»Haemost 2002; 87: 777-927
`
`Cog.MFyalns
`Volume 87
`omg. DorafeNey,
`Number5
`Smnes PBF5.8,"
`Pages 777-927
`
`
`May 2002 AU eep~ She.
`Neg oy20
`Sis
`Log.tayMog
`
`iS
`To,
`® ip ;
`Sig
`Sey
`
`E3185E
`
`
`
`ort
`ae
`PL , Journal of the International Society
`*,14 on Thrombosis and Haemostasis
`
`emostasis
`
`
`
`
`) Editor-in-Chief
`-PM.Mannucci,Italy
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`Senior Associate Editor
`H.R. Roberts, U.S.A,
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`Platelet Aging Jn Vivo Is Associated with Activation of Apoptotic
`Pathways: Studies in a Model of Suppressed Thrombopoiesis in Dogs
`e J. Pereira, M. Soto, L Palomo, M. Ocqueteau, L.-M. Coetzee,
`S. Astudillo, E. Aranda, D. Mezzano
`Tirofiban Blocks Platelet Adhesion to Fibrin with Minimal Perturbation
`of GplIb/IiIa Structure
`© R. R. Hantgan, M. C. Stahle, W. G. Jerome, C. Nagaswami,
`
`JW. Weisel
`
`LETTERS TO THE EDITOR
`
`Is a Nihilistic Attitude to Thrombophilia Screening Justified?
`© B. J, Hunt, M. Shannon, D. Bevan, V. Murday
`Mutation Screening for Thrombophilia: Two Cases with Factor V
`Cambridge without Activated Protein C Resistance
`eA. J. ten Cate, ¥. T. van de Hoek, P. H. Reitsma, H. ten Cate,
`
`P. Smits
`
`The Tissue Factor Pathway Inhibitor C536T Mutation is not Associated
`with the Risk of Stroke in Young Adults
`
`@R. Junker, J. Glahn, N. Tidow, T. Brinkmann, D. G. Nabavi
`
`Between-centre Agreementin Homocysteine Assays: Experience from
`the UK NEQASProficiency Testing Scheme
`
`e J, Jennings, S. Kitchen, J. Smith, T. A. L. Woods, F. E. Preston
`
`Factor V Arg2074Cys: A Novel Missense Mutation in the C2 Domain
`of Factor V
`© A. Bossone, F. D’Angelo, R. Santacroce, D, De Lucia,
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`M. Margaglione
`Pulmonary Embolism After Sequential Use of Recombinant Factor VIla
`and Activated Prothrombin Complex Concentrate in a Factor VITI
`Inhibitor Patient
`© S. B. Rosenfeld, K. K. Watkinson, B. H. Thompson, D. E. Macfarlane,
`
`S.R. Lentz
`A Rebuttal: Foetal Growth Restriction in Children with Prothrombotic
`Risk Factors
`:
`
`@/. Cetin, E. Biguzzi
`Reply to a Rebuttal: Foetal Growth Restriction in Children with
`Prothrombotic Risk Factors
`eR. vonKries, R. Junker, D. Oberle, A. Kosch, U. Nowak-Gottl
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`Thromb Haemost 2002; 87: 817-23
`
`Table | Demographics
`
`Gender: Male
`Female
`
`Race: White
`Black
`Hispanic
`American Indian/Alaskan Native
`Age [years]
`
`Weight [kg]
`
`Height [cm]
`
`Body Mass Index [kg/m’]
`
`Body Mass Index [kg/m’]: <30
`30 to <40
`40 to <45
`245
`
`N(%)
`
`N (%)
`
`Mean (SD)
`Min, Max
`Mean(SD)
`Min, Max
`Mean(SD)
`Min, Max
`Mean (SD)
`Min, Max
`N(%)
`
`22 (59.5)
`15 (40.5)
`
`23 (62.2)
`11 (29.7)
`2( 5.4)
`1( 2.7)
`35.4 (11.4)
`19, 69
`129.6 (20.5)
`101.1, 165.1
`174.6 (10.3)
`155.0, 198.0
`43.0 (8.7)
`26.3, 61.3
`1 ( 2.7)
`15 (40.5)
`4 (10.8)
`17 (45.9)
`
`sytinge, The calculated dose was given as a single injection; dose splitting was_activities). Sample times relative to administration were -0.25, 0, 0.25, 0.5,
`not permitted.
`0.75, 1, 1.5, 2, 3, 4, 5. 6, 8, 12, 16, 24, and 30h.
`Sodium citrated plasma samples were analyzed for anti-Xa activity
`(primary measure) and anti-[Ia activity (secondary measure) per the method
`described by Miitzsch (4). The specific methods used for determining the anti-
`Xa _and anti-IIa activities of tinzaparin in humanplatelet-poor plasma were
`based on procedures and reagents supplied with commercially available
`
`Sampling Procedures and Analytical Methodology
`
`Following each tinzaparin administration, blood samples were drawn over
`the next 30 hours to assess pharmacodynamic biomarkers (anti-Xa and anti-IIa
`
`
`
`
`
`
`
`“Harmonic mean and pseudo-standard deviation based on the jackknife variance technique.
`Tmax=time to maximal observedactivity; t’4=terminaldisposition half-life; }=terminal rate constant;
`Amax=observed maximal activity; CL=clearance; AUA=area underthe activity-time curveto infinity;
`AUAT=area undertheactivity-time curveto the last quantifiable measure; CV=coefficient of variation
`Note: Subjects who had insufficient data in the terminal phase were notincluded in pharmacodynamic
`parametercalculations.
`
`
`
`Table 2 Pharmacodynam-
`
`
`Anti-Xa Activity Anti-[a Activity_ic parameters for heavy-
`
`
`=
`75WU/kg ATS U/kg 75 W/kg75TU/kg
`Parameter
`weight
`subjects
`following
`Tmax [h]
`37
`35
`37
`35
`a 75 IU/kg and 175 Wlke
`4.0
`4.0
`4.0
`5.0
`SCinjection oftinzaparin
`1.5, 8.1
`3.0, 8.0
`2.0, 8.1
`1.5, 8.0
`
`N
`Median
`Min, Max
`
`t% [h)
`
`d {hy
`
`Amax [IU/mL]
`
`CL [L/h]
`
`AUA [IUeh/mL]
`
`N
`Mean (SD)*
`CV (%)
`
`N
`Mean (SD)
`CV (%)
`
`N
`Mean(SD)
`CV (%)
`
`N
`Mean (SD)
`CV (%)
`
`N
`Mean (SD)
`CV (%)
`
`36
`3.85 (1.09)
`28
`
`36
`0.18 (0.05)
`28
`
`37
`0.34 (0.11)
`33
`
`36
`3.11 (0.85)
`27
`
`36
`3.29 (0.84)
`25
`
`35
`4.23 (0.98)
`23
`
`35
`0.16 (0.04)
`23
`
`35
`0.81 (0.15)
`19
`
`35
`2.40 (0.97)
`40
`
`35
`9.99 (1.99)
`20
`
`33
`5.33 (2.06)
`39
`
`33
`0.13 (0.05)
`39
`
`37
`0.12 (0.05)
`40
`
`33
`9.01 (4.01)
`45
`
`33
`1.21 (0.37)
`30
`
`35
`5.39 (1.96)
`36
`
`35
`0.13 (0.05)
`36
`
`35
`0.34 (0.10)
`29
`
`35
`5.71 (2.24)
`39
`
`35
`4,34 (1.26)
`29
`
`
`
`AUAT[IUeh/mL]
`
`35
`37
`35
`37
`N
`3.53 (1.03)
`0.78 (0.48)
`9.54 (1.97)
`2.87 (1.00)
`Mean (SD)
`CV (%)
`35
`21
`62
`29
`
`
`818
`
`

`

`
`
`
`
`
`
`
`
`
`
`—O~— Normal-weight (n = 30)
`— Heavy-weight (n = 35)
`
`4.25
`
`Z 4.00
`
`G.75
`
`2 2
`
`220
`
`Oo
`
`|
`
`T
`6
`
`Sr a
`12
`18
`Time (h)
`
`
`24
`
`T
`30
`
`36
`
`—O— Normal-weight (n = 30)
`—e@~ Heavy-weight (n = 35)
`
` =
`6
`12
`18
`24
`30
`
`0
`
`36
`
`Time (h)
`
`-80
`
`*%3¢
`<q 0.25
`
`0.00
`
`0.5
`
`a 0.4
`
`2 &
`
`25
`
`03
`
`a&
`
`0.2
`
`=S
`+
`c
`<oo4
`
`r.
`
`
`
`Haineret al.: Tinzaparin Dosing in Heavy or ObesePatients
`
`
`
`
`
`(IU/mL) 0
`
`Anti-llaActivity
`
`—O— Normai-weight (n = 23)
`—@— Heavy-weight (n = 37)
`
`2
`E 03
`
`2 i
`
`02
`
`e=5
`
`4w *=
`
`oo<
`
`0.0 — ; pe
`0
`6
`12
`18
`24
`30
`36
`
`Time (h)
`
`
`—O-— Normal-weight (n = 23)
`—@— Heavy-weight (n = 37)
`
`
`
`6
`
`12
`
`418
`
`24
`
`30
`
`36
`
`Time (h)
`
`tAnti-Xa and anti-IJa activities for historical control, healthy normal-weight
`subjects at the 75 [U/kg doseis extrapolated from a 4500 TU fixed tinzaparin
`SC administration.
`
`
`0.4
`
`Fig. 1 Mean (SE) anti-Xa and anti-Ila activity in heavy-weight and historical
`control healthy normal-weight subjects receiving 175 [U/kg tinzaparin via SC
`injection
`
`Fig.2 Mean (SD)anti-Xa and anti-Ila activity in heavy-weight and historical
`control healthy normal-weight subjects receiving 75 IU/kg" tinzaparin via SC
`injection
`
`(Diagnostica Stago and American Diagnostica
`chromogenic assay kits
`Actichrome, respectively) validated at MDS Pharma Services (St. Laurent,
`Montreal, Canada). The anti-Xa/anti-[a analytical methods were optimized
`as previously described (5) to reduce the contributions of endogenous agents
`and sample handling to assay result variability. The validated assay ranges
`were 0.030 to 0.400 [U/mL for anti-Xa and 0.020 to 0.252 [U/mL for
`anti-I]a.
`
`Sample Size
`
`Thetrial was designed todetect 2 20% difference in anti-Xa parameters (Amax
`and AUA)using 95% confidenceintervalsfor the heavy/obese subjects relative to
`normal-weight subjects administered similar doses in prior studies.
`It was
`hypothesized that if the 95% confidenceintervalforthe heavy-weightsubjectsdid
`notoverlap the 95% confidence interval for the normal-weighthistorical control
`subjects, then the two group means would be considered different.
`
`Pharmacodynamic Analyses
`
`Anti-Xa and anti-Ila activities expressed in [U/mL were used to derive
`Amax (maximal observed activity), AUA (area underthe activity-time curve
`to infinity), Tmax (time of observed maximal activity), (4 (disposition half-
`life), CL’ (clearance), and \ (elimination phase rate constant) using noncom-
`partmental analyses. The harmonic mean and pseudo-standard deviation
`were calculated for t} based on the jackknife variance technique, Prior to
`analysis, Amax and AUA values were transformed using the natural loga-
`rithm.
`
`Comparison with Historical Normal-Weight Controls
`
`Measures ofcentral tendency with corresponding variance for anti-Xa and
`anti-Ila measures were calculated bydoselevel (175 IU/kg and 75 IU/kg). The
`95% confidence interval for each measure was the basis for comparisons to
`historical control normal-weight (<100 kg) healthy subject data. As subjects
`fromone ofthe control studies were not dosed on a weight-adjusted basis, but
`rather received a fixed 4500 IU dose (~64 IU/kg), their data were adjusted for
`weight and scaled to 75 IU/kg (assuminglinear pharmacodynamics).
`
`Safery Assessments
`
`Statistical Analyses
`
`Safety assessments consisted of monitoring adverse experiences, including
`blecding-related events; clinical laboratorytests; physical examinations; and
`vital signs. Injection-site hematoma was defined as a palpable or visible mass
`of > 2 cm in diameterat the injectionsite.
`
`A result was deemedstatistically significant whenthe teststatistic yielded a
`two-tailed probability of 0.05 or less, or when confidenceintervals failed to
`overlap. Confidence intervals were derived using normal theory based on the
`student’s t-distribution. Bascline values for all data were defined as the last
`
`819
`
`

`

`Thromb Haemost 2002; 87: 817-23
`
`
`
`1,60
`
`Anti-Xa Activity
`
`O 75 IUkg
`e
`aad
`175 IWkg
`
`Anti-Xa Activity
`
`20
`
`
`O 75 IUWkg
`
`© 175 IUkg
`
`Z 1.00 °
`=
`e
`@
`=
`= 0.784
`°
`5
`E
`< 0.50
`0.26
`
`5
`
`oO x)
`on
`
`eo
`
`®
`®
`
`°
`
`@®
`
`eo vf
`e
`se? 6
`°
`
`©
`°
`
`-
`& of
`
`Q
`
`*e
`0° e@
`
`*
`°
`98°
`
`°
`
`a
`
`> 15-5
`E
`5
`z
`2 104
`aot
`Ss
`=
`
`5
`
`e
`
`ee
`
`Pee
`
`°
`
`S
`
`iS
`
`
`
`
`
`
`
`0.00-———__
`90
`100
`
`110
`
`T
`120
`
`=
`130
`
`140
`
`—s
`160
`
`150
`
`170
`
`0
`
`90
`
`100
`
`110
`
`120
`
`130
`
`140
`
`150
`
`160
`
`170
`
`Weight (kg)
`
`Weight (kg)
`
`ose
`
`Anti-lla Activity
`
`© 75 IUkg
`@
`175 IWkg
`
`=
`£
`=]
`%
`E
`= 925
`
`0.00
`
`ee?
`
`ee®
`e°
`e
`bed
`On
`Og
`°
`& ° oO
`oO 8
`oO
`& S & 8 0 %%
`©o ?
`
`T
`T
`T or —-
`100
`110
`120
`430
`140
`150
`160
`
`170
`
`166
`‘
`
`2 7.6
`E
`2 5.0
`Ss
`=<
`
`2.6
`
`0.0
`
`Anti-lla Activity
`
`QO 75 IUkg
`@ 175 IWkg
`
`100
`
`110
`
`120
`
`130
`
`140
`
`150
`
`160
`
`170
`
`Weight(kg)
`Weight (kg)
`
`Fig. 3 Amax and AUAversus bodyweight based on anti-Xa and anti-[aactivity following 75 JU/kg and 175 IU/kg SC injectionsof tinzaparin in heavy-weight
`subjects
`
`measurements taken priorto (screening and baseline) thefirst dose of studydrug.
`By-period analyses used period-specific baseline values. As pre-doseactivity levels
`were below the quantification limit, no baseline adjustment of activity was
`necessary. Data were pooled by dose across sequencesas there were nostatistically
`
`significant carryover or sequence effects with respect to the primary anti-Xa
`measures of Amax and AUA. Linear regression models evaluated Amax and
`AUA as dependent variables for relationships with weight and BMI(test of
`slope = 0). All statistical analyses were performed using SAS® (Version 6.12),
`
`
`Table 3 Mean anti-Xa and
`anti-Ila activities of Amax
`75 WU/kg?
`175 TU/kg
`
`
`and AUA with 95% confi-
`Parameter ON Mean_
`(95% CT)
`N
`Mean__
`(95% CI)
`dence intervals for heavy-
`Anti-Xa Activity
`weight
`subjects
`and
`for
`AUA (TUeh/mL)
`historical- control normal-
`(8.961, 10.139)
`9.55
`28
`(2.164, 2.556)
`2.36
`27
`Normal-Weight
`weight subjects
`(9.336, 10.652)
`9.99
`35
`(3.017, 3.565)
`3.29
`36
`Heavy-Weight
`
`Amax(IU/mL)
`Norma]-Weight
`27
`0.30
`(0.281, 0.319)
`30
`0.87
`(0.784, 0.956)
`Heavy-Weight
`37
`0.34
`(0.303, 0.375)
`35
`0.81
`(0.759, 0.859)
`
`;
`
`
`
`Anti-IIa Activity
`AUA (TUeh/mL)
`Normal-Weight
`Heavy-Weight
`Amax (IU/mL)
`Normal-Weight
`23
`0.10
`(0.088, 0.112)
`Heavy-Weight
`37
`0.12
`(0.103, 0.133)
`
`
`23
`33
`
`0.77
`1.21
`
`(0.680, 0.860)
`(1.088, 1.340)
`
`27
`35
`
`30
`35
`
`3.53
`4.34
`
`0,33
`0.34
`
`(3.278, 3.782)
`(3.926, 4.760)
`
`(0.304, 0.356)
`(0.307, 0.373)
`
`4Anti-Xa and anti-Ila activities for historical control, healthy normal-weight subjects at the
`75 IU/kg doseis extrapolated from a 4500 JU fixed tinzaparin SC administration.
`
`
`820
`
`
`
`

`

`
`
`
`
`
`
`
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`45.0
`
`12.5
`
`Anti-XaAUA(IUehr/mL)
`
`0.0
`
`75
`
`5.0
`
`0.0
`
`Normal-Weight
`Subjects
`
`Heavy-Weight
`Subjects
`
`Nonmal-Weight
`Subjects
`
`Heavy-Weight
`Subjects
`
`75 IU/kg
`
`175 IU/kg
`
`Normal-Weight
`Subjects
`
`Heavy-Weight
`Subjects
`
`Normal-Weight
`Subjects
`
`Heavy-Weighi
`Subjects
`
`75 IWikg
`
`175 IU/kg
`
`Fig. 4 Box plots of AUA and Amax based on anti-
`Xaactivity following 75 IU/kgt and 175 W/kg SC
`injections of tinzaparin in normal-weight subjects and
`heavy-weight subjects
`
`TAnti-Xa activity for historical control, healthy normal-weight subjects at the
`75 IU/kg dose is extrapolated from a 4500 IU fixed tinzaparin SC administration.
`
`
`821
`
`Haineretal.: Tinzaparin Dosing in Heavy or Obese Patients
`
`
`
`1.4
`
`1.3
`
`1.2
`
`o9=oo069a
`
`°re
`
`
`
`2a
`
`
`
`Anti-XaAmax(IU/mL) a
`
`
`
`
`
`

`

`Thromb Haemost 2002; 87: 817-23
`
`Results
`
`Subject Disposition
`
`The studyprotocol required 32 subjects. To account for two subjects
`whodiscontinued (one becauseof an adverse experience and onelost to
`follow-up) and 3 subjects who had incomplete pharmacodynamic
`data, five replacement subjects were enrolled to ensure 32 subjects
`with complete profiles. As a result, 37 subjects received the 175 IU/kg
`dose of tinzaparin and 35 subjects received the 75 IU/kg dose. All
`available data from all
`study participants were included in the
`analyses.
`Ofthe 37 subjects, 22 were men and 15 were women. Demographics
`are presented in Table 1. The body weights of the subjects ranged from
`101 to 165 kg; 19 subjects weighed between 100 and 130 kg and 18
`~ subjects weighed over 130 kg. BMIs ranged from26 to 61 kg/m?, with
`21 subjects (57%) having a BMI 2 40 ke/nv’.
`
`Pharmacodynamics of Tinzaparin in Heavy-Weight Subjects
`
`the mean peak anti-Xa activity was
`For the 175 IU/kg dose,
`0.81 IU/mL at a median of 4.0 h post-dose, with a mean t% of 4.23 h
`(Table 2). For anti-IIla activity,
`the corresponding values were
`0.34 IU/mL, 5.0 h, and 5.39 h. For the 75 IU/kg dose, anti-Xa
`Amax was 0.34 IU/mL, Tmax was 4.0 h, and t4 was 3.85 h, and the
`respective anti-Ila values were 0.12 IU/mL, 4.0 h, and 5.33 h.
`Anti-Xa clearance was slightly reduced for
`the
`175 IU/kg dose
`telative to the 75 IU/kg dose (2.40 and 3.11 L/h, respectively).
`Exposure, as measured by AUA, wasslightly greater-than-dose pro-
`portional
`for both anti-Xa and anti-Ila measures. Mean activity-
`time profiles for anti-Xa and anti-Ila measuresare illustrated in Figs.
`1
`and 2.
`
`Effect ofBody Weight and Body Mass Index
`
`The relationship between pharmacodynamics (Amax and AUA
`based on anti-Xa and anti-Ila activities) and body weight are presented
`in Figure 3. The findings were similar for BMI. Regardless of the
`pharmacodynamic metric, these plots illustrate consistent values over
`the range of body weights and BMIs,indicating that when tinzaparinis
`dosed by body weight, there is no influence of body weight or BMI on
`the pharmacodynamics in heavy-weight subjects. Minimal intersubject
`variation was observed for anti-Xa measures. Regression analyses
`confirmed the absence of correlations between anti-Xa and anti-IIa
`activities and body weight or BMI(test of slope = 0; notsignificant),
`
`Pharmacodynamics in Heavy-Weight Subjects vs. Normal-Weight
`Subjects
`
`Comparisons ofthe activity-time courses for subjects in the current
`study with those from normal-weight subjects in prior studies are
`provided in Figures 1 and 2 for 175 IU/kg and 75 IU/kg, respectively.
`Overall, there is considerable overlap in these populations with respect
`to the activity-time profiles,
`illustrating that a weight-adjusted
`tinzaparin dosing paradigmyields a predictable response regardless of
`dose, body weight, or BMI.
`The 95% confidence intervals for the mean pharmacodynamic
`measures for normal-weight and heavy-weight subjects are presented in
`Table 3 for anti-Xa activity, the primary study measure, At a dose of
`175 TU/kg,
`the mean Amax and AUA values for the heavy-weight
`
`822
`
`subjects were notdifferent from those for normal-weight subjects dosed
`at 175 IU/kg,i-c., the confidence intervals overlap.
`Ata dose of 75 [U/kg, the mean Amax value for the heavy-weight
`subjects was notdifferent from the mean for the normal-weight subjects
`dosed at 4500 IU with the values scaled to 75 IU/kg, ie., the confidence
`intervals overlap. The mean AUA was higher
`in the heavy-
`weight subjects (the confidence intervals did not overlap), but the
`absolute difference in AUA was small as illustrated in summaryplots
`of heavy-weight and normal-weight subject data for AUA and Amax
`(Fig. 4).
`
`_
`
`Safety
`
`Adverse experiences were reported for 24 of 37 study subjects
`(65%) following the 75 [U/kg dose and for 32 of 35 subjects (91%)
`following the 175 TU/kg dose. The majority of adverse experiences
`were mild to moderate, and primarily consisted of injection site
`bruising (32 subjects overall). The frequencies of adverse experiences
`reported within the two body weightstrata (100 to 130 kg and >130 kg)
`were comparable.
`Thirty-two subjects experienced bleeding-related adverse experiences
`(injection site bruising and/or ecchymosis), but there were no majoror
`serious bleeding events. Although there was a dose-bleeding event
`effect (11 subjects had an event only after the 175 [U/kg dose while
`3 had a bleeding-related event only after the 75 [U/kg dose), there was
`no relationship between the incidence of bleeding-related adverse
`experiences and the volume of the administered dose (which was
`weight-based) foreithertinzaparin doselevel.
`
`Discussion
`
`to determine whether the pharmacodynamic
`This study sought
`rationale for weight-based tinzaparin dosing, which was established
`in normal-weight healthy subjects and validated in clinical efficacy
`studies, would also hold for patients with above-normal body weight
`or
`those who are obese. To assure adequate representation over
`the weight range of interest in this study (100 to 160 kg), enrollment
`was «targeted so that approximately half of
`the subjects would
`weigh from 100 to 130 kg and half from 131 to 160 kg. Enrollment
`metthis objective of a wide distribution of body weights,
`ranging
`from 101 to 165 kg. Forty-six percent of the subjects had BMIs
`that exceeded the 99"percentile for the U.S. population (2 45 kg/m”)
`(6).
`When tinzaparin is administeredat fixed doses, independent of body
`weight,
`to normal-weight subjects (52-93 kg), anti-Xa activity is
`dependent on both dose and body weight
`(7). However, when
`tinzaparin is dosed on a body weight basis to normal-weight subjects
`(56-93 kg) (5) or to heavy-weight subjects (101-165 kg) as in the
`current study, anti-Xa activity is not correlated with body weight.
`These findings suggest
`that weight-based dosing of tinzaparin is
`appropriate for subjects regardless of body weight. Previously reported
`tinzaparin population pharmacokinetic analyses ofclinical study sub-
`jects also support the dosing of tinzaparin on a body-weight basis(8).
`In general
`there is
`limited information available regarding the
`administration of LMWHsto heavy-weightpatients. For dalteparin and
`enoxaparin, reports suggestthat weight-based dosing is appropriate and
`requires no additional adjustment (9, 10), A recent review of LMWH
`dosing in special populations(11) suggested that body surface area and
`BMIcorrelate with anti-Xa activity and also with bleeding risk or VTE
`
`complications. Although anti-Xa activity is generally used as the bi0-
`
`

`

`
`
`Haineret al.; Tinzaparin Dosing in Heavy or Obese Patients
`
`marker for heparins as heparin itself cannot be measured directly, the
`correlation between anti-Xaactivity and the clinical efficacy and safety
`of these agents is not well established. More to the point, integrated
`safety analyses fromtinzaparinclinical studies do notindicate altered
`efficacy or increased bleedingrisk for subjects with BMI >30 kg/m?
`(12).
`is important to note that regulatory and expert agencies clearly
`lt
`recognize that LMWHsare producedbydifferent processes and are not
`interchangeable (13). Accordingly,
`the findings of the current study
`should be consideredspecific totinzaparin. While the data in this study
`represent relatively healthy, heavy subjects, weighing between 100 and
`165 kg, with normalrenalfunctioning,the anti-Xa andIla activities are
`consistent across a wide range of weights and BMIs, ve., there are no
`trends suggesting that the relationships would not hold abovea specific
`weight.
`The study’s safety findings are comparable to those in prior healthy
`subject and clinical studies, ie.
`tinzaparin is well
`tolerated and
`significant bleeding is uncommon, While injection site hematomais a
`recognized but uncommontinzaparin-related adverse experience, none
`were observed in this study. Bruising at the injection site was common
`and was somewhat more frequentat the 175 JU/kg treatment dose than
`the 75 IU/kg prevention dose, butthis was not related to the volume of
`tinzaparin administered.
`In conclusion,
`this study supports the recommendation that SC
`dosing of tinzaparin to heavy-weight or obese patients can be based on
`body weight alone. There was no evidence suggesting that the dose
`of tinzaparin should be capped at a maximal fixed dose or that further
`adjustments for weight or obesity are required.
`
`Acknowledgements
`
`The authors wish to thank Susan Stoughton and Sue Wilson fortheir writing
`expertise and manuscript preparation, and Kathryn Read for data preparation.
`
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`—
`
`Received November 26, 2001
`
`Accepted after revision January30, 2002
`
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`