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					                The Journal of Clinical
                   Pharmacology
                                              http://www.jclinpharm.org



Population Pharmacokinetic Analysis of the New Oral Thrombin Inhibitor Dabigatran Etexilate
   (BIBR 1048) in Patients Undergoing Primary Elective Total Hip Replacement Surgery
 Iñaki F. Trocóniz, Christiane Tillmann, Karl-Heinz Liesenfeld, Hans-Günter Schäfer and Joachim Stangier
                                      J. Clin. Pharmacol. 2007; 47; 371
                                      DOI: 10.1177/0091270006297228

                              The online version of this article can be found at:
                          http://www.jclinpharm.org/cgi/content/abstract/47/3/371


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                                    American College of Clinical Pharmacology



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        Population Pharmacokinetic Analysis
         of the New Oral Thrombin Inhibitor
      Dabigatran Etexilate (BIBR 1048) in Patients
        Undergoing Primary Elective Total Hip
                 Replacement Surgery
               Iñaki F. Trocóniz, PhD, Christiane Tillmann, BSc, Karl-Heinz Liesenfeld,
                         Hans-Günter Schäfer, PhD, and Joachim Stangier, PhD



Dabigatran etexilate (BIBR 1048) is an orally bioavailable                     and serum creatinine influenced ka, whereas gastrin and
double prodrug of the active principle dabigatran (BIBR 953                    creatinine clearance, only for days 2 to 10, affected CL/F
ZW), which exerts potent anticoagulant and antithrombotic                      (P < .001). The typical values for CL/F for a patient with gas-
activity. The objective of the analysis was to develop a pop-                  trin of 34.58 pmol/L and creatinine clearance of 76.16
ulation pharmacokinetic model characterizing and quanti-                       mL/min were 70.87 and 106.2 L/h on days 0 and 1 and days
fying the relationship between covariates and model                            2 to 10, respectively. The differences found in the pharma-
parameters. A total of 4604 BIBR 953 ZW plasma concen-                         cokinetics of dabigatran during the first 24 hours after
trations, obtained from 287 patients after once- or twice-                     surgery are most likely due to alterations in gastric motility
daily oral dosing for up to 10 days after surgery in the dose                  and pH following surgery. As a consequence, the rate of
range 12.5, 25, 50, 100, 150, 200, and 300 mg BIBR 1048,                       absorption is reduced and interindividual variability in
were available for the analysis. All the analyses were per-                    drug exposure increased. On the following days, the dispo-
formed with NONMEN V. Pharmacokinetics of dabigatran                           sition in plasma of BIBR 953 ZW is less variable.
were best described by a 2-compartment model. The data
supported the estimation of different apparent first-order                     Keywords:  dabigatran etexilate in total hip replacement;
absorption rate constants (ka) and apparent plasma clear-                                 population pharmacokinetics; NONMEM
ances (CL/F) for days 0 and 1 and days 2 to 10 after surgery.                     Journal of Clinical Pharmacology, 2007;47:371-382
Parameter estimates indicated a flip-flop phenomenon. Age                      ©2007 the American College of Clinical Pharmacology




T     hrombin, a trypsin-like serine protease, holds a
      central role in the process of thrombosis and
                                                                               hemostasis. It is a key enzyme in the blood coagula-
                                                                               tion cascade, exhibiting both pro- and anticoagulant
                                                                               properties.1 Given the key role of thrombin in throm-
                                                                               botic events, thrombin inhibition represents a thera-
From the Department of Pharmacy and Pharmaceutical Technology;                 peutic target for numerous thromboembolic diseases.
School of Pharmacy; University of Navarra, Pamplona, Spain (Dr Trocóniz)          BIBR 953 ZW (dabigatran) is a novel, synthetic,
and Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany               nonpeptidic, potent, specific, competitive, and
(Ms Tillmann, Mr Liesenfeld, Dr Schäfer, Dr Stangier). Conflict of interest:   reversible inhibitor of thrombin. Because BIBR 953
Trocóniz is a consultant for Boehringer Ingelheim and has declared no          ZW is not orally bioavailable, BIBR 1048, dabigatran
conflict of interest with regard to this publication. Submitted for publi-     etexilate, a double prodrug of BIBR 953 ZW conveying
cation July 27, 2006; revised version accepted November 5, 2006.
Address for correspondence: Christiane Tillmann, Boehringer Ingelheim
                                                                               oral bioavailability, has been synthesized.2 After oral
Pharma GmbH & Co. KG, Birkendorfer Str. 68, 88397 Biberach, Germany;           absorption, dabigatran etexilate is converted into the
e-mail: Christiane.Tillmann@bc.boehringer-ingelheim.com.                       active moiety, BIBR 953 ZW. Dabigatran etexilate is
DOI: 10.1177/0091270006297228                                                  under development as an orally active anticoagulant


J Clin Pharmacol 2007;47:371-382                                                                                                         371
                                                TROCÓNIZ ET AL


for the prevention of venous thromboembolism after         Inclusion and Exclusion Criteria
orthopedic surgery and for the long-term prevention of
stroke in patients with atrial fibrillation.3,4            The inclusion criteria were as follows: men or
   The pharmacokinetics (PK) of BIBR 953 ZW,               women 18 years or older scheduled to undergo a
obtained from phase I studies, show linear behavior,       primary elective total hip replacement, weighing
biexponential kinetics in plasma, and a terminal           at least 40 kg, and giving a written informed con-
half-life of 12 to 14 hours. The drug is mainly elimi-     sent for study participation. Patients fulfilling 1 of
nated by renal excretion because, after intravenous        the following criteria were excluded from the
administration of BIBR 953 ZW, urinary recovery            trial: bleeding diathesis; gastrointestinal or pul-
amounts to 80% of the dose. BIBR 953 ZW is meta-           monary bleeding within the past year; constitutional
bolically stable, and cytochrome P450 isoenzymes           or acquired coagulation disorders; cardiovascular
are apparently not involved in its metabolism. With        disease, including uncontrolled hypertension at
regard to the absorption characteristics, its bioavail-    time of enrollment or history of myocardial infarc-
ability (F) is susceptible to elevated gastric pH if       tion within the past 6 months; known liver, renal, or
administered as a preliminary tablet formulation, as       active malignant disease; history of deep venous
used in the BISTRO I study.5                               thrombosis or thrombocytopenia; major surgery or
   To date, the population PK of BIBR 953 ZW in            trauma within the past 3 months (hip fractures
patients have not been reported, and therefore the aim     associated with plate revisions at any time) or leg
of the current study is to develop a population PK         amputee; any history of hemorrhagic stroke; intracra-
model of BIBR 953 ZW after administration of the           nial or intraocular bleeding or cerebral ischemic
prodrug dabigatran etexilate in patients undergoing        attacks; use of long-term anticoagulants, antiplatelet
elective total hip replacement, assessing the interindi-   drugs, or fibrinolytics within 7 days prior to hip
vidual and residual variability in the PK model para-      replacement operation; current H2-blocker, proton
meters and identifying covariates potentially affecting    pump inhibitor, or cytostatic treatment; treatment
BIBR 953 ZW plasma concentrations in a clinically          with an investigational drug in the past month;
significant degree. Information on drug exposure           known allergy to radio opaque contrast media;
obtained in this first study in patients supported the     alcohol or drug abuse; and women of childbearing
planning of a phase IIb dose range finding study.          potential.

METHODS                                                    Drug Administration

Study Design                                               The study treatment was to be continued for 6 to 10
                                                           days after surgery. The first dose was given 4 to 8
This was a randomized, multicenter (Sweden [n = 11]        hours after completion of the surgery (ie, in the after-
and Norway [n = 7]), open-label, dose escalation phase     noon of day 0). The next dose was given on the fol-
IIa study, with dabigatran etexilate in the prevention     lowing day (day 1) at approximately 8:00 AM, resulting
of venous thromboembolism in patients undergoing           in a dosing interval of about 12 to 16 hours. If the
primary elective hip replacement surgery, BISTRO I.        patient vomited or had bleeding events after the oper-
Institutional review board approval was obtained by        ation, the first dose of dabigatran etexilate could be
health authorities and ethics committees governing         postponed until the morning after surgery. Study drug
the investigators and sites listed in the appendix.        could be administered either at fasted or fed condi-
   In total, 289 patients received dabigatran etexilate    tions. For twice-daily dosing regimens, study drug
orally at dose levels of 12.5 (n = 27), 25 (n = 28), 50    was administered in the morning and in the evening.
(n = 30), 100 (n = 40), 150 (n = 29), 200 (n = 28), and    For once-daily dosing regimens, study drug was
300 (n = 20) mg bid or 150 (n = 41) and 300 (n = 46)       administered in the morning.
mg qd. Of the 289 patients who received study med-            Study medication consisted of tablets of dabigatran
ication, 262 completed the study, and 27 discontinued      etexilate, which were manufactured in strengths of
prior to study completion, but all data available from     12.5-, 25-, 50-, 100-, and 200-mg free base of dabiga-
these patients were included in the analysis. Two          tran etexilate by Boehringer Ingelheim (Biberach,
patients were excluded because no PK information           Germany). The experimental tablet formulation did
was provided by these patients. Table I lists the demo-    not contain excipients maintaining drug solubility at
graphic characteristics of the studied population.         elevated gastric pH.



372 • J Clin Pharmacol 2007;47:371-382
                            NEW ORAL THROMBIN INHIBITOR DABIGATRAN ETEXILATE


                                    Table I      Summary of Demographic Characteristics
Covariate                                                                            Mean (SD)                              Range

Time to first dose after surgery (TTFD), h                                        6.448 (4.43)                            1.42-21.83
Age (AGE), y                                                                     66.97 (9.7)                                35-88
Body weight (WT), kg                                                             78.21 (14.9)                               49-130
Height (HGT), cm                                                                170.5 (9)                                  150-203
Body mass index (BMI), kg/m2                                                     26.78 (3.9)                             18.14-39.64
Serum creatinine (SCR), mg/dL                                                     0.964 (0.2)                             0.66-1.81
Creatinine clearance (CRCL), mL/mina                                             76.16 (24.3)                            29.35-161.1
Serum gastrin (GAST), pmol/L                                                     34.58 (55)                                 10-501
Alanine transferase (ALT), U/L                                                   47.36 (42)                                  8-457
Aspartate transferase (AST), U/L                                                 33.81 (22)                                  6-203
Bilirubin (BIL), mg/L                                                             4.543 (1.9)                             1.17-12.28
Cigarette consumption (PACK), packs/y                                             4.997 (11)                                 0-75
Fasting condition (FAST)
  Fasted                                                                         55
  Fed                                                                            45
Gender (SEX)
  Male                                                                           47
  Female                                                                         53
Alcohol consumption (ASTA)
  No alcohol                                                                     20
  Average consumption                                                            80
  Excessive consumption                                                           0
Smoking Status (SMOK)
  Never smoked                                                                   54
  Ex-smoker                                                                      31
  Current smoker                                                                 15
Comedication (COM)
  CYP 3A4 inhibitors (COM2)                                                      10
  Acceleration of GI passage (COM3)                                              28
  NSAIDS (COM7)                                                                  14
  Diuretics (COM9)                                                               20
  Paracetamol (COM10)                                                            70
  Opioids (COM11)                                                                57
  Others (COM12)                                                                 73
  Benzodiazepines (COM13)                                                        21
  Categorical covariates (FAST, SEX, ASTA, SMOK, COM) are expressed as percentage.
  a. Computed using the Cockcroft-Gault equation.



Sample Collection                                                            Day 5 until the last treatment day: sample taken imme-
                                                                                diately before the morning dose and 1 additional
Plasma concentrations of BIBR 953 ZW were deter-                                sample at 2 hours postdose except for the last treat-
mined on the basis of the following blood sampling                              ment day
scheme:
                                                                         In a subpopulation, a more extensive pharmacoki-
   Day 0, surgery: sample collected after surgery, before                netic sampling scheme with 7 blood samples col-
      drug administration (predose), and sample taken 4                  lected on day 4 was performed in only 1 center at the
      hours after drug administration                                    following specific times: predose and 0.5, 1, 2, 4, 8,
   Days 1 to 3: sample taken immediately before the                      12, and 14 hours postdose (2 hours after evening
      morning dose and 1 additional sample at 2 hours                    dose on twice-daily regimen). The blood sampling
      postdose                                                           scheme in all the study patients and on day 4 of
   Day 4: samples taken at trough and from 0 to 2, 2 to 4,               treatment in the subpopulation mentioned above is
      4 to 8, and 8 to 12 hours postdose                                 represented in Figure 1.


QUANTITATIVE CLINICAL PHARMACOLOGY                                                                                              373
                                                     TROCÓNIZ ET AL




Figure 1. Upper panel: Blood sampling scheme in all study patients. Lower panel: Sampling scheme in substudy patient on day 4 of
treatment. PK, pharmacokinetics; PD, pharmacodynamics.


Bioanalytical Method                                              electrospray ion source with atmospheric pressure
                                                                  ionization was used for measurement performed
Quantitative measurement of dabigatran and dabiga-                in the positive ionization mode. Separation was
tran glucuronide plasma concentrations was per-                   achieved by direct injection onto a precolumn and
formed using a liquid chromatography/tandem mass                  subsequent transfer by column switching onto a
spectroscopy (LC/MS/MS) method. Briefly, 80 µL                    high-performance liquid chromatography (HPLC)
of plasma was analyzed using a Sciex API 3000                     column (purospher RP-18 E analytical column [60 ×
(PerkinElmer, Boston) LC/MS/MS system. The inter-                 2 mm, 5 µm]). Monitored ions were 472.2       289.5
nal standard was [13C6]-labeled BIBR 953 ZW. An                   (dabigatran), 478.2   295.6 (internal standard), and


374 • J Clin Pharmacol 2007;47:371-382
                      NEW ORAL THROMBIN INHIBITOR DABIGATRAN ETEXILATE


648.2      288.9 (dabigatran glucuronide). The lower        BIBR 953 ZW is mainly eliminated by renal excre-
limit of quantification (LOQ) was 1 ng/mL. The lin-      tion, which led to the expectation that renal function
earity of the method (ie, the mean correlation coeffi-   status would have a major effect on CL/F, the appar-
cient of the standard curves) was 0.99953. At the        ent plasma clearance. Therefore, creatinine clear-
lower limit of quantification, the precision of the      ance (CRCL) was tested a priori during the basic
analytical method was 6.67% coefficient of variation     model development. In addition, and taking into
(CV), and accuracy (bias) was –2.66%.                    account that the absorption process might be slower
                                                         directly after surgery than on the following days
Data Analysis                                            because the motility of the gastrointestinal tract is
                                                         decreased because of surgical trauma and comedica-
Total BIBR 953 ZW (free plus conjugated BIBR 953         tions,10 day of surgery was also tested as a categorical
after cleavage of the glucuronide conjugate) in plasma   covariate on the absorption parameters.
has been used for population PK analysis. BIBR 953       2. Covariate model selection. Table I shows the covari-
ZW is subject to conjugation with glucuronic acid        ates tested for significance. Categorical covariates were
to yield pharmacologically active acylglucuronides.      investigated only if at least 2 categories were available,
Because the thrombin inhibitory potency of those         and each represents more than 10% of the population.
conjugates is comparable to free, nonconjugated BIBR     Therefore, only 8 out of 18 comedication classes were
953 ZW, the use of total BIBR 953 ZW, which is free      tested as covariates. Also vomiting, considered as a
plus BIBR 953 ZW released from conjugates after          potentially significant covariate, was not tested because
alkaline cleavage, was considered necessary.             of the above criteria. Each covariate was added indi-
   The population PK analyses and simulations were       vidually to the base model. Covariates were then
carried out in concordance with the Food and Drug        incorporated, starting with the covariate that led to
Administration (FDA) guidance on population phar-        the largest drop in –2LL, one at a time until the full
macokinetics,6 using the software NONMEM (Version        covariate model was obtained (forward inclusion).
V) and the first-order conditional estimation method     Afterward and starting from the full model, if a covari-
with the INTERACTION option implemented in               ate was found to be not significant, it was dropped in
NONMEM.7,8                                               favor of the simpler model, and this continued until
   Model selection was done based on a number of         no more terms could be dropped (backward elimi-
criteria such as the goodness-of-fit plots, preci-       nation). During the forward inclusion and backward
sion of model parameter estimates, and the differ-       elimination, the significance levels used were 5% and
ence in the minimum value of the objective function      0.1%, respectively.
(–2 log[likelihood]; –2LL) provided by NONMEM. A
difference of 3.84, 6.63, and 10.8 points in –2LL        3. Model evaluation. The final population PK model
between 2 nested models differing by 1 parameter is      was evaluated using internal evaluation methods.
significant at the 5%, 1%, and 0.1% levels, respec-      One hundred new data sets with the same number of
tively. The model-building process was performed         patients, the same covariates, and the same dosing
in 3 steps:                                              history and sampling schedule as the original data
                                                         set were simulated, based on the model parameters
1. Development of the basic population model. A          estimated from the original data set. Then model
model without incorporating any of the covariates        parameters were estimated for each of the simulated
was first developed. Disposition of drug in plasma       data sets. Bias and precision of the population PK
was described by compartmental models parameter-         model parameter estimates were evaluated by com-
ized in terms of elimination and distribution clear-     puting, across the simulated data sets, the median
ances, as well as apparent volumes of distribution.      performance error (MPE) and the median of the
Drug absorption was described using a first-order        absolute performance error (MAPE).11 For each of
rate of absorption model. Interindividual variability    the simulated data sets, the performance error (PE)
(IIV) was modeled exponentially, and a combined          for a specific PK parameter was estimated as follows:
error model was initially used to account for the        PE = [(Psim – Por)/Por] × 100, where Psim and Por were
residual variability. No interoccasion variability was   the population estimate for a parameter using the
tested because there was only 1 visit with more          simulated data set and the final model parameter
than 1 plasma sample per occasion.9 During this          obtained from the original data set, respectively. The
step, the significance of the off-diagonal elements of   absolute performance error (APE) was defined as the
the variance-covariance matrix Ω was also evaluated.     absolute value of PE.


QUANTITATIVE CLINICAL PHARMACOLOGY                                                                            375
                                                       TROCÓNIZ ET AL




Figure 2.   Observed plasma dabigatran concentrations versus time after last administered dose for each dose group.


   The impact of the selected covariates on the plasma               plasma (including glucuronides), from 287 patients
concentration versus time profiles was investigated by               were used in the current analysis. The distributions
computer simulations. For the case of a continuous                   of observations, sampling times, and patients per
covariate, 1000 individuals were simulated for each of               dose group can be considered balanced. Figure 2
the values corresponding to the 5th, 50th, and 95th                  shows the observed plasma concentration versus
percentiles of the covariate in the studied population,              time profiles of BIBR 953 ZW for each of the dose
assuming a 5-day treatment with BIBR 1048 adminis-                   groups and schedule of administration.
tered bid at the dose of 150 mg.
   The results from the population analysis were                     Development of the Basic Model
expressed as the parameter estimates together with the
relative standard error (RSE), computed as the ratio                 A 2-compartment model with first-order elimina-
between the standard error given by NONMEM and                       tion, parameterized in terms of CL/F, V2/F (apparent
the estimate of the parameter. The degree of interindi-              volume of distribution of the central compartment),
vidual and residual variability was expressed as CV%.                V3/F (apparent volume of distribution of the periph-
                                                                     eral compartment), and Q/F (apparent distribution
RESULTS                                                              clearance), described the disposition of the drug in
                                                                     plasma significantly better than the 1-compartment
A total of 4604 observations, consisting of measure-                 model (P < .001). A 3-compartment model was not
ments of concentrations of total BIBR 953 ZW in                      statistically better than the 2-compartment model

376 • J Clin Pharmacol 2007;47:371-382
                                   NEW ORAL THROMBIN INHIBITOR DABIGATRAN ETEXILATE


        Table II Pharmacostatistical Structure of                                   to the pharmacostatistical structure of the selected
              the Selected Basic Population                                         basic population model, and Table III lists the model
                Pharmacokinetics Model                                              parameter estimates and RSE for the basic popula-
                                                                                    tion model.
CL/F(<24 h) = θCL(<24 h) × eηCL(<24 h)
                                  CRCL                                              Covariate Model Selection
CL/F(>24 h) = θCL(>24 h) ×              ×eηCL(>24 h)
                                  76.17
V2/F = θV2
                                                                                    CL/F(<24 h) and CL/F(>24 h) were influenced by fasted
Q/F = θQ                                                                            serum gastrin concentrations (GAST) significantly
V3/F = θV3                                                                          (P < .001). Serum creatinine concentrations (SCR)
ka(<24 h) = θka(>24 h)                                                              and age (AGE) were covariates significantly affecting
ka(>24 h) = θka(>24 h) × eηka(>24 h)                                                ka(>24 h) (P < .001). An increase in both SCR and AGE
Residual error model:                                                               would result in a slower absorption rate.
                ^      ^
   Y(<24 h) = Y + Y × ε1                                                               Based on a decrease in –2LL, comedication classes
                ^      ^
   Y(>24 h) = Y + Y × ε2 + ε3                                                       COM3 (gastrointestinal passage accelerating drugs) and
                                                                                    COM12 (other drugs) were found to significantly affect
    CL/F, apparent total plasma clearance; V2/F, apparent volume of distri-
    bution of the central compartment; Q/F, apparent distribution clear-
                                                                                    CL/F (P < .001). In addition, it was found that patients
    ance; V3/F, apparent volume of distribution of the peripheral                   of the 12.5-mg and 25-mg dose groups and patients
    compartment; ka, apparent first-order rate constant of absorption; (<24         receiving once-daily treatment would show a slightly
    h), estimate corresponding to days 0 and 1 (day of surgery); (>24 h),
    estimate corresponding to days 2 to 10; θCL, V2, Q, V3, and ka, typical popu-
                                                                                    faster absorption. However, in all cases, the 95% confi-
    lation parameter estimates corresponding to CL/F, V2/F, Q/F, V3/F, and          dence intervals of the parameter estimates were over-
    ka, respectively; CRCL, creatinine clearance; ηCL, ηka, expressions corre-      lapping, and the respective covariates explained only a
    sponding to the interindividual variability in CL/F and ka, respectively;       negligible portion of IIV. Therefore, those results did
                                                                     ^  ^      ^
    Y and ε, observed and predicted plasma concentrations; Y1, Y2, and Y3,
    expressions corresponding to the residual variability.                          not represent a biological/physiological significance,
                                                                                    and consequently, they were not retained in the model.
                                                                                    None of the other covariates was found to significantly
(P > .05). Drug absorption was best described with                                  decrease –2LL (P > .05).
a first-order model including a lag time, although                                     Table IV shows the expressions corresponding to
other models, such as the zero-order model and the                                  the pharmacostatistical structure of the selected final
combination of zero- and first-order models, were                                   population model where all parameters appear esti-
also tested.                                                                        mated with adequate precision, and Table III lists also
   CRCL was found to have a linear and significant                                  the model parameter estimates and RSE for the final
effect on CL/F from days 2 to 10 (CL/F(>24 h), P < .001),                           population model. Figure 3 represents the goodness-
and absorption could be best described computing                                    of-fit plots split by dose group and treatment schedule.
different estimates of the apparent first-order rate                                For the population predictions, the tendency to
constant of absorption (ka) for days 0 to 1 (ka(<24 h))                             underpredict high concentrations was always present,
and for days 2 to 10 (ka(>24 h)). CL/F was also found to                            although different models for disposition or absorp-
be different on days 0 to 1 (CL/F(<24 h)) and days 2 to                             tion were tested. Figure 4 represents the relationship
10 (P < .001).                                                                      between the individual model estimates of CL/F(>24 h)
   Visual inspection of the goodness-of-fit plots                                   and the individual values of CRCL together with the
showed that data from the once- and twice-daily                                     typical population model prediction.
dosing schemes were described similarly, providing
an indication that the pharmacokinetics of dabiga-                                  Model Evaluation
tran were not affected by those schedule differences.
   Interindividual variability was included expo-                                   The values of MPE for all the model parameters were
nentially on CL/F (different between days 0 to 1 and                                lower than ±6.2%, with the exception of the para-
days 2 to 10) and ka, although IIV on ka could only be                              meter CL/F(<24 h), which showed a value of +20.5%.
estimated for ka(>24 h). Off-diagonal elements of the                               With respect to the MAPE calculations, all parame-
variance-covariance Ω matrix were found to be                                       ters in the model showed values lower than 32%.
nonsignificant (P > .05). Residual variability was                                     Figure 5 displays the impact of the covariates SCR
accounted for using a combined and proportional                                     and AGE on ka(>24 h) with regard to the plasma concen-
error model for days 0 to 1 and days 2 to 10, respec-                               tration versus time profiles of BIBR 953 ZW. The values
tively. Table II shows the expressions corresponding                                for ka(>24 h) in Figure 5 correspond to the lowest, median,


QUANTITATIVE CLINICAL PHARMACOLOGY                                                                                                        377
                                                               TROCÓNIZ ET AL


  Table III      Parameter Estimates From the Selected Basic and Final Population Pharmacokinetic Models
Parameter                                                                                Basic Model                                         Final Model

CL/F(<24 h), L/h                                                                         67.5 (0.16)                                         43.4    (0.27)
Parameter for effect of GAST on CL/F(<24 h)                                                   —                                             0.633    (0.42)
IIV in CL/F(<24 h), CV%                                                                 120.8 (0.16)                                        108.6    (0.16)
CL/F(>24 h), L/h                                                                          103 (0.03)                                         82.1    (0.06)
Parameter for effect of GAST on CL/F(>24 h)                                                   —                                             0.294    (0.26)
IIV in CL/F(>24 h), CV%                                                                  50.2 (0.1)                                         46.04    (0.9)
V2/F, L                                                                                  36.6 (0.18)                                         30.8    (0.17)
Q/F, L/h                                                                                 22.5 (0.24)                                         13.6    (0.35)
V3/F, L                                                                                   219 (0.26)                                          136    (0.42)
ka(<24 h), h–1                                                                          0.025 (0.25)                                        0.022    (0.25)
ka(>24 h), h–1                                                                             0.1 (0.006)                                      0.265    (0.11)
Parameter for effect of SCR on ka(>24 h)                                                      —                                             0.363    (0.13)
Parameter for effect of AGE on ka(>24 h)                                                      —                                             0.447    (0.11)
IIV in ka(>24 h), CV%                                                                    37.7 (0.17)                                        29.83    (0.23)
ALAG1, h                                                                                   0.4 (0.09)                                          0.4   (0.08)
Proportional error (<24 h), CV%                                                          67.3 (0.03)                                         66.9    (0.03)
Additive error (<24 h), SD µg/L                                                            0.4 (0.12)                                       0.375    (0.12)
Proportional error (>24 h), CV%                                                          36.5 (0.05)                                        36.61    (0.05)
  Results are presented as parameter estimate with relative standard error in parentheses. CL/F, apparent total plasma clearance; V2/F, apparent volume
  of distribution of the central compartment; V3/F, apparent volume of distribution of the peripheral compartment; Q/F, apparent distribution clearance;
  ka, apparent first-order rate constant of absorption; ALAG1, lag time; IIV, interindividual variability; CV, coefficient of variation; GAST, serum gastrin
  concentration; SCR, serum creatinine; AGE, age; (<24 h), parameter corresponding for days 0 and 1 of treatment; (>24 h), parameters corresponding to
  days 2 to 10.



and highest values computed using the covariate model                           absorption and first-order elimination. Inclusion of a
selected and the lowest, median, and highest values                             lag time was also required. The main characteristic
of SCR and AGE in the studied population. Figure 6                              of the population model selected was the fact that
shows the median plasma concentration versus time                               the rate constant of drug absorption and the appar-
profiles together with the 5th and 95th percentiles sim-                        ent plasma clearance during days 0 and 1 of treat-
ulated for the following groups representing different                          ment were significantly lower (P < .01) compared to
renal impairment status: normal (CRCL > 90 mL/min),                             days 2 to 10. This finding can be explained by the
mild (60 < CRCL ≤ 90 mL/min), moderate (40 < CRCL                               fact that absorption might be slower directly after
≤ 60 mL/min), and moderate to severe (CRCL ≤ 40                                 surgery due to changes in gastrointestinal motility
mL/min). In Figure 7, the model-predicted differences                           caused by surgical effects or comedication (eg, opi-
between the pharmacokinetic characteristics of the                              oids).10 In this context, a comparison with the direct
first day of administration with respect to the rest of                         competitor melagatran is not possible because it was
the treatment period are presented.                                             given subcutaneously first, subsequently followed
                                                                                by oral administration for continuous treatment.12,13
DISCUSSION                                                                      Other model parameterizations were tested to account
                                                                                for the difference in systemic exposure between days
The current study represents the first population PK                            0 to 1 and days 2 to 10, by means of estimating rela-
analysis of dabigatran in patients, providing esti-                             tive bioavailability in conjunction with different
mates of the degree of interindividual variability and                          IIVs for these parameters, resulting in similar fits.
information on patients’ characteristics that signifi-                          However, because no intravenous data were avail-
cantly affect drug disposition. The disposition char-                           able to estimate absolute bioavailability of the oral
acteristics of dabigatran in plasma were described                              dosage form to confirm the change in clearance and/or
with the use of standard absorption and compart-                                in bioavailability, model development was contin-
ment models, and they show linear kinetic charac-                               ued from the basic model represented in Table II.
teristics with respect to the magnitude of the dose                                The estimate of ka(<24 h) of 0.022 h–1 corresponds to
administered and duration of treatment.                                         an absorption half-life of 31.5 hours, implying that a
   The pharmacokinetics of BIBR 953 ZW were best                                flip-flop situation with the ka(<24 h) is related to elimi-
described by a 2-compartment model with first-order                             nation rather than absorption. The flip-flop situations

378 • J Clin Pharmacol 2007;47:371-382
                                   NEW ORAL THROMBIN INHIBITOR DABIGATRAN ETEXILATE


    Table IV Pharmacostatistical Structure of the                                      CRCL values were below 120 mL/min, which justi-
      Final Population Pharmacokinetic Model                                           fies the use of the linear function. The covariate
                                                                                       model predicts an increase in drug exposure from
                                                     GAST                              day 2 onward of 11% for each 10-mL/min decrease
CL/F(<24 h) = θCL(<24 h) × 1 + θGAST1 ×                           ×eηCL(<24 h)
                                                     34.58                             in CRCL. Such prediction is very similar to the one
                                                                                       reported recently for ximelagatran in patients with
                                  CRCL                                                 acute deep vein thrombosis.13 Despite the statisti-
CL/F(>24 h) = θCL(>24 h) ×                                                             cally significant effect of CRCL on CL/F(>24 h), results
                                  76.17
                                                     GAST                              from simulations represented in Figure 6 show an
                               × 1 + θGAST2 ×                      ×eηCL(>24 h)        apparent degree of overlapping in the drug concen-
                                                     34.58
                                                                                       tration versus time profiles for patients with normal
V2/F = θV2                                                                             renal function and patients with mild, moderate,
Q/F = θQ                                                                               and severe impairment, suggesting the use of a fixed
V3/F = θV3                                                                             dose for next clinical trials. These results should be
ka(<24 h) = θka(<24 h)
                                                                                       interpreted with caution and necessitate further con-
                                        SCR                                            firmation in the future because only a very small
ka(>24 h) = θka(>24 h) × 1 − θSCR ×
                                       0.964                                           number of patients with severe renal impairment
                                        AGE                                            (n = 9) were enrolled in the current study.
                           × 1 − θAGE ×                    ×eηka(>24 h)                   On the day of operation, a blood sample was drawn
                                        66.97
                                                                                       after the patient had fasted for 12 hours so that the
Residual error model:                                                                  serum level of gastrin could be analyzed. Gastrin is
             ^   ^
  Y(<24 h) = Y + Y × ε1                                                                a hormone releasing gastric acid from the parietal
             ^   ^
  Y(>24 h) = Y + Y × ε2 + ε3                                                           cells.14 Significantly elevated levels of fasted serum
    CL/F, apparent total plasma clearance; V2/F, apparent volume of distri-
                                                                                       gastrin are thought to indicate low gastric acid secre-
    bution of the central compartment; Q/F, apparent distribution clearance;           tion, resulting in increased gastric pH.14 The fact that a
    V3/F, apparent volume of distribution of the peripheral compartment; ka,           higher GAST value resulted in a lower exposure to
    apparent first-order rate constant of absorption; (<24 h), estimate corre-
    sponding to days 0 and 1 (day of surgery); (>24 h), estimate correspond-
                                                                                       BIBR 953 ZW suggests a reduction in bioavailability.
    ing to days 2 to 10; CRCL, creatinine clearance; GAST, serum gastrin               The effect of GAST on CL/F(<24 h) was estimated to be
    concentrations; SCR, serum creatinine; AGE, age; θCL, V2, Q, V3, and ka, typ-      100% higher than the effect on CL/F(>24 h), a finding
    ical population parameter estimates corresponding to CL/F, V2/F, Q/F,              that might be explained by a change in GAST pro-
    V3/F, and ka, respectively; θGAST1, parameter for effect of GAST on CL(<24 h)/F;
    θGAST2, parameter for effect of GAST on CL(>24 h)/F; θSCR, parameter for           duction and release during and just after surgery.15
    effect of SCR on ka(>24 h); θAGE, parameter for effect of AGE on ka(>24 h); ηCL,   However, such a potential source of interindividual
    ηka, expressions corresponding to the interindividual variability in CL/F          variability is likely to be overcome in the future and
                                    ^
    and ka, respectively; Y and Y, observed and predicted plasma concentra-
    tions; ε1, ε2, and ε3, expressions corresponding to the residual variability.
                                                                                       also due to changes in drug formulation, based on
                                                                                       results showing that an alternative capsule formula-
                                                                                       tion with tartaric acid as the relevant excipient was
are supported by the fact that in the final model,                                     less susceptible to elevated gastric pH. Tartaric acid
SCR and AGE were identified as statistical signifi-                                    provides an acid environment and improves solubility
cant covariates in ka(>24 h) because those 2 covariates                                and drug absorption. Administration of 150-mg BIBR
are likely to affect the elimination rate rather than                                  1048 capsules with pantoprazole pretreatment resulted
the rate of absorption.                                                                in a 30% reduction of AUC compared to the AUC with-
   Weight, gender, most laboratory measurements,                                       out pantoprazole, in contrast to the 80% reduction in
smoking, or alcohol consumption could not be shown                                     bioavailability found after a concomitant administra-
to influence significantly dabigatran pharmacokinet-                                   tion of an experimental tablet formulation of BIBR
ics. As expected, on the basis of urinary unaltered                                    1048 with pantoprazole.5 In the current analysis, the
drug recovery data obtained in previous studies,                                       food effect was not evaluated, but in previous studies,
CRCL affected significantly drug exposure. Figure 4                                    it was found that administration of 150-mg dabigatran
shows the individual model-predicted CL/F(>24 h) esti-                                 etexilate capsules with a high-fat, high-caloric break-
mates versus CRCL relationship. In general, the CL                                     fast did not affect the extent of absorption.5
versus CRCL relationship is modeled with a step                                           To summarize the results from the current study, the
function predicting a linear increase in CL up to a                                    pharmacokinetics of dabigatran were best described
certain value of CRCL, usually between 120 and 150                                     by a 2-compartment model. The data supported the
mL/min. In the current study, most of the individual                                   estimation of different first-order absorption rate


QUANTITATIVE CLINICAL PHARMACOLOGY                                                                                                          379
                                                                                                                         TROCÓNIZ ET AL



                                                            12.5 mg bid                                                                  25 mg bid                                                                                        50 mg bid
                      40                                                                                 100                                                                                           200

                                                                                                          80
                      30                                                                                                                                                                               150

                                                                                                          60
                      20                                                                                                                                                                               100
                                                                                                          40

                      10                                                                                                                                                                                50
                                                                                                          20

                       0                                                                                   0                                                                                             0
                           0       10          20     30     40 0         10         20     30    40           0    20    40   60   80    100 0    20                        40   60       80   100          0    50      100      150     200 0       50     100      150     200




                                                            100 mg bid                                                                   150 mg qd                                                                                        150 mg bid
                    400                                                                                 600
                                                                                                                                                                                                      600
                                                                                                        500
                    300
                                                                                                        400
                                                                                                                                                                                                      400
                    200                                                                                 300

                                                                                                        200                                                                                           200
                    100
                                                                                                        100

                      0                                                                                   0                                                                                             0
                           0       100     200        300    400 0    100        200        300   400          0   100 200 300 400 500 600 0      100 200 300 400 500 600                                    0     200       400         600   0       200       400         600




                                                            200 mg bid                                                                   300 mg bid                                                                                       300 mg qd
                    1000                                                                                1500
                                                                                                                                                                                                      2000
                    800                                                                                 1250

                                                                                                        1000                                                                                          1500
                    600
                                                                                                        750
                                                                                                                                                                                                      1000
                    400
                                                                                                        500
                    200                                                                                                                                                                               500
                                                                                                        250

                      0                                                                                   0                                                                                             0
                           0   200       400    600    800 1000 0    200       400    600    800 1000          0   250 500 750 1000 1250 1500 0   250 500 750 1000 1250 1500                                 0   500     1000 1500 2000        0   500       1000 1500 2000




Figure 3. Goodness-of-fit plot corresponding to the final population model. For each dose group, left panels show the PRED versus DV
relationship, and the right panels show the IPRED versus DV relationship, where PRED, IPRED, and DV correspond to the typical pop-
ulation predictions, individual model predictions, and observed dabigatran plasma concentrations, respectively. The solid lines repre-
sent the lines of identity.



                    500                                                                                                                                                       180

                                                                                                                                                                              160
                    400                                                                                                                                                       140
                                                                                                                                                      Concentration (µg/L)
  Clearance (L/h)




                                                                                                                                                                              120
                    300
                                                                                                                                                                              100

                                                                                                                                                                                  80
                    200
                                                                                                                                                                                  60

                    100                                                                                                                                                           40

                                                                                                                                                                                  20
                           0
                                                                                                                                                                                   0
                               0          20          40 60 80 100 120 140 160 180                                                                                                     0          3          6          9     12    15     18                       21             24
                                                      Creatinine Clearance (mL/min)                                                                                                                                    Time after dose (h)


Figure 4. Relationship between individual model estimates                                                                                     Figure 5. Typical population plasma concentration versus time
of CL/F(>24 h) versus the individual observed CRCL (points).                                                                                  profiles corresponding to a steady-state dose of 150 mg once daily
The solid line represents the predicted typical covariate                                                                                     and for values of ka of 0.035 (dotted line), 0.093 (solid line), and
relationship.                                                                                                                                 0.153 (dashed line) h–1, respectively.


380 • J Clin Pharmacol 2007;47:371-382
                           NEW ORAL THROMBIN INHIBITOR DABIGATRAN ETEXILATE




Figure 6. Dabigatran plasma concentration versus time profiles as a function of creatinine clearance (CRCL) expressed in units of
mL/min. Simulations were performed assuming a steady-state dose of 150 mg bid. Results are presented as the 5th (lower dashed line),
50th (middle solid line), and 95th (upper dashed line) percentiles of 1000 simulations.




Figure 7. Dabigatran plasma concentration versus time profiles during the first day of administration (left panel) and during the rest
of the treatment (right panel). Simulations were performed assuming a steady-state dose of 150 mg bid. Results are presented as the 5th
(lower dashed line), 50th (middle solid line), and 95th (upper dashed line) percentiles of 1000 simulations.


constants and apparent plasma clearances for days 0                   serum creatinine of 0.964 mg/dL were 0.022 and
to 1 and days 2 to 10 after surgery. Age and serum                    0.093 h–1 on days 0 to 1 and days 2 to 10, respec-
creatinine influenced ka, whereas gastrin and CRCL,                   tively. The typical value for CL/F for a patient with
only for days 2 to 10, affected CL/F (P < .001). The                  a gastrin of 34.58 pmol/L and a CRCL of 76.16
typical values for ka for a 67-year-old patient with a                mL/min were 70.87 and 106.2 L/h on days 0 to 1 and


QUANTITATIVE CLINICAL PHARMACOLOGY                                                                                                381
                                                     TROCÓNIZ ET AL


days 2 to 10, respectively. The differences found in             2. Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W.
the pharmacokinetics of dabigatran during the first              Structure-based design of novel potent nonpeptide thrombin
                                                                 inhibitors. J Med Chem. 2002;45:1757-1766.
24 hours after surgery compared to the following
                                                                 3. Eriksson BI, Dahl OE, Ahnfelt L, et al. Dose escalating safety
days are most likely due to alterations in gastric
                                                                 study of a new oral direct thrombin inhibitor, dabigatran etexi-
motility and gastric pH following surgery. As a con-             late, in patients undergoing total hip replacement: BISTRO I. J
sequence, the rate of absorption is reduced and                  Thromb Haemost. 2004;2:1573-1580.
interindividual variability in drug exposure                     4. Eriksson BI, Dahl OE, Buller HR, et al, for the BISTRO II Study
increased. On the following days, the pharmacoki-                Group. A new oral direct thrombin inhibitor, dabigatran etexilate,
netic behavior of BIBR 953 ZW is less variable.                  compared with enoxaparin for prevention of thromboembolic
   The present study provides population pharma-                 events following total hip or knee replacement: the BISTRO II
                                                                 randomized trial. J Thromb Haemost. 2005;3:103-111.
cokinetic parameter estimates that will facilitate
                                                                 5. Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic profile
clinical trial simulation studies aimed at a thorough            of the oral direct thrombin inhibitor dabigatran etexilate in healthy
characterization of the pharmacokinetic profile in               volunteers and patients undergoing total hip replacement. J Clin
patients with different stages of renal impairment.              Pharmacol. 2005;45:555-563.
                                                                 6. Guidance for Industry: Population Pharmacokinetics. Doc. No.
                                                                 R99-1150. Rockville, Md: US Department of Health and Human
                        APPENDIX                                 Services, FDA; 1999.
                                                                 7. Beal SL, Sheiner LB. NONMEM Users’ Guides. San Francisco:
The following investigators participated in this study:          NONMEM Project Group, University of California at San Francisco;
                                                                 1992.
Norway: O. Aarseth (Notodden sykehus, Notodden), H. C.
Blom (Kongsberg sykehus, Kongsberg), T. Kristiansen              8. Beal SL, Sheiner LB. NONMEN Users’ Guide: Conditional
                                                                 Estimation Methods. San Francisco: NONMEN Project Group,
(Sentralsjukehus i Hedmark, Elverum), R. Mjaaseth
                                                                 University of California at San Francisco; 1998.
(Telemark, Sentralsykehus, Skien), E. Mohr (Fylkessykehusset
i Haugesund, Haugesund), H. Sarkandi (Ringerike syke-            9. Karlsson MO, Sheiner LB. The importance of modeling inte-
                                                                 roccasion variability in population pharmacokinetic analyses. J
hus, Hønefoss), F. Snorrason (Buskerud Sentralsykehus,
                                                                 Pharmacokinet Biopharm. 1993;21:735-750.
Drammen); Sweden: L. Ahnfelt (NU-Sjukvården, Uddevalla),
C. Andersson (Universitetssjukhuset, Linköping), N. Anders-      10. Jorgensen H, Wetterslev J, Moiniche S, Dahl JB. Epidural local
                                                                 anaesthetics versus opioid-based analgesic regimens on postoper-
son (Länssjukhuser Ryhov, Jonkoping), B. Edshage
                                                                 ative gastrointestinal paralysis, PONV and pain after abdominal
(Kungälvs sjukhus, Kungälv), B. I. Eriksson (Sahlgrenska,        surgery. Cochrane Database Syst Rev. 2000;4:CD001893.
Universitetssjukhuset/Östra, Göteborg), A. Folestad (Sahlgren-
                                                                 11. Sheiner LB, Beal SL. Some suggestions for measuring predic-
ska, Universitetssjukhuset, Mölndal), P. Hansson (Länss-
                                                                 tive performance. J Pharmacokinet Biopharm. 1981;9:503-512.
jukhuset, Halmstad), A. Nordström (Vrinnevisjukhuset,
                                                                 12. Eriksson UG, Mandema JW, Karlsson MO, et al. Pharmacokinetics
Norrköping), B. Paulsson (Sjukhuset Lidköping, Lidköping),
                                                                 of melagatran and the effect on ex vivo coagulation time in
L. G. Petersson (Länssjukhuset i Kalmar, Kalmar), J. Sjögren
                                                                 orthopaedic surgery patients receiving subcutaneous melagatran and
(Länssjukhuset i Varberg, Varberg).                              oral ximelagatran: a population model analysis. Clin Pharmacokinet.
   The members of the BISTRO I (Boehringer Ingelheim             2003;42:687-701.
Study in ThROmbosis) study group were as follows:                13. Cullberg M, Eriksson UG, Wahlander K, Eriksson H, Schulman S,
Steering Committee: B. I. Eriksson (Study Chair), O. E. Dahl,    Karlsson MO. Pharmacokinetics of ximelagatran and relationship to
L. Ahnfelt, J. Stangier, G. Nehmiz, K. Hermansson, V.            clinical response in acute deep vein thrombosis. Clin Pharmacol
Kohlbrenner; Central Adjudication Committee: Venograms:          Ther. 2005;77:279-290.
P. Kälebo and B. E. Zachrisson, Bleeding: P. U. Angerås;         14. Schubert ML. Gastric secretion. Curr Opin Gastroenterol.
Statistician: G. Nehmiz; Sponsor: Boehringer Ingelheim           2005;21:636-643.
AB, Sweden.                                                      15. Yamashita Y, Toge T, Adrian TE. Gastrointestinal hormone in
                                                                 dumping syndrome and reflux esophagitis after gastric surgery.
                                                                 J Smooth Muscle Res. 1997;33:37-48.
   Financial disclosure: The sponsor of the BISTRO I study is
Boehringer Ingelheim AB, Sweden.



REFERENCES

1. Hyers TM. Management of venous thromboembolism: past, pre-
sent, and future. Arch Intern Med. 2003;163:759-768.




382 • J Clin Pharmacol 2007;47:371-382

				
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