Pharmacokinetic/pharmacodynamic modeling of drug interactions at the P2Y12 receptor between selatogrel and oral P2Y12 antagonists

Abstract

Selatogrel is a potent and reversible P2Y12 receptor antagonist developed for subcutaneous self‐administration by patients with suspected acute myocardial infarction. After single‐dose emergency treatment with selatogrel, patients are switched to long‐term treatment with oral P2Y12 receptor antagonists. Selatogrel shows rapid onset and offset of inhibition of platelet aggregation (IPA) to overcome the critical initial time after acute myocardial infarction. Long‐term benefit is provided by oral P2Y12 receptor antagonists such as clopidogrel, prasugrel, and ticagrelor. A population pharmacokinetic (PK)/pharmacodynamic (PD) model based on data from 545 subjects in 4 phase I and 2 phase II studies well described the effect of selatogrel on IPA alone and in combination with clopidogrel, prasugrel, and ticagrelor. The PK of selatogrel were described by a three‐compartment model. The PD model included a receptor‐pool compartment to which all drugs can bind concurrently, reversibly or irreversibly, depending on their mode of action. Furthermore, ticagrelor and its active metabolite can bind to the selatogrel‐receptor complex allosterically, releasing selatogrel from the binding site. The model provided a framework for predicting the effect on IPA of selatogrel followed by reversibly and irreversibly binding oral P2Y12 receptor antagonists for sustained effects. Determining the timepoint for switching from emergency to maintenance treatment is critical to achieve sufficient IPA at all times. Simulations based on the interaction model showed that loading doses of clopidogrel and prasugrel administered 15 h and 4.5 h after selatogrel, respectively, provide sustained IPA with clinically negligible drug interaction.

Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Selatogrel is a potent reversible P2Y12 receptor antagonist developed for subcutaneous self‐administration by patients in case of suspected acute myocardial infarction. Transition to oral P2Y12 receptor antagonists without drug interaction and sufficient inhibition of platelet aggregation must be assured at all times. WHAT QUESTION DID THIS STUDY ADDRESS?

The pharmacokinetic/pharmacodynamic model semimechanistically describes the effect of selatogrel on platelet inhibition alone and in combination with the oral P2Y12 receptor antagonists clopidogrel, prasugrel, and ticagrelor. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Model‐based simulations showed that loading doses of clopidogrel and prasugrel can be administered from 15 h and 4.5 h after selatogrel, respectively. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results support guiding the clinical transition from selatogrel emergency treatment to oral maintenance therapy in a safe and efficacious way.

Full text

CPT Pharmacometrics Syst. Pharmacol. 2021;10:735–747.
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735
www.psp-journal.com
Received: 26 January 2021
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Revised: 8 April 2021
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Accepted: 12 April 2021
DOI: 10.1002/psp4.12641
ARTICLE
Pharmacokinetic/pharmacodynamic modeling of drug
interactions at the P2Y12 receptor between selatogrel and oral
P2Y12 antagonists
AndreaHenrich1
|
Christian HoveClaussen2
|
JasperDingemanse1
|
AndreasKrause1
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.
© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and
Therapeutics.
1Clinical Pharmacology, Idorsia
Pharmaceuticals Ltd, Allschwil,
Switzerland
2Cognigen Corporation, A Simulation
Plus Company, Pharmacometrics
Services, Copenhagen, Denmark
Correspondence
Andreas Krause, Clinical Pharmacology,
Idorsia Pharmaceuticals Ltd, Allschwil,
Switzerland.
Email: andreas.krause@idorsia.com
Funding information
This study was funded by Idorsia
Pharmaceuticals Ltd.
Abstract
Selatogrel is a potent and reversible P2Y12 receptor antagonist developed for subcuta-
neous self- administration by patients with suspected acute myocardial infarction. After
single- dose emergency treatment with selatogrel, patients are switched to long- term
treatment with oral P2Y12 receptor antagonists. Selatogrel shows rapid onset and offset
of inhibition of platelet aggregation (IPA) to overcome the critical initial time after
acute myocardial infarction. Long- term benefit is provided by oral P2Y12 receptor an-
tagonists such as clopidogrel, prasugrel, and ticagrelor. A population pharmacokinetic
(PK)/pharmacodynamic (PD) model based on data from 545 subjects in 4 phase I and
2 phase II studies well described the effect of selatogrel on IPA alone and in combina-
tion with clopidogrel, prasugrel, and ticagrelor. The PK of selatogrel were described
by a three- compartment model. The PD model included a receptor- pool compartment
to which all drugs can bind concurrently, reversibly or irreversibly, depending on
their mode of action. Furthermore, ticagrelor and its active metabolite can bind to the
selatogrel- receptor complex allosterically, releasing selatogrel from the binding site.
The model provided a framework for predicting the effect on IPA of selatogrel followed
by reversibly and irreversibly binding oral P2Y12 receptor antagonists for sustained
effects. Determining the timepoint for switching from emergency to maintenance treat-
ment is critical to achieve sufficient IPA at all times. Simulations based on the interac-
tion model showed that loading doses of clopidogrel and prasugrel administered 15h
and 4.5h after selatogrel, respectively, provide sustained IPA with clinically negligible
drug interaction.
Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Selatogrel is a potent reversible P2Y12 receptor antagonist developed for subcutane-
ous self- administration by patients in case of suspected acute myocardial infarction.
Transition to oral P2Y12 receptor antagonists without drug interaction and sufficient
inhibition of platelet aggregation must be assured at all times.

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HENRICH Et al.
INTRODUCTION
Selatogrel is a potent reversible P2Y12 receptor antagonist
developed for subcutaneous (s.c.) self- administration by
patients with suspected acute myocardial infarction (AMI).
Selatogrel shows a fast onset of action,1 an important charac-
teristic to follow the "time is muscle" paradigm.2
Inhibition of platelet aggregation (IPA) via P2Y12 recep-
tor antagonists is key in the treatment of AMI and its sec-
ondary prevention.3– 5 Clopidogrel, prasugrel, and ticagrelor
are available as oral P2Y12 receptor antagonists. Although
clopidogrel and prasugrel are prodrugs with their active me-
tabolites binding irreversibly to the P2Y12 receptor, ticagrelor
and its active metabolite both bind reversibly.6 Ticagrelor and
its active metabolite bind noncompetitively, that is, exhibit
allosteric binding at a binding site different from that of sela-
togrel, clopidogrel, prasugrel, and the natural ligand adenos-
ine diphosphate (ADP).6
After emergency treatment with selatogrel, patients in
phase III of clinical development and later in clinical prac-
tice will be switched to treatment with an oral P2Y12 recep-
tor antagonist. Transfer between P2Y12 receptor antagonists
was associated with the risk of pharmacodynamic (PD)
drug interactions.7 For cangrelor, an intravenously admin-
istered reversible P2Y12 receptor antagonist, it is assumed
that clopidogrel's and prasugrel's active metabolites are
eliminated before cangrelor dissociates from the P2Y12 re-
ceptor. Thus, clopidogrel and prasugrel cannot convey their
sustained IPA if administered during cangrelor infusion.8,9
Similarly, reduced IPA was apparent with clopidogrel and
prasugrel if administered shortly after selatogrel.10 No re-
duction in IPA was seen for ticagrelor administered after
selatogrel.
The aim of this analysis was to develop a population phar-
macokinetic (PK)/PD model to describe the effect of sela-
togrel on IPA alone and in combination with the three oral
P2Y12 receptor antagonists. This model can be used to deter-
mine the optimum time to transition from one P2Y12 receptor
antagonist to another to maintain sufficient IPA at all times, a
critical component of AMI treatment.
METHODS
Data
The analysis comprised data from 4 phase I and 2 phase II
studies.
• Two single- ascending dose (SAD) studies covering an s.c.
dose range from 0.1to 16mg1
• A PD interaction study with the P2Y12 receptor antago-
nists clopidogrel, prasugrel, and ticagrelor (the SWITCH
study)10
• A study to investigate absorption, distribution, metabo-
lism, and excretion of selatogrel using 14C- radiolabeling
(PK only)11
• A study to investigate PK and PD in subjects with stable
coronary artery disease12
• A study to investigate PK and PD in subjects with AMI13
Table 1 provides details on study designs, populations,
study treatments, and PK/PD assessments. The selatogrel
plasma concentrations were determined using a validated
liquid chromatography assay.1 The PD variable was P2Y12
reaction units (PRU) determined by VerifyNow®.14– 16
VerifyNow® is a point- of- care device measuring platelet
aggregation turbidimetrically in whole blood after inducing
platelet aggregation with the natural P2Y12 receptor agonist
ADP. IPA was calculated as relative change from baseline:
PRU0 was defined as the naïve baseline PRU, that is, the
baseline PRU without influence of any P2Y12 receptor an-
tagonist. For subjects missing this information, for example,
%IPA =(PRU0−PRU)∕PRU0
⋅
100
WHAT QUESTION DID THIS STUDY ADDRESS?
The pharmacokinetic/pharmacodynamic model semimechanistically describes the ef-
fect of selatogrel on platelet inhibition alone and in combination with the oral P2Y12
receptor antagonists clopidogrel, prasugrel, and ticagrelor.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Model- based simulations showed that loading doses of clopidogrel and prasugrel can
be administered from 15h and 4.5h after selatogrel, respectively.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR
TRANSLATIONAL SCIENCE?
These results support guiding the clinical transition from selatogrel emergency treat-
ment to oral maintenance therapy in a safe and efficacious way.

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PK/PD MODELING OF P2Y12 RECEPTOR DDI
TABLE 1 Study overview
Study Study design Study population Study treatment PK/PD assessment timepoints
AC−076– 101
(NCT01954615)
Single- center, double- blind, placebo-
controlled, randomized SAD study
Eighthealthy male subjects
per cohort (sixon active,
two on placebo)
22 subjects in total
Selatogrel/placebo s.c.: C1, 0.1mg; C2,
0.4mg; C3, 1.6mg
Day −1a and 0 (predose); 5,b 10, 15, 20, 25,b
and 30min; and 1, 1.5,b 2, 3, 4, 5, 6, 8, 12,
24, 36, and 48h
AC−076– 1021Single- center, double- blind, placebo-
controlled, randomized SAD study
Eighthealthy male subjects
per cohort (sixon active,
two on placebo)
48 subjects in total
Selatogrel/placebo s.c.: C1, 1mg; C2,
2mg; C3, 4mg; C4, 8mg; C5,
16mg; C6, 32mg
Day – 1a and 0 (predose); 5,b 10, 15, 20, 25,b
and 30min; and 1, 1.5,b 2, 3, 4, 5, 6, 8, 12,
24, 36, and 48h
ID−076– 10310 Single- center, double- blind (selatogrel),
open- label (clopidogrel, prasugrel,
and ticagrelor), placebo- controlled,
randomized, two- way crossover study
12healthy male and female
subjects per cohort
77 subjects in total
16mg selatogrel/placebo s.c. followed
by: Part A: clopidogrel p.o.
C1, 600mg at 0.5h; C2, 300mg at12h;
C3, 600mg at 12h
Part B: prasugrel p.o.
C4, 60mg at 0.5h; C5, 60mg at12h
Part C: ticagrelor p.o.
C7, 180mg at 0.5h
Day – 1a and 0 (predose); 15 and 30min; and
1, 1.5, 2, 3, 4, 5, 6, 7,a 8, 9,a 10, 11,a 12, 24,
and 36h
ID−076– 10411 Single- center, open- label study to
investigate its mass balance, PK, and
metabolism
Sixhealthy male subjects 16mg 14C- radiolabeled selatogrel s.c. 0b (predose); 5,b 10,b 15,b 30,b and 45b min; and
1,b 1.5,b 2,b 3,b 4,b 5,b 6,b 8,b 12,b 24,b 36,b
48,b and 72b h
ID−076A20112 Multicenter, double- blind, randomized,
placebo- controlled study
345 male and female subjects
with coronary artery
syndrome
8 or 16mg selatogrel/placebo s.c. 0 (predose); 15 and 30min; and 1, 2, 4, 8, and
24h
ID−076A20213 Multicenter, open- label, randomized study 47 male and female subjects
with acute myocardial
infarction
8 or 16mg selatogrel s.c. 0b (predose), 15 and 30min, and 1 and 8hc
Abbreviations: C, Cohort; p.o., per oral; PD, pharmacodynamic(s); PK, pharmacokinetic(s); SAD, single- ascending dose; s.c., subcutaneous.
aPD sampling only.
bPK sampling only.
cThe 8- h PK postdose timepoint was flexible. If the subject received an invasive procedure (percutaneous coronary intervention/angiography) within 8h of study drug administration, the blood sample was to be collected at the
end of the procedure. If no invasive procedure was performed within 8h of study drug administration, the blood sample was to be collected approximately 8h after study drug administration.

738
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HENRICH Et al.
subjects in phase II studies on background medication of
oral P2Y12 receptor antagonists, a typical value close to the
observed median, 200 PRU, was imputed. The mean of the
baseline measurements of both periods was used for both
treatment periods in the crossover study, SWITCH. Missing
covariate values were imputed by the corresponding medians
of the entire data set.
Selatogrel PK model development
Starting from a two- compartment model with linear absorp-
tion from the s.c. injection site, the model was enhanced by
a further distribution compartment and a single transition
compartment for absorption. Interindividual variability with
log- normal distribution was included on all parameters. The
residual error term was proportional to the selatogrel concen-
tration. Concentration measurements below the lower limit
of quantification (LLOQ) were treated as censored values
and simulated from a truncated distribution restricted to the
range (0,LLOQ).17
Covariate relationships for continuous covariates were
implemented as power functions centered to a typical
value. Covariate selection was performed using conditional
sampling for stepwise approach based on correlation tests
(COSSAC), an automated covariate model- building algo-
rithm implemented in Monolix (Lixoft, Antony, France).18
Body weight, age, sex, and race were assessed as covariates
on all PK parameters. Injection site (thigh, abdomen) and
AMI disease status were assessed on absorption parameters,
and bilirubin and creatinine clearance on drug clearance.
After the automated COSSAC run, correlated covariates
such as sex and body weight were reduced to the covariate
with a stronger effect. Covariates with an estimated effect on
the parameter below 20% for the extremes of the covariate in
the data were considered not clinically relevant and removed
from the model. Covariate effects estimated with low pre-
cision, that is, relative standard error (RSE) >50% were re-
moved from the model stepwise (highest RSE first).
PK model development for other P2Y12
antagonists
Structural PK models for clopidogrel, prasugrel, and ticagre-
lor were implemented from the literature.19,20 Interindividual
variability was not included in this part of the model because
individual PK data of these compounds were not available.
As a consequence, the variability of the PD parameter es-
timates describing the effect of those compounds increases.
This higher variability in PD parameters reflects variability
in PK and PD and therefore allows for reasonable prediction
of the PD effect.
The clopidogrel literature model included dose as a
categorical covariate (75 and 600 mg) on bioavailability
and the formation rate constant of the inactive precursor
(2- oxo- clopidogrel) of the active metabolite. Parameter es-
timates for 300- mg doses were derived from the 600- mg pa-
rameter values based on the assumption that dose- dependent
processes are saturated at 300mg since deviations from dose-
proportionality in area under the concentration- time curve
decrease for doses of 300mg and higher.21 For ticagrelor,
identical activity was assumed for parent compound and ac-
tive metabolite AR- C124910XX.22
PD model development
The subject- specific individual parameter estimates from
the final PK model were used to predict the individual PK
and relate it to the PD effect. In a first step, a PK/PD model
for selatogrel was developed based on the SAD studies.
Thereafter, clopidogrel, prasugrel, and ticagrelor were in-
cluded sequentially based on PD data from the SWITCH
study. Finally, phase II data were included, and parameters
were re- estimated. Different structural models were investi-
gated to describe the complex PD effect of selatogrel in com-
bination with oral P2Y12 receptor antagonists, for example,
nonlinear binding kinetics.
Baseline PRU was described by the observed naïve base-
line PRU (or imputed with 200 PRU if the observation was
missing), allowing for an exponential error similar to the
baseline method B3.23,24 Interindividual variability was in-
cluded on all parameters assuming a log- normal distribution.
A combined (additive and proportional) residual error model
was used.
Disease status AMI was assessed on parameters related to
drug effect of any P2Y12 receptor antagonist using COSSAC
covariate selection. Subsequently, covariate relations esti-
mated with low precision (RSE >50%) were removed from
the model stepwise (highest RSE first). Other covariates such
as age or use of opioids were highly correlated to disease
status and therefore not considered.
Model selection and qualification
Model selection and qualification were based on goodness-
of- fit plots (observed data vs. model predictions, residuals
vs. time and population predictions), visual predictive checks
(VPCs), objective function values (OFVs), and RSEs of
parameter estimates. The corrected Bayesian information
criterion25,26 served as the model selection criterion in the
COSSAC step. The default settings with p value thresholds
of 0.5 for the addition and 0.01 for the removal of covariates
were used.

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PK/PD MODELING OF P2Y12 RECEPTOR DDI
Simulations to evaluate the influence
of covariates
Simulations were used to evaluate the clinical relevance of
covariates. The typical subject was defined with the refer-
ence covariate values body weight 70kg, age 60years, naïve
baseline PRU 200, and disease status healthy/coronary ar-
tery disease. Naïve baseline PRU was not implemented as
covariate; however, it was taken into account by the baseline
method and is therefore regarded as covariate in the follow-
ing. A total of 1000 subjects were simulated per covariate
value, including interindividual variability and without re-
sidual variability and parameter uncertainty. The area under
the concentration- time curve between 0 and 48h (AUC0– 48h)
and the proportion of responders as defined in the phase II
studies,12,13 that is, subjects with PRU <100 from 0.5 to 3h
after single- dose administration of selatogrel, were derived
from the simulated data. A response definition based on PRU
is preferable over IPA in a clinical setting in which concomi-
tant medication prevents the measurement of a naïve baseline
PRU that is required to derive IPA.
Model predictions of selatogrel in combination
with clopidogrel and prasugrel
Model- based predictions for the reference subject were per-
formed to investigate the effect of different time intervals be-
tween administration of selatogrel and clopidogrel/prasugrel.
In analogy to the SWITCH study, interaction was de-
fined as the ≥20 percentage points decrease of arithmetic
mean percent IPA at 24 and 36h following administration
of selatogrel or placebo.10 The primary end point in the clin-
ical study was the difference in mean IPA such that simu-
lations were based on typical profiles. A selatogrel dose of
16mg was administered at 0h. A clopidogrel loading dose
(600mg) or a prasugrel loading dose (60 mg) was admin-
istered at different times after selatogrel. For comparison,
clopidogrel or prasugrel alone were administered at differ-
ent timepoints (mimicking placebo treatment of selatogrel).
The SWITCH study showed PD interactions with clopido-
grel 600mg administered 0.5 and 12h after selatogrel such
that dosing times >12 h were investigated. For prasugrel,
the SWITCH study showed no interaction for dosing at 12h
but at 0.5h. Thus, dosing times between 0.5 and 12h were
investigated to estimate the dosing time after which no inter-
action can be expected.
Software
R version 3.6.1 (The R Project Foundation, Vienna, Austria)
was used for data set preparation, exploratory analyses, and
visualization of results. Population PK/PD modeling was per-
formed using Monolix version 2019R2 (Lixoft). Parameters
were estimated using the stochastic approximation of ex-
pectation maximization algorithm. The likelihood and the
Fisher information matrix were estimated using importance
sampling. Simulations were performed using Simulx ver-
sion 2019R2 (Lixoft), and model predictions were generated
with Berkeley Madonna version 8.3.18 (Macey and Oster,
Berkeley, CA).
RESULTS
Data
The data set comprised 545 subjects (405 on active treatment
and 140 on placebo, 434 males and 111 females) with 3924
PK and 7251 PD measurements, respectively (TableS1).
Missing data were imputed by the respective medians of
all subjects for laboratory parameters at baseline (four sub-
jects). Missing values for the covariate for race were imputed
by race Other (two subjects), and missing height and body
weight (the same two subjects in both) by the respective sex-
adjusted medians.
The PK of selatogrel showed a fast absorption followed
by an elimination with two or more phases depending on the
data set. PRU measurements showed high variability within
and between subjects. Doses of 8mg achieved full IPA for
most subjects. Higher doses prolonged the duration of the full
inhibition.
The concentration- response relation (FigureS1) showed a
dose- dependent effect with steeper relation for higher doses,
for example, at a selatogrel concentration of approximately
20 ng/ml the 32- mg dose led to almost complete plate-
let inhibition (PRU close to 0) while PRU remained above
100 for doses of up to 1.6mg (at the same concentration).
Investigation of hysteresis, a time- delayed effect, was incon-
clusive due to the rapid absorption and therefore lack of in-
formation in the early phase.
Selatogrel PK model development
A linear three- compartment model with a transit compartment
for absorption described the PK data best (Figure1, Table2).
The distribution to the second peripheral compartment from
the first peripheral compartment decreased the OFV by 161.71
points compared with a distribution from the central compart-
ment, yielding a decrease in OFV of 100.63 points. An addi-
tional transit compartment for the absorption process decreased
the OFV by 840.84 points without additional parameters.
Bilirubin on clearance as well as injection site and dis-
ease status on the absorption rate constant were statistically

740
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HENRICH Et al.
significant but did not meet the criteria for clinical relevance
and were therefore not included in the final model. The final
PK model included age and body weight on multiple PK
parameters.
VPCs showed a good alignment of PK model predictions
and observed selatogrel concentrations (FiguresS2 and pre-
dictive checks for data below the LLOQ in FigureS3). Some
very high concentrations after the administration of 32 mg
of selatogrel were slightly overpredicted. Parameters were
estimated with high precision (RSE ≤25.9%). The condition
number for the PK model was 72, indicating that the model
was well parameterized.27
PK/PD model development
The PK/PD base model structure is depicted in Figure2, pa-
rameter estimates are provided in Table2, and the differential
equations are provided in the Supplementary Material. The
free P2Y12 receptors were modeled on an arbitrary scale with
a baseline of 1nmol/L. Free P2Y12 receptors are generated
with a zero- order formation rate constant, kin, and eliminated
with a first- order elimination rate constant, kout. Selatogrel,
ticagrelor, and its active metabolite as well as the active me-
tabolites of clopidogrel and prasugrel can all bind to the free
receptor. The relationship between receptor binding and PRU
was modeled using a sigmoidal function. The condition num-
ber of the PK/PD model was 17, indicating that the model
was well parameterized (VPCs in FiguresS3- S5).27
A cumulative effect compartment integrating the fraction
of bound receptors with the rate constant kCum is cleared with
the same rate constant. A factor modifying the binding ac-
tivity of the selatogrel and prasugrel active metabolite was
derived based on the cumulative effect compartment value: a
high fraction of bound receptors increases the value of the cu-
mulative effect compartment, ultimately leading to increased
binding rates for selatogrel and prasugrel. Implementation of
this effect for clopidogrel and ticagrelor led to an increase in
the OFV for both and was thus not used.
Ticagrelor and its active metabolite can bind allosteri-
cally to the selatogrel– receptor complex, releasing selatogrel
from its binding site. Adding this (un)binding mechanism de-
creased the OFV by 46.83 points without additional parame-
ters. However, fitting ticagrelor with all PD data from phase
I and phase II resulted in an underprediction of PRU between
24 and 36h for the corresponding Cohort 7 of the SWITCH
study. Therefore, ticagrelor parameters including interindi-
vidual variability were estimated with phase I data only and
fixed to those values in the final model. This step increased
the OFV by 5.12 points, indicating that the overall goodness
of fit was similar. The phase II data with sparse PD sampling
can possibly be described by more than one parameter set,
whereas the dense sampling in phase 1 with fewer subjects
provided a solid basis for structural model identification. For
the purpose of the simulations, the phase I data, including
the SWITCH interaction study, were considered to be more
relevant to describe the ticagrelor effect.
Similarly, the binding rate constant for clopidogrel was
estimated with phase I data only and fixed to this estimate
in the final model. This step was necessary to adequately
describe the effect of clopidogrel alone (i.e., selatogrel-
matching placebo in the SWITCH study Cohorts 1– 3). The
OFV increased by 17.46 points by fixing this parameter and
its interindividual variability.
Influence of covariates
Low body weight and high age led to higher exposure
(AUC0– 48 h), with body weight having the larger influence
(Figure 3). Despite the relevance for PK, the effect on PD
and the proportion of responders was limited for both body
weight and age. Nevertheless, a higher exposure led to a
prolonged PD effect: subjects with low body weight (50kg)
had returned to 100 PRU after 14.4 h, whereas subjects
with high body weight (150kg) returned to 100 PRU after
9.3h. Although naïve baseline PRU influenced the shape of
the PRU profile, IPA was not affected. As responders were
FIGURE 1 Pharmacokinetic model structure. CL, clearance;
ka, absorption rate constant; Qp1, intercompartmental clearance for
distribution between central and first peripheral compartment; Qp2,
intercompartmental clearance for distribution between first and
second peripheral compartment; s.c., subcutaneous; Vcent, central
volume of distribution; Vp1, volume of distribution of first peripheral
compartment; Vp2, volume of distribution of second peripheral
compartment

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PK/PD MODELING OF P2Y12 RECEPTOR DDI
TABLE 2 PK/PD parameter estimates
Parameter Description
Fixed effects parameters
Interindividual variability
(random effects)
Estimate %RSE
P value
(covariates) Estimate %RSE %CV
ka (1/h) Absorption rate constant 5.95 2.11 - 0.362 4.35 37.4
βka_age (- ) Effect of age on ka−0.280 19.9 4.98 * 10−7 - - -
CL (L/h) Clearance 8.51 2.15 - 0.297 3.85 30.4
βCL_age (- ) Effect of age on clearance −0.437 10.1 <2.2 * 10−16 - - -
βCL_WT (- ) Effect of body weight on CL 0.678 12.1 2.22 * 10−16 - - -
Vcent (L) Central volume of distribution 17.0 2.33 - 0.307 4.19 31.4
βVcent_age (- ) Effect of age on Vcent −0.293 16.1 5.67 * 10−10 - - -
βVcent_WT (- ) Effect of body weight on Vcent 0.990 8.84 <2.2 * 10−16 - - -
Qp1 (L/h) Intercompartmental clearance
between central and first
peripheral compartment
3.19 2.92 - 0.329 6.13 33.8
βQp1_age (- ) Effect of age on Qp1 −0.137 42.0 1.72 * 10−2 - - -
βQp1_WT (- ) Effect of body weight on Qp1 1.00 11.1 <2.2 * 10−16 - - -
corrCL_Qp1 Correlation between CL and Qp1 - - - 0.702 6.27 -
corrCL_Vcent Correlation between CL and
Vcent
- - - 0.724 3.69 -
corrVcent_Qp1 Correlation between Qp1 and
Vcent
- - - 0.349 18.8 -
Vp1 (L) Volume of distribution of first
peripheral compartment
51.4 2.28 - 0.181 8.94 18.2
βVp1_WT (- ) Effect of body weight on Vp1 1.58 6.39 <2.2 * 10−16 - - -
Qp2 (L/h) Intercompartmental clearance
between first and second
peripheral compartment
4.18 1.87 - - - -
βQp2_WT (- ) Effect of body weight on Qp2 1.43 5.65 <2.2 * 10−16 - - -
Vp2 (L) Volume of distribution of second
peripheral compartment
448 25.9 - 1.18 12.3 174
βVp2_age (- ) Effect of age on Vp2 1.95 23.8 2.69 * 10−5 - - -
PRU0 (PRU) Variability in baseline PRU 0 Fix - 0.0694 7.15 6.95
PD50 (- ) Half- maximum PRU signal 0.278 1.44 - 0.05 fix -
γ (- ) Hill coefficient for PRU signal 2.49 3.89 - 0.641 4.89 71.3
R0 (- ) Baseline receptor 1 Fix - - - -
kout (1/h) Receptor elimination rate
constant
0.00641 7.94 - 0.755 10.6 87.7
E50 (- ) Half- maximum cumulative effect 0.0473 1.90 - 0.05 fix 5.00
γc (- ) Hill coefficient cumulative effect 3.63 2.19 - 0.05 fix 5.00
kCum (1/h) Rate constant cumulative effect 0.00820 1.70 - 0.05 fix 5.00
kSel (L/nmol/h) Selatogrel binding rate constant
to receptor
6.57 3.49 - 0.05 fix 5.00
KdSel (nmol/L) Selatogrel dissociation constant 11.0 4.10 - 0.542 6.20 58.4
βKdSel _AMI (- ) AMI on KdSel 1.60 10.7 <2.2 * 10−16 - - -
MkSel (- ) Selatogrel maximum cumulative
effect
2.22 1.81 - 0.05 fix 5.00
(Continues)

742
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HENRICH Et al.
defined based on PRU, lower naïve baseline PRU resulted in
a higher proportion of responders. Presence of AMI led to a
shorter PD effect (PRU returned to 100 after 4.1h compared
with 13 h) with a lower proportion of responders (76.3%
compared with 99.7%).
A sensitivity analysis to assess the influence of imput-
ing missing naïve baseline PRU (PRU0) due to concomitant
P2Y12 background therapy showed that model parameter es-
timates remained stable with PRU imputations of 150, 180,
200, 220, and 250. Comparing parameter estimates for these
imputations, only kout and its interindividual variability as
well as interindividual variability of PRU0 and kPr changed
by more than 10% (TableS2).
Model predictions of selatogrel in combination
with clopidogrel and prasugrel
Based on the model predictions of different dosing times
of clopidogrel after selatogrel, a clopidogrel loading dose
(600 mg) administered ≥15 h after selatogrel did not lead
to an interaction of >20 percentage points IPA at times 24
and 36h (Figure4). A prasugrel loading dose (60mg) could
be administered ≥4.5h after selatogrel without a clinically
relevant interaction.
To address interindividual variability, an extended
simulation was conducted that included the estimated
random effects of the PD model parameters. The simula-
tions are limited in that no individual PK data were avail-
able for clopidogrel and prasugrel such that all estimated
variability had to be attributed to the PD parameters. The
simulations confirmed the known large interindividual
variability for clopidogrel and showed a shift in predic-
tion intervals similar to the shift in median PD effects
(FigureS6).
DISCUSSION
To our knowledge, this work is the first semimechanistic PK/
PD model describing the effect of multiple concurrent P2Y12
inhibitors with receptor- level interactions, including the in-
vestigational drug selatogrel. The model was used to evaluate
clinically relevant scenarios of combined uses of selatogrel and
other P2Y12 inhibitors and to determine the time to safely and
efficaciously transition to oral P2Y12 inhibitors after s.c. emer-
gency administration of selatogrel in suspected cases of AMI.
The PK/PD model included a nonlinear relation be-
tween receptor occupancy and PRU as described in the lit-
erature.16,28 The estimated elimination rate constant of the
P2Y12 receptor (kout) corresponds to an average life span of
6.5 days, approximately in line with the physiological life
span of platelets of 7.1 to 9.5days.29,30
The PK/PD model included an adjustment, that is, the
cumulative effect compartment, for nonlinearity in the bind-
ing of selatogrel alone and in combination with oral P2Y12
receptor antagonists to the P2Y12 receptor. Different physi-
ological hypotheses could explain the empirical implemen-
tation of the observed nonlinearity. Platelet aggregation is
a complex process with many factors involved. Synergistic
Parameter Description
Fixed effects parameters
Interindividual variability
(random effects)
Estimate %RSE
P value
(covariates) Estimate %RSE %CV
kPr (L/nmol/h) Prasugrel binding rate constant
to receptor
0.0071 12.6 - 0.724 18.6 83.0
MkPr (- ) Prasugrel maximum cumulative
effect
1.32 1.92 - 0.05 fix 5.00
kClo (L/nmol/h) Clopidogrel binding rate constant
to receptor
0.00773 Fix - 0.492 fix 52.3
kTi (L/nmol/h) Ticagrelor allosteric binding rate
constant to receptor
2.21 Fix - 0.05 fix 5.00
KdTi (nmol/L) Ticagrelor dissociation constant 193 Fix - 0.489 fix 52.0
Residual error term
b1 Proportional error for PK 0.140 1.72
a2 Additive error for PD 3.65 2.90
b2 Proportional error for PD 0.170 2.07
CV (%)=
100 ⋅
√
e𝜔2
−1
with ω the standard deviation of the associated random effect. P values derived from the Wald test.
Abbreviations: %CV, coefficient of variation; %RSE, relative standard error; AMI, acute myocardial infarction; PD, pharmacodynamics; PK, pharmacokinetics; PRU,
P2Y12 reaction units.
TABLE 2 (Continued)

|
743
PK/PD MODELING OF P2Y12 RECEPTOR DDI
effects between ADP and nitric oxide,31,32 prostacyclin,33
and prostaglandin E1
34 were postulated. Another hypothesis
is the occurrence of positive cooperativity, that is, the bind-
ing of a molecule to a receptor resulting in an increase of
binding affinity of the binding sites. Such positive coopera-
tivity can occur for the binding of molecules with multiple
binding sites,35 as suggested for the P2Y12 receptor.36 This
phenomenon is consistent with the observations in the pres-
ent data analysis.
Finally, P2Y12 receptors desensitize in vitro to ADP rap-
idly upon receptor occupation.37 Although the prolonged
binding to the receptor is caused by an antagonist in this
case, it is possible that a similar desensitization of binding to
ADP after selatogrel dissociation occurs. This would result in
an apparent stronger IPA for higher doses due to prolonged
binding to the receptor.
The selatogrel dissociation constant KdSel was estimated
to be 11.0nmol/L, approximately seven times the observed
in vitro value (1.5nmol/L, data on file). Similarly, the dis-
sociation constant of ticagrelor was estimated substantially
higher than described in literature (193 nmol/L compared
with 10.5nmol/L).38 The differences in binding kinetics be-
tween in vitro experiments and this analysis probably result
from the different model structure that includes the cumula-
tive effect.
The model included the ability of ticagrelor to bind to
the allosteric binding site of the P2Y12 receptor, making it
an allosteric antagonist.39,40 This binding can occur even if
a reversible P2Y12 receptor antagonist such as selatogrel is
bound to the ADP binding site. The allosteric binding of ti-
cagrelor will cause selatogrel to dissociate from the receptor.
This mechanistic element in the model reflecting the actual
receptor- antagonist interactions was found to provide the best
description of the observed joint effect of ticagrelor and se-
latogrel, strengthening confidence in the predictive perfor-
mance of the model.
FIGURE 2 Pharmacokinetic/pharmacodynamic model structure. Solid lines, mass transfers; dashed lines, no mass transfer. Cum, cumulative
effect; E50, half- maximum for cumulative effect; fkPr, factor resulting from cumulative effect modulating prasugrel binding; fkSel, factor resulting
from cumulative effect modulating selatogrel binding; fRf, fraction of free receptor; kClo, clopidogrel binding rate constant to receptor; kCum, rate
constant for cumulative effect; KdSel, selatogrel dissociation constant; KdTi, ticagrelor dissociation constant; kin, formation rate constant of receptor;
koffSel, dissociation rate constant of receptor complex with selatogrel; koffTi, dissociation rate constant of receptor complex with ticagrelor; kout,
receptor elimination rate constant; kPr, prasugrel binding rate constant to receptor; kSel, selatogrel binding rate constant to receptor; kTi, ticagrelor
allosteric binding rate constant to receptor; MkPr, prasugrel maximum cooperativity effect; MkSel, selatogrel maximum cooperativity effect; PD50,
half- maximum for PRU signal; PRU, P2Y12 receptor units; PRU0,baseline P2Y12 receptor units; R0, baseline receptor; Rf, free receptor; γ, Hill
coefficient for PRU signal; γc, Hill coefficient for cumulative effect

744
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HENRICH Et al.
The PK model included body weight and age as covari-
ates on multiple PK parameters influencing absorption, dis-
tribution, and elimination. Older subjects showed a slower
absorption, lower clearance, and smaller volume of distribu-
tion, possibly explained by reduced skin perfusion41 and liver
function. Reduced volume of distribution is typical for polar
drugs42 such as selatogrel. Despite significant effects of body
weight and age on PK, the effect on onset and maximum plate-
let inhibition was limited. Nevertheless, higher exposure led to
a prolonged effect on IPA. The proportion of responders was
not influenced to a relevant extent since also with low expo-
sure, for example, due to high body weight of 150kg, median
PRU remained below 100 for 9.3h after selatogrel dosing.
With respect to PK/PD, the presence of AMI (i.e., pa-
tients vs. healthy subjects) was statistically significant on
the selatogrel dissociation constant leading to shorter IPA.
The reduced effect of selatogrel might result from increased
platelet reactivity during AMI.43,44 PD measurements in pa-
tients in the phase II study were only performed up to 1h
after selatogrel dosing.13 Therefore, the effect of AMI re-
quires further investigation to validate the model prediction
beyond 1h for patients with AMI. Observed naïve baseline
PRU influenced the PRU profile since it is contained in the
baseline model. Plausibly, subjects with lower naïve baseline
PRU are more likely to remain below the 100 PRU threshold
while this is more difficult to achieve for subjects with higher
naïve baseline PRU. Correction for baseline, that is, using
percent IPA, eliminates these differences.
All PK and PK/PD model parameters were estimated
with high precision. The PK model described the selatogrel
FIGURE 3 Covariate effects on pharmacokinetic and pharmacodynamic after 16mg selatogrel administration. Lines, median shaded
areas, 90% prediction interval (including 90% of simulated subjects with interindividual variability), values in the top row panels, area under the
concentration- time curve between 0 and 48h after selatogrel administration; values in the middle row panels, proportion of responders, that is,
subjects with PRU <100 from 0.5 to 3h after selatogrel administration. Reference subject: body weight 70kg, age 60years, naïve baseline PRU
200, and disease status healthy/CAD. AMI, acute myocardial infarction; IPA, inhibition of platelet aggregation; PRU, P2Y12 reaction units; PRU0,
naïve PRU measured at baseline; WT, body weight

|
745
PK/PD MODELING OF P2Y12 RECEPTOR DDI
concentration data well for all studies and doses. The additional
absorption and distribution compartments particularly improved
the fit of low selatogrel concentrations. These are important for
the PD effect since the half- maximum inhibitory concentration
is low (41.9pmol/L = 25.9ng/ml)45 compared with the concen-
trations reached (435ng/ml geometric mean maximum concen-
tration after 16mg of selatogrel).1 VPCs showed a good fit for
the mean selatogrel PD effect and its variability. Median PRU
FIGURE 4 Joint effects of selatogrel, clopidogrel, and prasugrel on platelet aggregation for selected transition regimens. Model predictions
of a reference subject with dosing of selatogrel (16mg at time 0h) and/or clopidogrel (600mg; a) and prasugrel (60mg; b) at different timepoints
relative to selatogrel. Vertical arrows visualize the decision criterion for administration of clopidogrel 15h after selatogrel/placebo and prasugrel
4.5h after selatogrel/placebo. IPA, inhibition of platelet aggregation; PRU, P2Y12 reaction units

746
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HENRICH Et al.
effects for prasugrel and ticagrelor alone were well described,
whereas PRU was slightly overestimated for clopidogrel alone
for one of the 600- mg cohorts and the 300- mg cohort in the
SWITCH study. The model adequately characterized the me-
dian PRU profiles of the combinations of selatogrel with all
three oral P2Y12 receptor antagonists. The variability in PD of
the oral P2Y12 receptor antagonists and their combination with
selatogrel was generally overestimated, possibly inflated in the
PK/PD model as only population- average PK data of the oral
P2Y12 inhibitors without variability were available. Particularly
clopidogrel is known to have a high variability in the PK of the
active metabolite due to genetic polymorphisms and environ-
mental factors.6 This variability was reflected in the variability
of the effect parameters of these compounds when administered
alone with interindividual variability of up to 83%. Further indi-
vidual data including PK of the oral P2Y12 receptor antagonists
are needed to differentiate between interindividual variability in
PK and PD to reduce model uncertainty and overestimation of
variability.
Model predictions were used to interpolate and extrapolate
different dosing intervals between selatogrel and clopidogrel/
prasugrel administration. Extrapolation (for clopidogrel ad-
ministration with data at 12h and extrapolation to 15h after
selatogrel administration) requires more caution than inter-
polation (for prasugrel); however, the extrapolation in time
is not very large.
These simulations showed that loading doses of clopido-
grel and prasugrel can be administered from 15h and 4.5 h
after selatogrel, respectively, without clinically relevant PD
drug interactions.
The PK/PD model developed here describes the effect
of s.c. selatogrel on platelet inhibition alone and in combi-
nation with the oral P2Y12 receptor antagonists clopidogrel,
prasugrel, and ticagrelor in a semimechanistic manner. It was
used to evaluate the interactions of multiple antagonists at the
P2Y12 receptor and its effect on PRU/IPA. These results are
helpful to guide the transition from emergency treatment with
selatogrel to oral maintenance therapy safely and effectively.
ACKNOWLEDGMENTS
The authors thank Dr. Markus Riederer and Martine Baumann
(Idorsia Pharmaceuticals Ltd, Drug Discovery Biology) for
the fruitful discussions throughout the project and Mrs. Chih-
hsuan Hsin for help with simulations of scenarios.
CONFLICT OF INTEREST
A.H., J.D., and A.K. were employees of Idorsia at the timing
of writing the manuscript. C.H.C. worked as a consultant for
Idorsia on this project.
AUTHOR CONTRIBUTIONS
A.H., C.H.C., J.D., and A.K. wrote the manuscript, designed
the research, performed the research, and analyzed the data.
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SUPPORTING INFORMATION
Additional supporting information may be found online in
the Supporting Information section.
How to cite this article: Henrich A, Claussen CH,
Dingemanse J, Krause A. Pharmacokinetic/
pharmacodynamic modeling of drug interactions at
the P2Y12 receptor between selatogrel and oral P2Y12
antagonists. CPT Pharmacometrics Syst. Pharmacol.
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