Population Pharmacokinetics of Rabeprazole and Dosing Recommendations for the
Treatment of Gastro-Oesophageal Reflux Disease in Children Aged 1-11 Years
S ARAH M C L EAY 1 , B RUCE G REEN 1 , W ILLIAM T REEM 2 , A N T HYSSEN 3 , E RIK M ANNAERT 3 & H OLLY K IMKO 2
Model Answers Pty. Ltd., Brisbane, QLD, Australia; 2 Janssen Research & Development, LLC, Raritan, New Jersey, USA; 3 Janssen Research & Development, LLC, Turnhout, Belgium.
x Bioavailability
IV Dose
D1 after ALAG
1000
100
10
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1
10
100
1000
0.1
50
200
500
1600
1200
−8
−6
200
4
2
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0
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400
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−6
CWRES
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1000
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CWRES
AUC (ng.hr/mL)
1200
20
CWRES
1400
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−2
M ETHODS
5
Individual Predicted Concentration (ng/mL)
4
1600
100
0
LLOQ
2
2
Median adult, 10 mg dose
5th−95th adult percentiles, 10 mg dose
2.5 mg dose
5 mg dose
10 mg dose
12.5 mg dose (10 + 2.5 mg)
15 mg dose (10 + 5 mg)
20 mg dose
10
400
1000
5
Figure 4: Predicted AUC Across Weight Overlaid with 90%
Predicted Adult AUC Range for a Dose of 10 mg
1
Population Predicted Concentration (ng/mL)
Frequency
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200
Peripheral
Compartment
(Vp)
CLp
Observed Concentration (ng/mL)
Central
Compartment
(Vc)
KA
Depot
Compartment
LLOQ
2000
Population Predicted Concentration (ng/mL)
1800
Subjects
PK data were obtained from seven Phase 1 and
two Phase 3 studies.
A total of 4417 PK observations were obtained
from 597 subjects aged 6 days to 55.7 years, with
body weights of 1.15-100 kg.
LLOQ
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1
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0.1
A IM
To develop a population pharmacokinetic
(PK) model for rabeprazole that describes
concentration-time data arising from Phase 1 and
3 studies conducted in adults, children, neonates,
and preterm infants, and propose GORD dosing
recommendations for subjects aged 1-11 years.
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0.1
Oral Dose
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0.1
Figure 1: Schematic of the Structural PK Model
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Observed Concentration (ng/mL)
●
50
An enteric-coated granule formulation for
rabeprazole has been developed for children <12
years of age.
Figure 2: Goodness of Fit Plots
10
GORD is estimated to affect a quarter of all
children and adolescents.
Visual predictive checks confirmed that the
model had good simulation characteristics across
all ages and routes of administration (Figure 3).
1000
Standard goodness of fit plots showed that
the model described the data well and was
unbiased (Figure 2; note that a mirror plot [top
right] demonstrates that the observed versus
population predicted concentration plot [top left]
is as expected due to censoring of data below the
lower limit of quantification [LLOQ]).
100
Rabeprazole sodium is a proton pump inhibitor indicated for the short-term treatment of
symptomatic gastro-oesophageal reflux disease
(GORD) in patients aged ≥12 years.
10
R ESULTS (C ONTINUED )
1
B ACKGROUND
Observed Concentration (ng/mL)
1
500
100
1000
1500
0
5
Time Since First Dose (hr)
10
15
20
25
Time Since Last Dose (hr)
Weight (kg)
Figure 3: Visual Predictive Check for the Final Model by Age
●
1000.0
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10.0
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0
1
The PK of rabeprazole after an oral dose was
best described by a zero- first-order absorption
and 2-compartment disposition (Figure 1).
Weight and age were included in the structural
model to describe clearance (CL) and central volume of distribution (Vc ).
Other covariates included formulation on
bioavailability and absorption parameters, and
fed status on absorption rate (KA; Table 1).
C ONCLUSIONS
The model described the PK of rabeprazole
with good precision following administration of
rabeprazole across a range of doses and in a range
of formulations.
A dosage regimen of 5 mg once daily for subjects
<15 kg, and 10 mg for subjects ≥15 kg, is recommended for the treatment of symptomatic GORD
in patients aged 1-11 years.
●
2
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0.1
Pharmacokinetics
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100.0 1000.0
Concentration (ng/mL)
The final model was used to determine doses
for paediatric subjects aged 1-11 years to achieve
areas under the concentration time-curve (AUCs)
within the target 90% adult AUC range obtained
following a 10 mg rabeprazole dose.
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1000.0
Subjects <1 yr
100.0
Population PK Modelling
Nonlinear mixed effects modelling was performed using NONMEM.
Covariates considered during model development included weight, age, sex, race, creatinine
clearance, hepatic function, formulation, feeding
status, and route of administration.
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7
Time Since Last Dose (hr)
Dosing Recommendations
Table 1: Parameter Estimates for the Final Model
Parameter
Estimate (%SE)
Clearancea (CL, L/h)
15.5 (2.0)
Effect of weight†
0.353 (10.6)
AGE50 (yrs)
0.283 FIX
γAGE †
1.62 (20.1)
Central volume of distributiona (Vc , L)
15.3 (2.8)
Effect of weight†
0.370 (14.5)
AGE50 (yrs)
0.310 (29.6)
γ AGE †
1.01 (21.0)
Intercompartmental clearance (CLp , L/h)
3.09 (5.1)
Peripheral volume of distribution (Vp , L)
28.9 (16.5)
Bioavailability: Ph1 and Ph3 granules (BIO, %)
42.2 (5.2)
Bioavailability: tablet and to-be-marketed granules (BIO, %) 56.0 (3.0)
Absorption lag time: tablet formulation (ALAG, h)
2.00 (0.1)
Absorption lag time: Ph1 and Ph3 granules (ALAG2 , h)
0.467 (7.6)
Absorption lag time: to-be-marketed granules (ALAG3 , h) 0.633 (2.4)
Effect of nasogastric administration†
1.31 (6.3)
Duration of input into the depot compartment (D1, h-1 )
1.36 (4.4)
Effect of tablet formulation†
0.576 (9.0)
BSV (%SE) BOV (%SE)
41.2 (26.4)
14.2 (35.4)
39.2 (30.1)
103 (26.5)
45.9 (51.7)
109 (11.3)
48.8 (13.6)
37.9 (12.7)
42.5 (17.7)
52.3 (11.9)
Absorption rate constant (KA, h-1 )
1.72 (6.9)
39.1 (21.3) 36.5 (15.4)
Effect of fed status (not fasted or unknown status)†
0.344 FIX
Effect of tablet formulation†
1.38 (9.6)
RUV for oral formulations (%CV)
32.4 (3.6)
RUV for the IV formulation (%CV)
17.9 (8.7)
SE = standard error; BSV = between subject variability as %CV; BOV = between occasion variability as
%CV; AGE50 = age in years at which parameter has reached 50% of adult value; a parameterised as
γ
Parameter = θ9 · (Weight/70)Effect of weight · (Ageγ /(AGE50 + Ageγ )); † no units.
Figure 4 shows predicted typical
AUC across weight for a range of
dosing regimens.
The model supported a dosage
regimen of 5 mg once daily for
subjects <15 kg, with the typical
AUC falling within the target adult
range (284-581 ng.hr/mL as shown
by the grey shaded area in Figure
4).
For subjects ≥15 kg, a 10 mg once
daily dose best achieves the target
AUC across weight.