mechanism-based pk-pd model of remoxipride with rat-to ... · models were tested and evaluated...
TRANSCRIPT
Mechanism-based PK-PD model of remoxipride with rat-to-human extrapolation: Mechanism-based PK-PD model of remoxipride with rat-to-human extrapolation: Mechanism-based PK-PD model of remoxipride with rat-to-human extrapolation:
characterizing remoxipride CNS target site PK and positive systems homeostatic feedback characterizing remoxipride CNS target site PK and positive systems homeostatic feedback characterizing remoxipride CNS target site PK and positive systems homeostatic feedback characterizing remoxipride CNS target site PK and positive systems homeostatic feedback
Jasper Stevens1, Bart Ploeger2, M. Hammarlund-Udenaes3, Piet Hein van der Graaf4, Meindert Danhof1, Elizabeth C.M. de Lange1Jasper Stevens1, Bart Ploeger2, M. Hammarlund-Udenaes3, Piet Hein van der Graaf4, Meindert Danhof1, Elizabeth C.M. de Lange11 Division of Pharmacology, LACDR, Leiden, NL, 2 LAP&P Consultants, Leiden, NL, Uppsala University, SE 4Pfizer Global R&D, Sandwich, Kent, UK1 Division of Pharmacology, LACDR, Leiden, NL, 2 LAP&P Consultants, Leiden, NL, Uppsala University, SE 4Pfizer Global R&D, Sandwich, Kent, UKDivision of Pharmacology, LACDR, Leiden, NL, LAP&P Consultants, Leiden, NL, Uppsala University, SE Pfizer Global R&D, Sandwich, Kent, UK
Results Pharmacokinetics cont.)Introduction Results Pharmacokinetics cont.)Introduction Results Pharmacokinetics cont.)Introduction
Our ultimate aim is to develop a translational MB PKPD model for dopaminergic
Results Pharmacokinetics cont.)
Our ultimate aim is to develop a translational MB PKPD model for dopaminergic plasma Brain-ECF
Our ultimate aim is to develop a translational MB PKPD model for dopaminergic
compounds, for the prediction of PKPD relationships following different routes of plasma Brain-ECFcompounds, for the prediction of PKPD relationships following different routes of plasma Brain-ECFcompounds, for the prediction of PKPD relationships following different routes of
administration and animal-human extrapolation. To that end, information on drug administration and animal-human extrapolation. To that end, information on drug
specific- and biological system specific parameters is needed. Many dopaminergic IN data
specific- and biological system specific parameters is needed. Many dopaminergic IN data
specific- and biological system specific parameters is needed. Many dopaminergic
compounds suffer from poor oral bioavailability and/or poor blood-brain barrier Fig 1. VPC for 1000 IN data
compounds suffer from poor oral bioavailability and/or poor blood-brain barrier Fig 1. VPC for 1000
simulations, depicted per compounds suffer from poor oral bioavailability and/or poor blood-brain barrier
transport. Intranasal administration could offer an attractive alternative route of simulations, depicted per
data set and per transport. Intranasal administration could offer an attractive alternative route of
administration by enhancing the distribution to the brain. Here we present a
data set and per
compartment. Badministration by enhancing the distribution to the brain. Here we present a
compartment. B
lue dots; observed REM administration by enhancing the distribution to the brain. Here we present a
translational PKPD model of prolactin (PRL) release following intravenous (IV) and lue dots; observed REM
concentrations over time,
IV datatranslational PKPD model of prolactin (PRL) release following intravenous (IV) and concentrations over time,
black line; median of IV datatranslational PKPD model of prolactin (PRL) release following intravenous (IV) and
intranasal (IN) administration of the dopamine D2-receptor antagonist remoxipride black line; median of IV data
intranasal (IN) administration of the dopamine D2-receptor antagonist remoxipride
(REM) as model compound. The model allows translation between i) different
black line; median of
simulations, grey area’s;
(REM) as model compound. The model allows translation between i) different simulations, grey area’s;
95% confidence intervals.(REM) as model compound. The model allows translation between i) different
routes of administration in rats, and ii) rat and human.
95% confidence intervals.
routes of administration in rats, and ii) rat and human.routes of administration in rats, and ii) rat and human.
MethodsMethodsResults Pharmacodynamics
MethodsResults Pharmacodynamics
Animal experiments (as previously publishedA). Dataset 1; 0, 4, 8, or 16 mg/kg REM Results Pharmacodynamics
Animal experiments (as previously publishedA). Dataset 1; 0, 4, 8, or 16 mg/kg REM Results Pharmacodynamics
Animal experiments (as previously published ). Dataset 1; 0, 4, 8, or 16 mg/kg REM
administration (30-min IV / 1-min IN infusion). Dataset 2; consecutive dosing of PRL profiles were accurately described following IV single as well as administration (30-min IV / 1-min IN infusion). Dataset 2; consecutive dosing of PRL profiles were accurately described following IV single as well as
consecutive dosing (fig 2 & 3, respectively). administration (30-min IV / 1-min IN infusion). Dataset 2; consecutive dosing of
3.8 mg/kg REM ( 30 min IV infusions, different time intervals). consecutive dosing (fig 2 & 3, respectively). 3.8 mg/kg REM ( 30 min IV infusions, different time intervals).
Analytical procedures. REM concentrations were analyzed by online solid phase
consecutive dosing (fig 2 & 3, respectively).
Analytical procedures. REM concentrations were analyzed by online solid phase Analytical procedures. REM concentrations were analyzed by online solid phase
extraction coupled to LC-MSB. PRL was measured in plasma (ELISA).extraction coupled to LC-MSB. PRL was measured in plasma (ELISA).extraction coupled to LC-MS . PRL was measured in plasma (ELISA).
Modeling. Modeling (NONMEM VI.2) was based on plasma- and brainECF REM Modeling. Modeling (NONMEM VI.2) was based on plasma- and brainECF REM
concentrations, and plasma PRL concentrations. PK was fixed during PD modeling.ECF
concentrations, and plasma PRL concentrations. PK was fixed during PD modeling.concentrations, and plasma PRL concentrations. PK was fixed during PD modeling.
Validation. Models were tested and evaluated (likelihood ratio test (p<0.05), Validation. Models were tested and evaluated (likelihood ratio test (p<0.05), Validation. Models were tested and evaluated (likelihood ratio test (p<0.05),
goodness-of-fit, parameter estimate endpoints, and individual plots).goodness-of-fit, parameter estimate endpoints, and individual plots).
Rat-to-human translation. Based on the animal PKPD model, human PKPD was Rat-to-human translation. Based on the animal PKPD model, human PKPD was Rat-to-human translation. Based on the animal PKPD model, human PKPD was
simulated in Berkeley-Madonna and compared to a clinical dataset, kindly provided simulated in Berkeley-Madonna and compared to a clinical dataset, kindly provided simulated in Berkeley-Madonna and compared to a clinical dataset, kindly provided
by M. Hammarlund-UdenaesC. Simulated human brainECF concentration effect-by M. Hammarlund-UdenaesC. Simulated human brainECF concentration effect-
relations were applied. Clinical PD parameters were obtained from literature when ECF
relations were applied. Clinical PD parameters were obtained from literature when relations were applied. Clinical PD parameters were obtained from literature when
possible, otherwise allometric scaling was applied. possible, otherwise allometric scaling was applied. possible, otherwise allometric scaling was applied.
ModelModelFig 2; VPC of PRL plasma profiles after single IV REM, Fig 3; typical individual predictions (black line) and ModelFig 2; VPC of PRL plasma profiles after single IV REM,
per dose (DO, in mg/kg). (O) observed PK (black line);
Fig 3; typical individual predictions (black line) and
observed PRL plasma PK O) after consecutive
REM PK-model. Following IN administration, total absorption of REM is defined by per dose (DO, in mg/kg). (O) observed PK (black line);
median of simulations, (grey area) and 95% confidence
observed PRL plasma PK O) after consecutive
dosing of REM, per dosing regiment (DOSE, hours)REM PK-model. Following IN administration, total absorption of REM is defined by median of simulations, (grey area) and 95% confidence
interv.als)
dosing of REM, per dosing regiment (DOSE, hours)REM PK-model. Following IN administration, total absorption of REM is defined by
systemic uptake (1.ABS) and direct nose-to-brain transport (2.ABS). REM is interv.als)
systemic uptake (1.ABS) and direct nose-to-brain transport (2.ABS). REM is
distributed (blue arrows) in a central-, peripheral- and brain compartment, and Results Translationdistributed (blue arrows) in a central-, peripheral- and brain compartment, and Results Translationdistributed (blue arrows) in a central-, peripheral- and brain compartment, and
eliminated from plasma (k ) and brain ECF (k ).
Results Translationeliminated from plasma (ke,REM,pl) and brain ECF (ke,REM,brainECF). The translational properties for IN REM indicate slight under-prediction eliminated from plasma (ke,REM,pl) and brain ECF (ke,REM,brainECF).
PK-PD model. An Emax model for relation between brainECF REM concentrations The translational properties for IN REM indicate slight under-prediction
of measurements (fig 4), attributed to larger variability in the IN dataset PK-PD model. An Emax model for relation between brainECF REM concentrations
and PRL release. A turnover model described PRL synthesis rate (k ), release of of measurements (fig 4), attributed to larger variability in the IN dataset
and PRL release. A turnover model described PRL synthesis rate (ks,PRL,rat), release of of measurements (fig 4), attributed to larger variability in the IN dataset
and more complex brain distribution. The model showed accurate and PRL release. A turnover model described PRL synthesis rate (ks,PRL,rat), release of
PRL from lactotrophs into plasma (k ), and PRL plasma elimination (k )and more complex brain distribution. The model showed accurate
PRL from lactotrophs into plasma (kr,PRL,rat), and PRL plasma elimination (ke,PRL,rat)and more complex brain distribution. The model showed accurate
translational properties in reduction of human PKPD (Fig 5, PK not PRL from lactotrophs into plasma (kr,PRL,rat), and PRL plasma elimination (ke,PRL,rat)
System-feedback model. An Emax model for the relation between PRL plasma translational properties in reduction of human PKPD (Fig 5, PK not
shown)System-feedback model. An Emax model for the relation between PRL plasma
concentration and rate of synthesis. shown)
concentration and rate of synthesis. k
shown)concentration and rate of synthesis.
ke, REM,plke, REM,pl
1.ABS 3.central 5.Peripheral1.ABS 3.central 5.Peripheral1.ABS 3.central 5.Peripheral
ph
arm
aco
kin
eti
csp
ha
rma
cok
ine
tics
ph
arm
aco
kin
eti
csp
ha
rma
cok
ine
tics
ph
arm
aco
kin
eti
cs
ke,REM, brainECF4.brain2.ABS
ph
arm
aco
kin
eti
cs
ke,REM, brainECF4.brain2.ABS
ph
arm
aco
kin
eti
csp
ha
rma
cok
ine
tics
ph
arm
aco
kin
eti
cs
Emax,REM,brainECF * CREM,brainECF(t) / (EC50,REM,brainECF + CREM,brainECF(t))Drug-effect Emax,REM,brainECF * CREM,brainECF(t) / (EC50,REM,brainECF + CREM,brainECF(t))Drug-effect
modelmodel
ph
arm
aco
dy
na
mic
s
kKK
ph
arm
aco
dy
na
mic
s
Fig 4 (up); translation to intranasal administration. VPC ke,PRL, ratKr, PRL, ratKs, PRL, rat
ph
arm
aco
dy
na
mic
s
TurnoverFig 4 (up); translation to intranasal administration. VPC
showing the median simulated PRL concentrations
lactotroph PRL, plasma
ke,PRL, ratKr, PRL, ratKs, PRL, rat
ph
arm
aco
dy
na
mic
s
Turnover
modelshowing the median simulated PRL concentrations
(black line) with the 95% confidence interval, and the lactotroph PRL, plasma
ph
arm
aco
dy
na
mic
s
model (black line) with the 95% confidence interval, and the
experimental data (open symbols)
ph
arm
aco
dy
na
mic
s
experimental data (open symbols)
ph
arm
aco
dy
na
mic
s
System-effect Fig 5 (right); translation to human PD. Based on
ph
arm
aco
dy
na
mic
s
System-effect
model
Fig 5 (right); translation to human PD. Based on
estimated human brainECF PK the predicted PRL PK (grey
1+ (SE * C (t) / (SEC + C (t))
ph
arm
aco
dy
na
mic
s
model estimated human brainECF PK the predicted PRL PK (grey
line) are in accordance with the clinical data (O)1+ (SEmax,PRL,rat * CPRL,pl, rat(t) / (SEC50,PRL,rat + CPRL,pl, rat(t))
ph
arm
aco
dy
na
mic
s
line) are in accordance with the clinical data (O)1+ (SEmax,PRL,rat * CPRL,pl, rat(t) / (SEC50,PRL,rat + CPRL,pl, rat(t))
Conclusions and perspectivesConclusions and perspectivesConclusions and perspectivesResults Pharmacokinetics
The preclinical PKPD model provides, for the1st time, quantification of Results Pharmacokinetics
The preclinical PKPD model provides, for the1st time, quantification of Results Pharmacokinetics
The preclinical PKPD model provides, for the1 time, quantification of
direct nose-to-brain transport in terms of rate and extent following IN Following IN administration total bioavailability was 89%. Brain distribution differs direct nose-to-brain transport in terms of rate and extent following IN
administration. It also indicates a positive feedback of PRL plasma
Following IN administration total bioavailability was 89%. Brain distribution differs
between administration routes. The brain ECF/plasma ratio improved for IN versus administration. It also indicates a positive feedback of PRL plasma between administration routes. The brain ECF/plasma ratio improved for IN versus administration. It also indicates a positive feedback of PRL plasma
concentrations on PRL synthesis. Finally it provides a useful approach for
between administration routes. The brain ECF/plasma ratio improved for IN versus
IV administration (28% vs. 19%). Brain concentrations were slightly under- concentrations on PRL synthesis. Finally it provides a useful approach for IV administration (28% vs. 19%). BrainECF concentrations were slightly under- concentrations on PRL synthesis. Finally it provides a useful approach for
rat-to-human translation of PKPD relationships of dopaminergic drugs.
IV administration (28% vs. 19%). Brain concentrations were slightly under-
predicted, indicating more complex brain distribution (fig 1) rat-to-human translation of PKPD relationships of dopaminergic drugs.predicted, indicating more complex brain distribution (fig 1)
A. Stevens et al., Pharm.Res,2009,26(8);1911-1917A. Stevens et al., Pharm.Res,2009,26(8);1911-1917
B. Stevens et al., J. Chromatogr. B Analyt Technol. Biomed. Life Sci., 2010, 878; 969-975 B. Stevens et al., J. Chromatogr. B Analyt Technol. Biomed. Life Sci., 2010, 878; 969-975 B. Stevens et al., J. Chromatogr. B Analyt Technol. Biomed. Life Sci., 2010, 878; 969-975
C. Movin-Osswald et al., J.Pharmacol.Exp.Ther.,1995, 274:921-927C. Movin-Osswald et al., J.Pharmacol.Exp.Ther.,1995, 274:921-927