomerular filtration rate maturation. Akaike Information Criteria (AIC) and visual predictive checks were used for evaluation. Results: No model gave an improved AIC in all age groups, but one model for gentamicin and three models for midazolam gave slightly improved global AIC fits albeit using more parameters: AIC drop (number of parameters) -4.1(5), -9.2(4), -10.8(5) and -10.1(5) respectively. The 95%CI of estimated CL for all top performing models overlapped. Conclusions: No evidence to reject the standard model was found; given the benefits of standardised parameterisation, it's use should therefore be recommended.