Table 4. Geometric mean ratios (hepatic impairment/normal hepatic function) and 90% confidence
`intervals for subjects with hepatic impairment and normal hepatic function
`
`.
`Total
`
`Point estimate
`90% Cl
`0.926
`(0 830 to l 035
`.
`AUCO—ZA
`0.922
`0.959
`1.071
`1.261
`
`
`
`
`
`
`
`
`
`
`
`
`ct.
`ct.
`
`Point estimate
`1.112
`
`90% Cl
`(0.9]8 to l 347
`.
`
`use
`om
`
`—
`
`
`
`
`
`
`
`
`
`The 90% confidence intervals of the geometric mean ratios for AUC0_., Cm, and CLT were within 0.80
`to 1.25 range based on 199.1 daptomycin concentrations but outside of the 0.80 to 1.25 range based on
`unbound daptomycin concentrations. The differences in the pharrnacokinetic parameter estimates based
`on unbound concentrations were not statistically significantly different between subjects with impaired
`hepatic function and normal hepatic function. Thus, the magnitude of the difference of the AUCO- and
`Cm” between subjects with hepatic impairment and healthy subjects does not warrant a dosage
`adjustment.
`
`The mean percentage of unbound daptomycin at 0.5 hrs and 8 hrs in subjects with hepatic impairment
`were 8.13% and 9.20%, respectively. The mean percentage ofunbound daptomycin at 0.5 hrs and 8 hrs
`in healthy subjects were 6.72% and 7.38%, respectively. At 0.5 hrs and 8 hrs, the percent unbound was
`21.1% and 16.1% greater, respectively in subjects with hepatic impairment. A comparison of the
`percentage unbound of daptomycin is shown in figure 2.
`
`Figure 2. Mean individual percent unbound of daptomycin at 0.5 hrs and 8 hrs in subjects with
`hepatic impairment (H) and normal hepatic function (N)
`
`16
`
`14
`
`212
`
`“ 8
`§
`a.
`'3
`
`6
`
`4
`
`O
`
`-
`
`.
`O
`.
`
`j
`
`'
`
`0
`
`i
`.
`
`'
`
`'
`I
`
`0
`:
`O
`
`2
`
`I
`
`0.5 (H)
`
`0.5 (N)
`
`8 (H)
`
`8 (N)
`
`Group
`
`CONCLUSIONS:
`
`The AUCO. and Cm, were not statistically significantly different between subjects with impaired hepatic '
`function and normal hepatic function based on total and unbound daptomycin concentrations.
`.. “.,
`_ “.,
`
`140
`
`

`

`The fraction of unbound daptomycin increased 21.1% at the end of the infusion and 16.1% at 8 hrs after
`the start of the infusion in subjects with hepatic impairment compared to healthy subjects.
`
`No dosage adjustment of daptomycin is recommended for subjects with hepatic impairment.
`
`COMMENTS:
`
`~—--
`1. The sponsor has not provided data to support the stability of the daptomycin.
`daptomycin in urine and the
`—-
`assay for daptomycin in serum t
`~—
`_
`~—~
`and the stability of daptomycin in extracted plasma _
`samples). The sponsor is encouraged to submit all validation data with the validation report.
`
`' assay for
`
`_
`Apr-‘33:“;
`ON Gaza-13;;L
`
`__ “.,
`
`141
`
`

`

`A single dose study to evaluate the pharmacokinetics and safety of CidecinG (daptomycin for
`injection) in healthy geriatric and younger healthy subjects following a dose ON mg/kg total body
`weight (Protocol DAP-GER—Ol-l 1)
`
`Dates: January 7, 2002 to March 6, 2002
`Clinical sites:
`/
`/
`_ /
`
`Analytical site: .
`
`RATIONALE:
`
`The pharmacolcinetic difierencés between the young and elderly are generally attributed to physiological
`and pathophysiological changes that occur more often in the elderly, which can include altered renal
`function. This study was undertaken to assess the single-dose pharmacokinetics and safety of daptomycin
`in healthy geriatric subjects compared with younger healthy subjects to determine if phannacokinetic or
`safety differences exist between the two populations.
`
`OBJECTIVES:
`
`The primary objective of this study was to evaluate the pharmacokinetics (single dose) of daptomycin in
`healthy geriatric subjects 275 years of age and younger healthy subjects 18 to 30 years of age. The
`secondary objective was to evaluate the safety of daptomycin in healthy geriatric subjects and younger
`healthy subjects.
`
`FORMULATIONS:
`
`Daptomycin 500 mg vial (Cubist, Lot No. 680413A)
`
`S I'UD‘)’ DESIGN:
`
`This study was an open-label, single-dose, parallel design, two—center study to evaluate the
`pharmacokinetics of daptomycin in 12 healthy adult subjects 275 years old and 11 healthy young subjects
`between 18 and 30 years old. Planned enrollment called for 12 geriatric subjects and 12 younger subjects
`and an attempt was made to enroll an equal number of men and women in each group. All subjects
`received a single dose of intravenous (IV) daptomycin at 4 mg/kg based on total body weight in 50 ml. of
`normal saline.
`
`'
`
`Blood samples for determination of daptomycin concentrations were obtained predose, mid-way through
`the infusion (0.25 hrs), end of the infusion (0.5 hrs), 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hrs from the
`initiation of the infusion.
`
`Urine samples for determination of daptomycin concentrations were obtained at predose and then at 0-2
`hrs, 2-4 hrs, 4-8 hrs, 8-12, 12-16 hrs, and 16 to 24 hrs from the initiation of infusion. Urine was collected
`for 24 hrs to allow a 24-hr urine creatinine clearance calculation.
`
`h“..
`
`142
`
`

`

`DAPTOMYCIN ASSAY METHODOLOGY:
`
`Not stated
`
`Not stated
`
`
`
`
`
`
`
`——m——
`
`3-28 t6 545pg/mL
`33610 562
`2/mL
`
`
`
`LLOQ
`-
`Satisfactory
`
`
`
`
`Satisfactory
`
`
`Precision
`.
`\
`
`
`
`
`
`Satisfacto
`Unsatisfacto
`
`DATA ANALYSIS:
`
`Plasma daptomycin concentration data were analyzed by non-compartmental pharmacokinetic analysis.
`The following parameters were determined for plasma daptomycin concentration data: the maximum
`plasma concentration (Cw), time to Cm, (Tmu), plasma concentration at 24 hrs post-dose (C24), the area
`under the plasma concentration-time curve from zero to the last quantifiable concentration (AUCo.t), AUC
`from zero to infinity (AUCo-o), plasma clearance (CLT), volume of distribution (V2 = CL/Ke), volume of
`distribution at steady state (V55: CL x MRT), mean residence time (MRT), and terminal elimination
`half-life (tm).
`~
`
`The following parameters were calculated based on daptomycin urine concentration data: the renal
`clearance (CLR) and the fraction of dose excreted in urine as parent drug over 24 hrs (Ae).
`
`STATISTICAL ANALYSIS:
`
`Pharmacokinetic parameters were summarized as mean, SD, median, and range. The geometric mean
`ratios and 90% confidence intervals for daptomycin Cm”, AUCO.., CLT, CLR, and Fe were reported.
`
`RESULTS:
`
`Although 12 healthy elderly and 12 healthy young subjects were enrolled into the study, only 1 1 healthy
`young subjects completed the study. Subject 021 was excluded from the pharmacokinetic analysis
`because this subject received a dose of daptomycin over 8 mg/kg, twice the protocol dose. The mean
`(SD) demographic data for the 23 subjects who completed the study are shown in Table 1. Most of the
`subjects were Hispanic (50% of elderly and 100% of young) and the elderly subjects tended to be taller,
`weight more, and have a lower creatinine clearance.
`
`Table I. Mean (SD (range) demographics for healthy elderly and healthy young subjects
`
`
`
`m—'
`
`
`mL/min
`
`mL/min
`
`vrs
`
`k_
`
`The mean plasma concentration-time profiles of daptomycin following a single dose of daptomycin IV 4
`mg/kg in elderly and young subjects are shown in Figure 1. Although the mean plasma concentrations of
`daptomycin were similar immediately following administration, plasma concentration were greater in
`healthy elderly subjects compared to healthy young subjects and may be due to differences in clearance
`among the two groups of subjects.
`
`_. “_,
`
`143
`
`

`

`Figure 1. Mean plasma concentration-time profiles of daptomycin following a single dose of4
`mg/kg IV to healthy elderly and young subjects
`
`
`
`Plump:('nnuntnllu-n
`
`(IzmiJ
`
`linn‘ thumb
`
`The daptomycin pharmacokinetic parameter estimates following the administration ofa single dose of
`daptomycin IV 4 mg/kg are shown in Table 2. The mean Cm“, AUC0_., and AUCG... were 0.04-fold, 0.46-
`fold, and 0.58-fold greater, respectively in elderly subjects than young subjects. The sponsor‘s estimate of
`AUCM. may be an underestimate in young subjects since a plasma concentration of zero was used at 24
`hrs (10 of 1] subjects) when the concentration was below the LLOQ. The mean CLT, CLR, and Ae were
`0.35-fold, 0.4) -fold, and 0.19-fold lower in elderly subjects compared to young subjecs. The V2 and V55
`were 0.13-fold and 0.]4-fold greater in elderly subjects. The terminal elimination half-life was 0.74-fold
`greater.
`
`Table 2. Mean (CV%) daptomycin pharmacokinetic parameter estimates when administered to
`healthy elderly and healthy young subjects
`
`Parameter
`
`AUCo..( e'hr/mL
`Auctu E‘hr/mL
`AUCo.
`g‘hr/ml.)
`cm.
`a/mL
`
`Healthy Elderlv n=12
`
`Healthy Youn
`
`n=ll
`
`361 (18%)
`361 (18%)
`
`248 (13°)
`268(11%)
`
`)
`
`
`
`
`
`
`
`
`
`
`
`CLRUTthT/k-)
`
`
`
`
`Ae(°/o)
`
`a - n=l; the plasma concentration was below the LOQ; _.-—-v
`
`by 24 hrs in 10 of 1] healthy young subjecs
`
`The reviewer calculated the geometric mean ratios (healthy elderly/healthy young) and 90% confidence
`intervals for daptomycin Cm”, AUCM, AUCOJ, CLT, CLR and Ae (see Table 3). The AUG;b AUCM,
`CLT, CLR and Fe were statistically significantly different between healthy elderly and healthy young
`subjects. The 90% confidence intervals for daptomycin Cmax was within the predetermined limits of 0.80
`to 1.25 and was not statistically‘sign‘ificantly different between the two groups ofsubjects.
`._ “v
`
`144
`
`

`

`Table 3. Geometric mean ratios and 90% confidence intervals for daptomycin (healthy
`elderly/healthy young subjects)
`
`
`
`Aug-
`
`
`
`Ae
`
`
`
`
`
`
`
`
`
`Stick plots showing the individual AUC0_.., CLT, and CLR values for daptomycin and aztreonam alone and
`in combination are shown in Figure 2. Subject #012 had the greatest AUCo... value'of 772 ug‘hr/mL and
`the lowest CLT and CLR (5.56 mL/hr/kg and 1.62 mL/hr/kg, respectively). Subject #009 had a CLR (8.86
`mL/hr/kg) that exceeded the CLT (8.07 mL/hr/kg); the CLT was the third lowest among healthy elderly
`subjects. The sponsor did not give an explanation for the CLR value that exceeded CLT.
`
`,a-_\
`
`Figure 2. Stick plots demonstrating individual AUCM CLT, and CLR values for healthy elderly and
`young subjects
`
`
`25
`
`N0
`
`
`'o'G
`TotalCL(mmetg)
`
`
`RenalCL(mL/hdkg)
`
`Elderly
`
`Category
`
`Yomg
`
`._ My.
`-.. “.r
`
`145
`
`

`

`Although the mean AUCO- increased 0.58-fold in healthy geriatric subjects compared to healthy young
`subjects, the mean pharmacokinetic parameter estimates from healthy geriatric subjects were similar to
`healthy subjects from Study DAP-OO-OZ following administration ofthe first dose ofdaptomycin IV 4
`mg/kg. The mean (SD) age of the healthy subjects was 33.4 (3.6) yrs in Study DAP-OO-OZ, whereas the
`mean age of healthy young subjects from Study DAP-GER-Ol-l] was 23.5 (4.30) yrs. A comparison of
`the phannacokinetic parameters from both studies is shown in Table 4.
`
`Table 4. Mean (CV°/o) daptomycin pharmacokinetic parameter estimates from Study DAP-GER-
`01-1] and Study DAP-OO-OZ
`
`
`— Studv mp-cm-or-rr
`Studv DAP-OO-OZ
`HealthvElderlv n=12
`Health\'Youn_ n=11
`Health\‘Youn_ n=6
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CL1 (mL/hrfk-)
`CLn (mL/hrfkg
`
`9.86 (25%
`
`15.09 (16%
`
`9.55 (13%)
`
`
`a - n=l; the plasma concentration was below the LOQI —- pymL) by 24 hrs in 10 of l 1 healthy young subjects
`
`The mean AUCo.24, AUC0-, C24, and CLT were similar between healthyelderly subjects (Study DAP-
`GER-01-11)and healthy young subjects from Study DAP-OO-OZ. The lower mean V2 and V55 observed
`in study DAP-00—02 may have contributed to the greater mean Cmax and longer elimination half-life in that
`study. Since the mean measured creatinine clearance from healthy elderly subjects (66.8 i 15.1 mL/min)
`was similar to the mean measured creatinine clearance from subjects to mild renal impairment (58.8 i 7.7
`mL/min) in Study MRDl-Ol-O9, no dosage is necessary for elderly subjects 275 yrs of age.
`
`SAFETY:
`
`One of 12 subjects in the elderly group experienced one treatment-emergent adverse event and three
`subjects in the young group experienced three adverse events. Subject #006 in the geriatric group
`experienced vomiting or) the day following closing that was mild in severity and was not considered to be
`treatment related. Subject #014 in the young group experienced headache approximately 4 hours after
`dosing, which persisted until the following day. _ The event was mild in severity, possibly related to the
`study drug, and it resolved without treatment. Subject #021 in experienced a rash on her left upper arm
`the arm (opposite to study drug administration arm) approximately 12 hours following dosing, which
`persisted for approximately 48 hours. It was considered possibly related to study treatment, although the
`investigator noted that the rash was characteristic of insect bites. Subject #024 experienced headache as
`an adverse event approximately 5 hours following dosing. There were no deaths or serious adverse
`events during the study and none of the subjects discontinued due to an adverse event.
`
`CONCLUSIONS:
`
`The mean AUCa. of daptomycin in healthy elderly subjects was 0.57-fold greater compared with healthy
`young subjects whereas the CLT was 0.35-fold less in healthy elderly subjects.
`
`The mean phannacokinetic parameters of daptomycin in healthy elderly subjects were similar to those
`._ h..—
`from healthy young subjects in Study DAP-OO-OZ.
`
`146
`
`

`

`The safety profile of single-dose daptomycin (4 mg/kg) in healthy elderly subjects was not different fi’om
`that of healthy young subjects.
`
`Based on the results of the renal impairment study, no dosage adjustment of daptomycin is warranted
`when administered to elderly patients with normal renal function for their age.
`
`COMMENTS:
`
`-—'— assay for
`1. The sponsor has not provided data to support the stability of the daptomycin.
`_
`daptomycin in plasma and urine t
`-
`\‘fi
`-—~
`' the stability of daptomycin in extracted plasma samples). The Sponsor is encouraged to
`submit all validation data with the complete study report in the future.
`.
`
`2. Even though daptomycin plasma concentrations were below the LLOQ in 10/ l 1 healthy young subjects
`by 24 hrs, the sponsor reported the AUCM; for all subjects. The AUCM. was calculated using a value of
`zero at 24 hrs. The sponsor is encouraged to calculate AUCM in the future rather than assuming a
`concentration of zero at sampling points in which the plasma concentration is below the LLOQ.
`
`_-~..
`
`__ _~,.
`
`147
`
`

`

`A single dose study to evaluate the pharmacokinetics and safety of CidecinQ9 (daptomycin for
`injection) in obese and non-obese matched subjects following a dose 0” mg/kg total body weight
`(Protocol DAP-OBSE-01-07)
`
`Dates“ January 3, 2002 to February 28, 2002
`Clinical site:
`_
`/
`Analytical site2i
`
`/
`
`RATIONALE:
`
`Since the pathophysiology of the obese body may affect drug distribution and elimination of daptomycin,
`this study was designed to assess the single-dose pharmacokinetics and safety of daptomycin in
`moderately to extremely obese subjects as compared with non-obese subjects that are matched for gender,
`age, and renal function.
`
`OBJECTIVES:
`
`The primary objective of this study was to evaluate the pharmacokinetics of daptomycin in moderately to
`extremely obese subjects compared with non-obese subjects that were matched for gender, age, and renal
`function. The secondary objective of the study was to evaluate the safety of daptomycin in moderately to
`extremely obese subjects.
`
`FORMULATION:
`
`Daptomycin 500 mg vial (Cubist, Lot No. 680413A)
`
`STUDY DESIGN:
`
`This study was an open-label, single-dose, parallel design, single-center study to evaluate the
`pharmacokinetics and safety of daptomycin in adult subjects who were moderately or extremely obese
`and matched non-obese healthy subjects. The sponsor planned to enroll 6 moderately obese subjects
`(body mass index [BMI] 25-39.9 kg/mz) and 6 gender, age, and renal function matched non-obese
`subjects and 6 extremely obese subjects (BMI 240 kg/mz) and 6 gender, age, and renal function matched'
`non-obese subjects. For matched non-obese subjects, the BMI had to be between 18.5 and 24.9 kg/mz,
`age had to be within 10 years of the obese subject, and renal function had to be similar (creatinine
`clearance 270 mL/min as calculated by the Cockcroft and Gault equation using total body weight). All
`subjects received a single dose of intravenous (IV) daptomycin at 4 mg/kg based on total body weight
`infused over 30 min in 50 mL of normal saline.
`
`Blood samples for determination of daptomycin concentrations were obtained predose, mid-way through
`the infusion (0.25 hrs), end of the infusion (0.5 hrs), 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hrs from the
`initiation of the infusion.
`
`Urine samples for determination of daptomycin concentrations were obtained at predose and then at 0-2
`hrs, 2-4 hrs, .4—8 hrs, 8-12, 12-16 hrs, and 16 to 24 hrs from the initiation of infusion. Urine was collected
`for 24 hrs to allow a 24-hr urine creatinine clearance calculation.
`
`I.
`
`.... ‘_ _,.
`_--_‘—..
`
`I48
`
`

`

`DAPTOMYCIN ASSAY METHODOLOGY:
`’-
`
`
`
`
`
`
`
`
`——-am Comments
`Concentration range
`328 to 545 ug/ml. .
`336 to 562
`/m1.
`Satisfactory
`LLOQ
`Satisfactory
`
`/
`
`
`
`/” __
`-
`! Satisfactory
`
`
`
`'
`Sattsfacto
`
`
`
`Linearity
`
`Precision
`
`DATA ANALYSIS:
`
`
`
`Plasma daptomycin concentration data were analyzed by non~compartmental pharmacokinetic analysis.
`he following parameters were determined for plasma daptomycin concentration data: the maximum
`plasma concentration (Cum), time to Cm, (Tm), plasma concentration at 24 hrs post-dose (C24), the area
`under the plasma concentration-time curve from zero to the last quantifiable concentration (AUCm), AUC
`from zero to infinity (AUC0-), plasma clearance (CLT), volume of distribution (V2 = CL/Ke), volume of
`distribution at steady state (V55: CL x MRT), mean residence time (MRT), and terminal elimination
`half-life (ti/2).
`
`The following parameters were calculated based on daptomycin urine concentration data: the renal
`clearance (CLR) and the fiaction of dose excreted in urine as parent drug over 24 hrs (Fe).
`
`STATISTICAL ANALYSIS:
`
`.‘~_
`
`Pharrnacokinetic parameters were summarized as mean, SD, median, and range. The geometric mean
`ratios and 90% confidence intervals for daptomycin CM, AUCo.“ AUC0_, CLT, CLR, V55, and Fe were
`calculated.
`
`.
`RESULTS:
`Thirteen obese (6 moderately obese and 7 extremely obese) subjects and 12 non-obese matched controls
`completed the study. The mean (SD) demographic data for 24 subjects (one extremely obese subject
`without a matched control was excluded) are shown in Table 1. The majority of subjects were male and
`Hispanic (6/6 of moderately obese, 5/6 of the moderately obese-matched controls, 4/6 of extremely obese,
`and 5/6 of the extremely obese-matched controls).
`
`Table 1. Mean (SD) demographics for obese subjects and matched controls
`
`vrs
`
`k_
`
`1
`
`mL/min
`
`52.8 (4.2)
`49.3 4.0
`
`160.7 (5.0)
`156.8 (4.2
`
`107.7 (21.8)
`88.8 15.4
`
`61.9 (10.5)
`62.7 10.2
`
`166.3 (9.8)
`168.0 9.1
`
`
`
`137.1 (4514)
`82.2 24.3
`
`2F/4M
`2F/4M
`
`38.3 (13.5)
`36.7 15.4
`
`127.5 (18.1)
`67.7 7.9
`
`The mean plasma concentration-time profiles of daptomycin following a single IV 4 mg/kg dose to
`moderately or severely obese subjects and non—obese matched controls are shown in Figure 1. The mean
`plasma concentrations of daptomycin were greatest in extremely obese subjects and the lowest in
`-_-“--
`__ h_,
`
`149
`
`
`
`Wit-Iran
`
`
`
`
`
`
`6F/OM
`6F/0M
`
`40.7 (7.3)
`36.5 8.5
`
`85.7 (8.6)
`60.9 3.8
`
`Moderately obese
`Obese
`Control
`Extremely obese
`Obese
`
`
`Control
`
`‘ABW = actual body weight; IBW = ideal body weight
`
`

`

`moderate obesity matched controls. The mean plasma concentrations of daptomycin were similar in
`moderately obese subjects and extremely obese matched controls.
`
`Figure 1. Mean plasma concentration-time profiles of daptomycin following a single dose of4
`mg/kg IV to healthy elderly and young subjects
`
`73
`
`
`
`PlasmaConcentrationngmL)
`
`33
`
`4— Moderately Obese
`—v—- Euiemety 03959
`+ Match Controls t:v Mode-ately Ohm
`—0- Match Cont'ols Ext-emely Obese
`
`10
`
`20
`
`0
`
`4
`
`‘8
`
`12
`
`16
`
`20
`
`24
`
`Time(Hours)
`
`The mean daptomycin pharmacokinetic parameter estimates following the administration of a single dose
`of daptomycin IV 4 mg/kg are shown in Table 2.
`
`Table 2. Mean (CV%) daptomycin pharmacokinetic parameter estimates in obese subjects and
`matched controls
`
`
`
`
`
` — Moderatelv Obese
`Obese
`
`Extremely Obese
`
`Aucm e‘hr/ml.
`AUCM 2'hr/mL)
`
`375 (16%)
`379 (15%)
`
`269 (13%)
`288 (10%)
`
`473 (17%)
`473 (17%)
`
`353 (20%)
`361 (17%)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`V: (L
`
`52.3 16%
`
`42.7 14%
`
`‘plasma concentration below LLOQ in 1/6 subjecs; plasma concentration below LLOQ in 5/6 subjects; ‘plasma
`concentration below LLOQ in 2/6 subjects
`-
`\
`
`In moderately obese subjects, the mean Cm and AUCo... were 0.25-fold and 0.30-fold greater,
`respectively in obese subjects than matched controls. The Sponsor's estimate of AUCM. may be an
`h-“u'
`underestimate in matched controls since a plasma concentration of zero was used at 24 hrs in 5/6
`_-._._—‘
`
`150
`
`

`

`moderate obesity-matched controls when the concentration was below the LLOQ. The mean CLT and
`CLR (not corrected by body weight) were 0.18-fold and O.l6-fold greater in moderately obese subjects
`compared to matched controls.
`
`Table 3. Mean (C\’%) daptomycin pharmacokinetic parameter estimates corrected for actual and
`ideal body weights
`
`
`
`
`Parameter
`CLr(mL/hr/k-ABW
`
`
`
`CLatmL/hrlkelBW)
`
`
`
`\I'ssMeABW)
`
`\-'ss(L/kalBW
`
`
`
`
`
`
`
`
`
`
`When corrected for actual body weight (ABW), the mean CLT and CLR were 0.15-fold and O.l6-fold
`lower in moderately obese subjects compared to matched controls (Table 3).
`In contrast, the mean CLT
`and CLR were O.lO-fold and 0.09-fold greater in moderately obese subjects compared to matched controls
`when correcred for ideal body weight (IBW). The mean Fe was similar between moderately obese
`subject and matched controls (51.8% vs. 52.3%, respectively).
`
`The mean V2 and V55 (not corrected for body weight) were 0.26-fold and 0.23-fold greater in moderately
`obese subjects compared to matched controls. Not surprisingly, the mean elimination half-life was 0.07-
`fold longer. When V2 and V55 were corrected for actual body weight, the parameters decreased 0.09-fold
`and O.lZ-fold. respectively compared to matched controls.
`In contrast, the mean V2 and V55 were 0.19-
`fold and O.lS-fold greater in moderately obese subjects compared to matched controls when corrected for
`ideal body weight.
`
`In extremely obese subjects, the mean CW, and AUCr... were 0.26-fold and 0.31-fold greater, respectively
`in obese subjects than matched controls. Similar to moderately obese subjects, the sponsor‘s estimate of
`AUCOM may be an underestimate in matched controls since a plasma concentration of zero was used at
`24 hrs in 2/6 extreme obesity-matched controls when the concentration was below the LLOQ. The mean
`CLT and CLR (not corrected by body weight) were 0.46-fold and 0.34-fold greater in extremely obese
`subjects compared to matched controls. When corrected for actual body weight (ABW), the mean CLT
`and CLR were 0.23-fold and 0.30-fold lower in extremely obese subjects compared to matched controls.
`In contrasr, the mean CLT and CLR were 0.48-fold and 0.37-fold greater in moderately obese subjects
`compared to matched controls when corrected for ideal body weight (IBW). The mean Fe was 0.12-fold
`lower in extremely obese subject compared to matched controls.
`
`The mean V2 and V55 (not corrected for weight) were 0.52-fold and 0.60-fold greater in extremely obese
`subjects compared to matched controls. When V2 and V55 were corrected for actual body weight, the
`parameters decreased 0.19-fold and O.lS-fold, respectively compared to matched controls. In contrast, the
`mean V2 and V55 were 0.55-fold and 0.62-fold greater in extremely obese subjects compared to matched
`controls when corrected for ideal body weight.
`
`The reviewer calculated the geometric mean ratios (obese subjects/matched controls) and 90% confidence
`intervals for daptomycin Cm, AUC, CLT, CLR, V55, and Fe. The geometric mean ratios and 90%
`confidence intervals are shown in Table 3. For moderately obese subjects, the Cm and AUCO. were
`._. “—7
`.._--._~.,
`
`lSl
`
`

`

`outside of the 0.80 to 1.25 predetermined range and were statistically significantly different between
`moderately obese subjects and matched controls. For extremely obese subjects, the Cm, and AUCO.
`were also outside of the 0.80 to 1.25 predetermined range and were statistically significantly different
`between extremely obese subjects and matched controls. The 90% confidence intervals of the geometric
`mean ratios were outside of the 0.80 and 1.25 range for all pharmacokinetic parameters.
`
`Table 3. Geometric mean ratios and 90% confidence intervals for daptomycin (obese subjects/
`matched controls)
`'
`
`
`
`'
`Moderatelv obese
`90% Cl
`
`
`
`Severelv obese
`Point estimate
`90% CI
`
`-
`
`1 2510
`
`1.081216 1.4476
`
`1 2599
`
`1 1816
`
`1.0970 to 1.2727
`
`1 4857
`
`0 8423
`
`11045
`
`1.1662
`
`0.8313
`
`0.7642 to 0.9284
`
`1.0311101.1833
`
`0.9926 to 1.3701
`
`0.6837 to 1.0107
`
`“ 0.9310 to 1.2764
`
`1.2260
`
`1.0873 to 1.3823
`
`0.7918
`
`1.5065
`
`1.3150
`
`0.7008
`
`1.3333
`
`1.6023
`
`
`
`
`1.1272 to 1.4083
`
`0.9730 to 2.2687
`
`0.5731 to 1.0940
`
`107001021211
`
`0.884019 1.9560
`
`0.5326 to 0.9223
`
`0.9925 to 1.7912
`
`1.3213 to 1.9432
`
`e'hr/ml.
`
`
`
`‘hr/mL)
`
`e’ml.
`
`CLT
`mL/hr
`
`CLT
`(mL/hr/k- AB
`
`(mL/hr/ke lBW
`
`
`
`
`
`
`
`I.“
`
`0.8739
`
`0.7788 to 0.9807
`
`0.8540
`
`0.7522 to 0.9695
`
`n 1.0398 to 1.2631
`
`
`0.9950
`0.8518 to 1.1622
`
`1.6247
`
`0.8851
`
`1.3940 to 1.8936
`
`0.7385 to 1.0607
`
`
`
`When daptomycin was dosed by actual body weight, the Cm and AUCO- were greater in obese subjects
`compared to non-obese matched controls. The V55 and V55 corrected for IBW were greater in obese
`subjects compared to non-obese matched controls but not V55 corrected for ABW. These differences may
`be due to the fact that obese individuals have larger absolute lean body masses as well as masses of
`adipose tissue compared to non-obese individuals of the same age, gender and height.
`
`The CLT and CLT corrected for [BW were greater in obese subjects compared to non-obese matched
`controls but not CLT corrected for ABW. The same relationship was true with renal clearance. The
`differences in daptomycin clearance between obese and matched non-obese controls can be attributed to
`an increase in daptomycin clearance with increased body mass index. The decreases in daptomycin
`plasma clearance (mL/hr/kg AB) between obese subjects and matched controls was similar to the
`decrease in daptomycin renal clearance (mL/hr/kg ABW), suggesting that the observed alteration in
`daptomycin plasma clearance may be due to differences in renal clearance.
`
`~ “—r
`.. ‘Ir
`
`l52
`
`

`

`Stick plots showing the individual Cm and AUC0_ values for daptomycin are shown in Figure 2 whereas
`individual CL; and CLR values for daptomycin are shown in Figure 3.
`
`Figure 2. Stick plots demonstrating individual Cm, and values in obese subjects and non~obese
`matched controls
`'
`
`60
`
`60
`
`40
`
`:c-
`
`Cl
`
`
`
`Cmax(jug/mu
`
`”1'0“”
`Ewe"
`“3°91” WT“ '°’
`0°?“
`””9”“ 03°” 0”“ h‘mm
`
`90c
`
`.1
`~ 70!:-
`g 600
`.5E” 50c
`E:.5 “X3
`éo -
`D soc
`<'
`2G:-
`
`10c
`
`C
`
`We Contra s to
`Obese Mocelate Obese
`
`Exnrne
`Obese
`
`CW0; tor
`Extreme Obese
`
`Figure 3. Stick plots demonstrating individual CL1 and CLR values in obese subjects and non-obese
`' matched controls
`
`1:3:
`
`29:
`
`:30:
`
`533
`
`so:
`
`403
`
`200
`
`C
`
`CL(mUhr)
`
`Mooerate Mm!
`Ooese
`Obese
`Match Central:
`
`Emma
`(has.
`
`Enema
`Obese
`M3131 (Lo-mots
`
`830
`
`~30
`
`6C!)
`
`1‘ 591'
`£_J
`g no
`:1
`0 330
`
`230
`
`'30
`
`3
`
`Mooemte
`Obese
`
`Momma
`Obese
`- Match Controls
`
`Exzreme We
`Obese
`Obese
`Match Controls
`
`Dosage Adjustment:
`The reviewer calculated the weight of each individual subject to "normalize" the apparent volume of
`distribution between obese subjects and non-obese matched controls. The reviewer termed this weight
`the dosing weight (DW), which is the body weight (for purposes of dosing) that would result in a similar
`Cm after administration of daptomycin. For moderately obese subjects, the DW=IBW + 0.45(ABW-
`[BW). For severely obese subjects, the DW=IBW + O.65(ABW-1BW).
`
`The reviewer fit the measured daptomycin plasma concentration-time profiles from obese subject and
`non-obese matched control to a 2-cmpt model using WinNonlin (version 4.0, Pharsight) and the
`.5 “u.
`- “u.
`
`l53
`
`

`

`administered dose (4 mg/k'g based on ABW). Then, the daptomycin plasma concentration-time profiles
`for each patient were simulated using a 2-cmpt model and the recommended dosage (4 mg/kg based on
`DW for obese subjects and ABW for non-obese matched controls) to verify the accuracy of the DW. A
`compariéon of the measured daptomycin plasma concentrations and the simulated concentrations using
`the DW are shown in Figure 4.
`
`Figure 4. Measured daptomycin plasma concentrations (symbols) and simulated daptomycin
`plasma concentrations (solid lines) in moderately obese (left) and extremely obese (right) subjects
`and non-obese matched controls
`
`Moderately obese
`
`
`\lO
`
`Severelv obese
`
`E.
`g
`
`E
`
`
`
`Concentration(mgmL).
`
`,7...
`
`88888
`
`O
`
`.5 O
`
`NOTE: It is difficult to distinguish the simulated plasma concentration-time profiles for moderately obese subjects
`and non-obese matched controls.
`
`For moderately obese subjects, the simulated daptomycin plasma concentration-time profiles were
`superimposable for obese subjects and non-obese matched controls when the dosage of obese subjects
`was based on the DW and non~obese matched controls based on ABW. For severely obese subjects, the
`simulated daptomycin plasma concentration-time profiles were similar between obese subjects and non-
`obese matched controls when the dosage of obese subjects was based on the DW. Thus, the DW appears
`to correct for differences in the apparent volume of distribution between obese and non-obese subjects
`and may be used to adjust the daptomycin dosage in moderately and severely obese patients. However,
`due to the modest alteration in daptomycin pharmacokineticparameters, no dosage adjustment is
`warranted for patients who are moderately obese or extremely obese.
`
`SAFETY:
`
`One of seven subjects in the extremely obese group experienced three treatment—emergent adverse events;
`the six moderately obese subjects and the 12 matched control subjects did not experience any adverse
`events during the study. The subject in the extremely obese group experienced nausea, vomiting, and
`headache eight or more hours after dosing. The three events were mild in severity and were not
`considered to be treatment related. There were no deaths or serious adverse events during the study and
`none of the subjects discontinued due to an adverse event.
`
`CPK concentrations were within normal limits for all subjects at baseline, Day 1, and Day 2.
`
`._ -—-»
`..~..v
`
`l54
`
`

`

`CONCLUSIONS:
`
`The Cm, and AUCM of daptomycin were statistically significantly greater in obese subjects compared to
`non-obese matched controls when dosed by actual body weight.
`
`The CLT, CLR, and V55 of daptomycin were greater in obese subjects compared to non-obese matched
`controls. When the parameters were corrected for actual body weight, the parameters were lower in obese
`subjects than non-obese subjects. When the parameters were corrected for ideal body weight, the
`parameters were greater in obeselsubjects than non-obese subjects.
`
`Obese individuals probably have a larger absolute lean body masses as well as larger adipose tissue
`masses compared to non-obese individuals of the same age, gender and height.
`
`For moderately obese subjects, the dosing weight = IBW + 0.45(ABW-IBW). For severely obese
`subjects, the dosing weight = IBW + O.65(ABW-IBW).
`
`Due to the modest alteration in daptomycin pharmacokinetic parameters, no dosage adjustment is
`warranted in moderately and extremely obese patients.
`
`COMMENTS:
`
`1. The sponsor has not provided data to support the stability of the daptomycin
`daptomycin in'nlasma and urine (
`-
`W
`/ the stability of daptomycin in extracted plasma samples). The sponsor is encouraged to
`submit all validation data with the complete study report in the future.
`
`assay for
`
`-—-
`
`2. Even though daptomycin plasma concentrations were below the LLOQ in 10/11 healthy young subjects
`by 24 hrs, the sponsor reported the AUCmr for all subjects. The AUCMt was calculated using a value of
`zero at 24 hrs. The sponsor is encouraged to calculate AUCW in the future rather than assuming a
`concentration of zero at sampling points in which the plasma concentration is below the LLOQ.
`
`.”‘2
`
`~_-.—
`
`155
`
`

`

`A double—blind, randomized, three-way crossover evaluation ofthe pharmacokinetics of
`daptomycin and aztreonam when administered alone and when administered in combination in
`normal volunteers (Protocol DAP-DI-Ol-Ol)
`
`Dates: November 8, 2001 to December 8, 2001
`Clinical site:
`-
`
`/
`
`Analytical sites:
`'
`
`_
`
`/.
`
`/
`
`RATIONALE:
`
`Aztreonam is an antibacterial agent with strictly Gram-negative agivity; therefore, daptomycin and
`aztreonam can complement one another when co-administered in the treatment of mixed infections.
`However, since both drugs are primarily excreted via the kidneys, the potential for a pharmacokinetic
`interaction may exist based