CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-572
`
`Clinical Pharmacology and Biopharmaceutics
`Review
`
`

`

`NDA#
`
`21-572
`
`_
`
`PRODUCT
`FORMULATION
`DOSAGE STRENGTH .
`SUBMISSION DATES
`
`:
`
`SUBMISSION TYPE
`SPONSOR
`OCPB DIVISION
`
`MEDICAL DIVISION
`REVIEWER
`PM REVIEWER
`TEAM LEADER
`
`Daptomycin (Cubicin“‘)
`Sterile powder for injection
`250 mg and 500 mg vials
`12/19/02, 3/17/03, 3/26/03, 3/27/03, 4/11/03, 5/19/03, 5/20/03, 5/28/03,
`5/29/03, 6/19/03, 8/8/03, 9/3/03
`_
`.
`New Molecular Entity, 1P
`Cubist Pharmaceuticals, Inc., Lexington, MA 02421
`Division of Pharmaceutical Evaluation 111
`
`a
`
`Division of Anti-Infective Drug Products
`Charles R. Bonapace, PharmD.
`Jenny J. Zheng, PhD.
`Philip M. Colangelo, Phann.D., PhD.
`
`CLINICAL PHARIHACOLOGY & BIOPHARMACEUTICS REVIEW
`
`1: EXECUTIVE SUMMARY
`
`Cubist Pharmaceuticals, Inc. submitted a priority review New Drug Application for CubicinTM
`(daptomycin for injection) on December 19, 2002. Daptomycin is a cyclic Iipopeptide antibiotic derived
`from the fermentation of a strain of Streptomyces roseosporus that demonstrates in vitro activity against
`Gram-positive bacteria, including methicillin—resistant Staphylococcus aureus. The proposed dosing
`regimen of daptomycin is 4 mg/kg intravenously administered over 30 min q24h for 7 to 14 days. The
`sponsor is seeking an indication for complicated skin and skin structure infections
`“\-
`~——
`caused by susceptible strains of the following Gram-positive organisms:
`Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes, Streptococcus
`agalactiae, Streptococcm dysgalactiae subsp. equisimilis, Enterococcusfaecalr's (vancomycin-
`'
`susceptible strains only), .
`——
`'
`
`Daptomycin represents a new class of antibacterial agents with a novel mechanism of action that involves
`binding to the bacterial cell membrane followed by membrane depolarization and cell death. Since the
`mechanism of action of daptomycin is different from other antimicrobial agents, it may offer a therapeutic
`alternative in select cases of antimicrobial resistance. The goal of Cubist continues to be focused on
`delivering daptomycin to the market as quickly as possible to address the pressing public health need for
`new classes of antibiotics effective in treating serious and lifeothreatening infections caused by Gram-
`positive pathogens, particularly Staphylococcus aureus (including methicillin~resistant strains).
`
`Several review issues have been identified that impact the quality of data submitted for review. These
`issues consist of the analytical methodology in the renal impairment study, the impact of using estimated
`creatinine clearance (Cockcroft and Gault equation) vs. measured creatinine clearance, the unusually large
`degree of inter-study variability among studies with healthy adult subjects, and the impact of this
`variability in assessing a dosage recommendation in elderly subjects.
`
`In the renal impairment study (Study DAP-OO-Ol), plasma concentrations of daptomycin were initially
`determined by a validated.
`~— ,
`' method for all subjects (controls and renal impairment). Since
`plasma concentrations of daptomycin were greater than other phase 1 studies with the same once-daily
`dose, the sponsor determined the concentration of daptomycin in subjects with normal renal function
`using a validated
`""‘
`assayaThe
`-— method overestimated the plasma concentrations of
`
`fl"\‘
`
`

`

`
`daptomycin by an average of 46% (accuracy ranged from 73% to 187%). Thus, the sponsor convened
`plasma concentrations of daptomycin determined by A ‘ to the
`" for all
`subjects1n study DAP00- 01 using the equation denved from the linear relationship between samples
`determined by
`—-~
`The accuracy of daptomycin concentrations exceeded 100
`+ 15%1n 34% of plasma samples as determined by the reviewer. The sponsor re-assayed all plasma
`samples from Study DAP-00-01 (subjects with normal and impaired renal function) using the validated
`,_
`assay.
`
`Also in Study DAP-OO-Ol , the sponsor assigned subjects for the pharmacokinetic analysis‘to treatment
`groups based on estimated creatinine clearance (CLCR) using the Cockcroft & Gault equation and ideal
`body weight (113W). However. many of the subjects were obese based on a mean body mass index of
`31.1 kg/mZ that ranged from . —“
`kg/mz. The reviewer assigned subjects to treatment groups
`based on their measured creatinine clearance. Due to differences between the estimated CLCR using
`Cockcroft & Gault and the measured CLCR, only one subject remained1n the 30- 50 mL/min treatment
`group.
`
`In a second renal impairment study (Study DAP-MDRI-Ol -09), the sponsor enrolled eight subjects with
`moderate renal impairment (C143 30-50 mL/min). The sponsor did not enroll a control group. All
`subjects had a CLCR of 30-50 mL/min using IBW, three subjects had a CLCR of 30-50 mL/min using
`actual body weight, and one subject had a CLcR of 30-50 mL/min based on a measured creatinine
`clearance. This study was unable to provide information about the pharmacokinetics of daptomycin in
`subjects with CI.“ 30-50 mL/min.
`
`The mean daptomycin C"m ranged from 42.3 to 62.4 uyml. (1.48-fold) and the AUCO- ranged from 301
`to 517 ug‘hr/mL (1. 72- fold) from Phase 1 studies in which healthy volunteers received a single 4 mg/kg
`dose of daptomycin. The intersubject variability of Cm and AUCct. within a study was generally <20%.
`The source of variability between studies15 unknown.
`
`In the geriatric study (Study DAP-GER-Ol-l 1), the mean AUCO. from healthy elderly subjects was
`within the range of values for healthy subjects from previous Phase 1 studies, although the AUG)- from
`the control group (healthy young subjects) was less than previously observed from healthy subjects. The
`mean AUCO. for elderly subjects was 58% greater than the control group of young subjects. Based on
`these findings and safety data from Phase 3 clinical studies, no dosage adjustment ofdaptomycin is
`warranted for elderly subjects with normal (for their age) renal function.
`
`In skin blister study (DAP—00-04), the sponsor used a microbiological assay validated with serum to
`determine the concentration of daptomycin from plasma. No data were submitted to demonstrate the
`cross-validation of the microbiological assay in serum and plasma. It is known that anticoagulants can
`alter the in vr'rr'o protein binding of highly protein bound drugs (M. Klassen, S.C. Edberg. 1996.
`Measurement of antibiotics in human body fluids: Techniques and significance, p. 230-294. In V. Lorian
`(ed), Antibiotics in laboratory medicine, Fourth edition, Williams and Wilkins, Baltimore) and thus,
`impact the results of a microbiological assay. Since the plasma concentrations of daptomycin from study
`DAP-00-04 were greater than any previous Phase 1 study in which healthy subjects received the same
`dose, the results of this study were deemed unacceptable for labeling purposes.
`
`COMMENTS:
`
`1. Although the sponsor used cryopreserved hepatocytes to assess the potential of daptomycin to act as an
`inhibitor and inducer of cytochrome P450 isoforms, the sponsor has not assessed the potential of
`daptomycin to act as a substrate. The sponsor is encouraged to evaluate the potential of daptomycin to act
`as a substrate of the predominant cytochrome P450 isoforms.
`._ ‘3‘ 1:.
`
`lax.
`
`

`

`2. The reviewer recommends a dosage adjustment for patients with renal impairment, beginning at
`moderate renal impairment (CLCR 30-50 mL/min). However, there was only one subject with a CLCR of
`30-50 mL/min in the renal impairment study (StudyDAP-OO-Ol) based on measured creatinine clearance.
`Although the relationship between CLCR and CLT is linear with increasing renal impairment, additional
`data are necessary to characterize the pharmacokinetics of daptomycin in subjects with moderate renal
`impairment.
`
`.‘
`
`A. RECOMMENDATIONS:
`The Office of Clinical Pharmacology and Biophannaceutics/Division of Pharmaceutical Evaluation III
`(OCPB/DPE-Ill) has reviewed NDA .
`The submission is acceptable from a Clinical
`Pharmacology point of view provided that the sponsor agrees wiih the Agency’s label recommendations.
`
`The Phase IV Commitment recommendations and labeling comments outlined in the annotated label
`should be conveyed to the sponsor.
`
`B. {HASH IV COMMITMENTS:
`l.
`
`'
`
`J
`
`2. it is recommended that the sponsor perform a clinical study to assess the safety, efficacy, and
`phamiacokinetics of daptomycin in renal impairment patients with complicated skin and skin structure
`infections. The sponsor is encouraged to include patients with foot and decubitus ulcers complicated by
`diabetes. Enrollment into the study should be limited to patients with an estimated (via the Cockcroft and
`Gault equation using ABW) creatinine clearance $50 mL/min and an attempt should be made to enroll an
`equal number of patients into the following categories: CLCR 30-50 mL/min, CLCR <30 rnL/min,
`hemodialysis patients, and CAPD patients.
`
`
`
`[‘3/
`
`'
`
`Charles R. Bonapace, PharmD.
`Office of Clinical Pharmacology/Biopharrnaceutics
`Division of Pharmaceutical Evaluation Ill
`
`RD/FT Initialedby Philip M. Colangelo, Phann.D., Ph.D.,
`
`/
`
`Team Leader
`
`cc:
`
`Division File: NDA 21-572
`
`RFD-520 (CSO/Peat)
`RFD-520 (MO/Ross, Thompson, Nambiar, Sorbello)
`HPD-52O (Microbiology/Sheldon, Coderre)
`HFD-88O (Division File, Lazor, Selen, Colangelo, Bonapace)
`CDR (Clin. Pharrn./Biophar_m.)
`
`

`

`Table of Contents
`
`1. Executive Summary .................................................................................
`A. Recommendations: .........................................................................
`B. Phase IV Commitments .........._...........................................................
`
`11. Table of Contents .....i.............................................................................
`
`111. Summary of Clinical Pharmacology and Biopharmaceutics Findings ..........-.......
`
`IV. Question-Based Review
`A. General Attributes .........................................................................
`B. General Clinical Pharmacology ..........................................................
`C. Intrinsic Factors ............................................................................
`D. Extrinsic Factors ....................... '.-'...................................................
`
`E. General Biopharmaceutics ................................................................
`F. Analytical Section....| ............
`................
`
`V; Labeling Recommendations ......................................................................
`
`V1. Appendices
`A. Proposed Labeling
`Sponsor's proposed label ............ ‘. ..............................................
`Annotated label ..................................... '. ................................
`_
`B. Individual Study Reviews
`'
`ADME Report No. 12 ..............................................................
`ADME Report No. 13 ..............................................................
`B8B-LC~AVAC .....................................................................
`DAP-00~02 ...........................................................................
`DAP-OO-Ol ...........................................................................
`DAP-MDRI-Ol-O9 ...................................................................
`
`DAP-MDR1-01-03 ..................................................................
`DAP-HEP-00-09 ....................................................................
`DAP-GER-Ol -1 l ....................................................................
`DAP-OBSE-Ol-07 ..................................................................
`DAP~DI-01-Ol ..........................................................T............
`DAPLDlW-Ol-OS ....................................................................
`
`'
`
`DAR-STAT-Ol -1 O ................._ .................................................
`DAP~QTNC-01-06 ..................................................................
`DAP~00-04 ............................................................................
`C. Published Literature Reviews ............................................................
`D. Pharmacometric Consult .................................................................
`
`E. OCPB Filing/Review Form ...............................................................
`
`1
`3
`3
`
`4
`
`5
`
`9
`13
`27
`40
`
`48
`50
`
`52
`
`p
`
`53
`70
`
`92
`94
`97
`103
`l 11
`124
`
`130
`136
`142
`148 "
`156
`162
`
`1 69
`175
`185
`189
`191
`
`209
`
`

`

`II]. Summary of Clinical Pharmacology and Biopharmaceutics Findings
`
`Eli Lilly and Company initiated the original development of daptomycin. Cubist licensed worldwide
`rights for daptomycin from Eli Lilly and Company on November 7, 1997 and submitted its
`lnvestigational New Drug Application (IND 57,693) on December 31, 1998 to begin clinical trials for
`daptomycin. The pre-clinical and clinical data previously generated by Eli Lilly and Company were used
`to suppon Cubist’s initial clinical trials. Concurrently with conducting Phase 2 and3 studies, Cubist
`initiated a full Phase 1 clinical pharmacology program with daptomycin to investigate daptomycin's
`pharrnacokinetic profile in healthy subjects, special populations (renal impairment, hepatic impairment,
`elderly, and obesity), drug-drug interactions (probenecid, aztreonam, warfarin, and simvastatin), effects
`on nerve conduction and cardiac repolarization, and penetration d" daptomycin into cantharides-induced
`skin blister fluid.
`
`L
`
`3 . Cubist modified Eli Lilly‘s
`‘
`clinical strategy of administering divided daily doses to once-daily dosing since previous preclinical
`studies, data analysis, and modeling that showed that once-daily dosing may maximize the antibacterial
`efficacy while minimizing adverse effects.
`
`Many of the Phase 1 clinical pharmacology studies performed by Eli Lilly and Company were not
`included in this review due to missing analytical validation data, illegible study reports, and/or assessment
`of pharrnacokinetics with sub-clinical doses.
`
`Pharmacokinetics in healthy subjects
`The pharrnacokinetics of daptomycin were assessed in 18 healthy subjects who received 4 mg/kg IV q24h
`for 7 days, 6 mg/kg IV q24h for 7 days, and 8 mg/kg IV q24h for 14 days. After the first dose of
`daptomycin, the phannacokinetics were approximately linear based on total and unbound concentrations
`from 4 mg/kg to 6 mg/kg, whereas the total and unbound Cm, and AUCO. increased modestly greater
`than-dose proportional for the 8 mg/kg dose. After administration of7 doses, the Cm, and AUCM4 based
`on total concentrations increased similar to the predicted accumulation for all three doses. Based on
`unbound concentrations, the Cmam also increased similar to the predicted accumulation.
`
`Distribution '
`
`After intravenous administration, the mean steady-state apparent volume of distribution ranged from
`0.0875 to 0.0925 L/kg for 4 mg/kg to 6 mg/kg. The plasma concentration-time profiles were adequately
`fit using a 2-compartrnent model for doses ranging from 4 mg/kg to 8 mg/kg. The mean protein binding
`of daptomycin was approximately 92% and was independent of the plasma Concentration. Daptomycin is
`primarily bound to human serum albumin in a concentration-independent manner, and to a lesser extent,
`human alpha-l -acid glycoprotein in a concentration-dependent manner (ranging fi'om 40% to 25% over
`daptomycin concentration from 2.5 to 80 pg/mL, respectively).
`
`The pharmacokinetics of daptomycin were assessed in four healthy adults with cantharides-induced skin
`blisters following a single 4 mg/kg IV- dose of daptomycin. The mean plasma CM and AUCmr were
`80.] pg/mL and 473 ug‘hr/mL, respectively. The mean skin blister fluid Cm, AUCMr, and Tm were
`22.7 ug/mL, 287 ug‘hr/mL, and 3.5 hrs. The mean percent penetration in skin blister fluid was 61.0%.
`However, the results are unacceptable since the sponsor used a microbiological assay validated with
`serum to determine the concentration of daptomycin in plasma.
`
`

`

`Metabolism
`
`The sponsor has not assessed the potential of daptomycin to act as a substrate of cytochrome P450
`isoforrns using in vitro methods. A mass balance study demonstrated the presence of inactive metabolites
`of daptomycin1n urine since the concentration of daptomycin determined by microbiological assay was
`iess than the concentration based on total radioactivity It15 unknown ifactive metabolites of daptomycin
`are present in serum and/or urine.
`
`Excretion
`
`.
`
`..
`
`Based on the results of the mass balance study, approximately 78% of the administered dose was excreted
`in urine based on total radioactivity and 5.7% ofthe administered dose was excreted in feces collected for
`up to nine days. Only 52% of the administered dose was recovered from urine using microbiological
`assay.
`
`Pharmacokinetics in Special Populations
`-
`Renal impairment
`The effect of renal impairment on the pharmacokinetics of daptomycin were assessed afier a single
`intravenous 4 mg/kg dose to 29 subjects with varying degrees of renal impairment. The mean AUCO...
`was 50%, 92%, and 128% higher in subjects with CLCR 50- 80 mL/min, 30-50 mL/min, and CLCR <30
`mL/min, respectively compared to subjects with normal renal function The mean AUC0_..was 120%
`higher1n hemodialysis patients___not receiving hemodialysis and 165% higherin CAPD patients compared
`to subjects with normal renal function. The CLT was associated with measured creatinine clearance (rz——
`O. 688) and the mean CLT progressively decreased as the degree ofrenal impairment increased. The mean
`CLT was 32%, 49%, and 56% lower in subjects with CLCR 50-80 mL/min, 30-50 mL/min, and CLCR <30
`mL/min, respectively compared to subjects with normal renal function. The mean CLT was 55% lower in
`hemodialysis patients M receiving hemodialysis and 63% in CAPD patients compared to subjects with
`normal renal function. The unbound fraction of daptomycin was similar among subjects with creatinine
`clearance ranging from >80 mL/min to <30 mL/min, whereas the unbound fraction increased in
`hemodialysis and CAPD patients. The reviewer recommends a dosage adjustment for patients with
`creatinine clearance <30 mL/min.
`'
`
`Hepatic impairment
`The effect of hepatic impairment on the pharmacokinetics of a single 4 mg/kg dose of daptomycin were
`assessed in 10 subjects with hepatic impairment (Child-Pugh Class B) and 9 matched healthy controls.
`Compared to healthy subjects, the mean Cm and AUC0__ values were similar between subjects with
`hepatic impairment and healthy subjects. The mean CLT was 8% greater in subjects with hepatic
`impairment compared to healthy subjects and the mean terminal elimination half-life was shorter in
`subjects with hepaticimpairment compared to healthy volunteers (8.97 hrs vs. 9.44 hrs, respectively). No
`dosage adjustment is.warranted for patients with mild to moderate hepatic impairment. The effect of
`severe hepatic impairment was not assessed.
`
`Elderly
`The effect of age on the phannacokinetics ofa single 4 mg/kg dose of daptomycin were assessed in 12
`healthy elderly subjects (275 years of age) and l 1 matched young controls (18 to 30 years of age). The-
`mean Cm, AUCM, and AUCa. were 4%, 46%, and 58% greater, respectively in healthy elderly subjects
`compared to youngsubjects. The mean CLT, CLR, and Ae were 35%, 41%, and 19% lOWer in elderly
`subjects compared to young subjects whereas the terminal elimination half-life was 74% greater in elderly
`subjects. However, the mean AUCcm, AUCo..., C24, and CLT were similar between healthy elderly
`subjects and healthy subjects from study DAP-OO-OZ. Based on the findings ofthis study and safety data
`from the Phase 3 clinical studies, no dosage adjustment is warranted for elderly patients with normal (for
`blu"
`... M.,
`their age) renal function.
`
`

`

`Obesity
`The pharmacokinetics of daptomycin were assessed in six moderately obese subjects (BMl 25-399-
`kg/mz), six extremely obese subjects (BMI 240 kg/mz), and 12 matched control subjects matched for
`gender, age, and renal function following the administration of a single 4 mg/kg 1V dose (based on total
`body \\ c1 ght).
`In moderately obese subjects, the mean Cm, and AUCO. were 25% and 30% greater,
`respectively in obese subjects than matched controls. The mean CLT and CLR (not corrected by body
`weight) were 18% and 16% greater, respectively in moderately obese subjects compared to matched
`controls. In extremely obese subjects, the mean Cm, and AUCO. were 26% and 3f°_/o greater,
`respectively in obese subjects than matched controls. The mean CL; and CLR (not corrected by body
`weight) were 46% and 34% greater, respectively in extremely obese subjects compared to matched
`controls. Correction of CLT and CLR by actual body weight resulted in values that were less than weight-
`corrected clearance terms for matched controls, whereas correction of CLT and CLR by ideal body weight
`resulted in values that were greater than weight-corrected clearance terms for matched controls. The
`reviewer identified a dosage correction factor for moderately obese and extremely obese subjects (see
`page 149). However, the increase in exposure among obese subjects was less than other special
`populations and the dosage adjustment is not recommended for obese patients.
`
`Drug-Drug Interactions
`B_ased on the in vitro results, daptomycin IV 4 mg/kg is unlikely to inhibit or induce the metabolism of
`drugs dependent on cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6,
`CYPZEl , or CYP3A4. However, it is unknown if daptomycin is a substrate of cytochrome P450
`isoforms. The sponsor conducted clinical pharmacology studies to assess the interaction between
`daptomycin and aztreonam, probenecid, warfarin, simvastatin, and tobramycin.
`
`Aztreonam
`
`The pharmacokinetics of daptomycin and aztreonam were assessed in 15 healthy subjects following the
`administration ofa singe dose of both daptomycin IV 6 mg/kg and aztreonam 1V 1,000 mg. When
`daptomycin was administered with aztreonam, the mean Cm, AUCo..., CLT, CLR of either daptomycin or
`aztreonam were not substantially altered. The 90% confidence intervals of the geometric mean ratios for
`AUCO- and Cm, were within the predetermined limits of 0.80 to 1.25 for daptomycin and aztreonam and
`were not statistically significantly different. No dosage adjustment of either daptomycin or aztreonam is
`warranted when co-administered to patients.
`
`Probenecid
`
`The pharmacokinetics ofa single daptomycin TV 4 mg/kg dose co-administerechith probenecid 500 mg
`q6h for 10 doses were assessed in five healthy subjects. When daptomycin was administered with
`probenecid, the mean daptomycin Cw, AUCoa, CLT, and CLR of daptomycin was essentially unchanged.
`The 90% confidence-intervals of the geometric mean ratios for AUCO. and CW for daptomycin were
`within the predetermined limits of 0.80 to 1.25 and were not statistically significantly different. No
`dosage adjustment of daptomycin is warranted in patients receiving probenecid 500 mg QID.
`
`Warfarin
`
`In a study to assess the phannacokinetics of daptomycin and warfarin as well as the pharrnacodynamics of
`warfarin, 16 healthy adult subjects received daptomycin IV 6 mg/kg q24h or placebo for 9 days with a
`single oral dose of warfarin 25 mg on Day 5. The mean Cm, AUCM, and CLT of daptomycin were
`similar when co-administered with warfarin. The mean Cm, AUC0_.., and CLT/F of R-warfarin and S-
`warfarin were not appreciably altered when co-administered with daptomycin. No phannacodynamic
`interaction between warfarin and daptomycin was observed when warfarin was administered with
`daptomycin at steady-state: No dosage adjustment of either daptomycin or warfarin is recommended
`“H‘s”
`when co-administered to patients.“ _,
`
`

`

`Simvastan'n
`
`In a study to assess the safety of daptomycin in subjects on a stable daily dose of simvastatin, 20 adult
`(230 years of age) subjects received daptomycin IV 4 mg/kg q24h or placebo for 14 days with simvastatin
`40 mg daily. The mean trough concentration of daptomycin co-administered with simvastatin was similar
`to values reported in other studies. The mean plasma trough concentrations of simvastatin between
`subjects receiving daptomycin or placebo (NS) were similar. CPK concentrations remained below the
`upper limit of normal (60 to 400 U/L for males, 40 to 150 U/l. for females) over 14 days of daptomycin
`or placebo administration. Although no dosage adjustment of daptomycin or simvastatin is warranted
`when co-administered to patients, concomitant administration of daptomycin and simvastatin is not
`recommended since inhibitors of l-IMG-CoA reductase may cause myopathy.
`
`Tobramycin
`
`Based on the results from a published study, the mean CM and AUCD. of daptomycin increased 12.7%
`and 8.7%, respectively when administered with tobramycin, whereas the mean Cm, and AUCO. of
`tobramycin decreased 10.7% and 6.6%, respectively when administered with daptomycin. No significant
`differences in any ofthe phannacokinetic parameters were detected between the individual and
`combination treatments of the two agents. However, the dose of daptomycin assessed in the study (2
`mg/l-tg) is less than the proposed therapeutic dose (4 mg/kg) for the treatment of complicated skin and
`skin~structure infections and the dose of tobramycin (1 mg/kg) is the minimal customary dose (3-5 mg/kg
`in divided doses or 7 mg/kg as a Single dose). Caution is warranted when daptomycin is co~administered
`with tobramycin.
`
`Cardiac Repolarization
`In a randomized, placeboocontrolled, double-blind study of 120 healthy adult subject, peripheral nerve
`function and cardiac repolarization were compared in subjects administered either IV daptomycin 6
`mg/kg q24h or placebo for 14 consecutive days. Peripheral nerve function was assessed by
`electrophysiological measurement of the median nerve motor function, vibratory perception thresholds,
`and a neurological questionnaire (total, neuropathy, and myopathy components) on the day prior to
`dosing, Day 14, and two weeks after the end of treatment (Day 28). No statistically significant
`differences were observed in a comparison of change from baseline for electrophysiological measurement
`of the median nerve motor function or vibratory perception threshold. A statistically significant
`difference was observed between groups at Day 28 based on total score (p=0.024) and neuropathy
`specific questions (p=0.048) of the neurological 'questionnaire.
`
`.
`
`QT values from all subjects on Day I and Day 8 (pre-dose, 0.5, l, 1.5, 2, 6, and 12 hrs) were corrected
`using Bazett‘s correction formula. The range in QTc values were similar between subjects receiving
`daptomycin and placebo and there were no statistically significant differences in the mean QTc values at
`any time point. QTc values corrected for baseline were not statistically significantly different between the
`treatment groups with respect to mean change from baseline. In addition, QT values corrected using
`Friden'cia's correction formula were similar to those corrected using Bazert’s.
`
`

`

`IV. QUESTION-BASED REVIEW
`
`A. General Attributes
`
`1. What are the highlights of the chemistry and physical-chemical properties ofthe drug substance,
`and the formulation ofthe drug product? What is the proposed mechanism of drug action and
`therapeutic indications? “’hat is the proposed dosage and route of administration?
`
`Daptomycin is a cyclic lipopeptide antibiotic derived from the fermentation of a strain of Streptomyces
`roseosporus.
`
`The chemical name of daptomycinrs N-decanoyll--tryptophyl--L-asparaginylL--aspanyl-
`L--threonylglycyl---L-omiLhyl---L aspartyl-D--alanyl-L”aspartylglycylD--serylthreo-3--methyl--Lglutamyl--3-
`anthraniloyl---Lalanine 81--lactone The chemical formula15 C72H10,N.7026 and the molecular weight15
`1620.67. The chemical structure of daptomycin is shown below:
`
`0m;
`
`”925
`
`HN
`
`
`
`“02¢
`
`Daptomycin for injection is supplied as a sterile, preservative-free, pale yellow to light brown, lyophilized
`cake containing approximately 900 mg/g of daptomycin for intravenous use following reconstidrtion with
`0.9% sodium chloride injection, USP. The only inactive ingredient is sodium hydroxide, which is used
`for pH adjustment. The formulation components of daptomycin for injection are shown in Table 1.
`
`Table 1. Components and quantitative formulation of the unit dosage form - drug product
`
`———mm- u.antirvIZSOmviaI
`zsommooxo
`
`
`
`
`
`uanfin-/500m_vial
`soommm
`
`
`
`
`
`
`
`
`Sodiumlwdroxide, NF
`
`0H ad'ustment
`
`' f.
`
`21
`
`The proposed mechanism of action for daptomycin is shown below in Figure l. Daptomycin inserts
`directly into the cytoplasmic membrane of Gram-positive bacteria via a calcium-dependent process (Step
`1). An ion-conduction structure is formed by the oligomen'zation of the inserted drug (Step 2). Finally,
`the ion structure disrupts the functional integrity of the membrane, resulting in release of intracellular
`potassium ions and dissipation of the membrane potential (Step 3). Depolarization of the membrane is
`followed by the arrest of bacterial DNA, RNA, and protein synthesis, and cell death. A secondary effect
`of daptomycin on Gram-positive bacteria may be the inhibition of lipoteichoic acid synthesis.
`
`

`

`The antibacterial activity ofdaptomycin requires the presence of free (ionized) calcium. The effect of
`calcium over a range of 0-200 mg/L on the in vitro MIC of daptomycin using S. aureus ATCC 25923 and
`E. faecalis ATCC 29212 demonstrated that as the calcium concentration increased over this range, the
`MIC ofdaptomycin decreased 8 log; (8-fold) for E. faecalis and 7 log: (7-fold) for S. aureus. Broth
`supplemented with 50 mg/L calcium has a free (ionized) calcium concentration of 110 mmol/L and15
`similar to the normal range found111 human serum (1.15-1.31 mmoI/L).
`
`Figure 1. Model for the mechanism of action of daptomycin
`
`‘
`
`E
`
`Daptomycin demonstrates in vitro activity against Gram-positive aerobes and Gram-positive anaerobes.
`Daptomycin demonstrates poor in vitro activity (MIC values 8 to >128 pg/mL) against Gram-negative
`aerobes and Gram-negative anaerobes.
`
`The sponsor is seeking an indication for the treatment of complicated skin and skin structure infections
`'12:»:
`3 caused by susceptible strains of the following Gram-
`positive organisms: Staphylococcus aureus (including methicillin-resistant strains), Streptococcus
`p)ogenes, Streptococcus agalactiae, Streptococcus afisgalactiae subsp. equisimilis, Enterococcusfaecalis
`(vancomycin-susceptible strains only)=
`-—
`The proposed dosing regimen
`of daptomycin is 4 mg/kg administered intravenous (IV) over 30 min q24h for 7 to 14 days.
`
`2. What efficacy and safety information contribute to the assessment of clinical pharmacology and
`biopharmaceutics study data?
`
`The sponsor performed two Phase 3 clinical studies evaluating the safety and efficacy of daptomycin for
`the treatment of complicated bacterial skin and soft tissue infections (DAP-SST-98-01 and DAP-SST-99-
`01). Two additionalPhase 3 clinical studies (DAP-CAP-OO-OS and DAP-CAP-(JO-O8) were submitted to
`provide supportive safety data of daptomycin in the treatment of community acquired pneumoniae. The
`Phase 3 clinical studies supporting the treatment of complicated bacterial skin and soft tissue infections
`are summarized below.
`
`DAP-SST-98-01: This study was a multicenter, investigator blinded, randomized trial comparing the
`safety and eflicacy of IV daptomycin to that of IV vancomycin or selected IV semi-synthetic penicillins
`in the treatment of complicated bacterial skin and soft tissue infections known or suspected to be due to
`Gram-positive organisms. Subjects were randomized to receive either IV daptomycin 4 mg/kg q24h
`(n=264 randomized) or comparator drug (n=266 randomized) for 7 to 14 days. Comparators consisted of
`vancomycin and antistaphylococcal penicillins (nafcillin, oxacillin, cloxacillin, and flucloxacillin).
`Subjects with a CLCR of 70 to 30 mL/min were to receive a modified dosing regimen for daptomycin (4
`mg’kg loading dose, followed by 3 mg/kg q36 hr); subjects with CLCR <30 mL/min were excluded from
`:“w
`the trial.
`N....
`
`10
`
`

`

`DAP-SST-99-Ol: This study was a multicenter, investigator blinded, randomized trial comparing the
`safety and efficacy of IV daptomycin to that ofIV vancomycin or selected IV semi-synthetic penicillins
`in the treatment of complicated bacterial skin and soft tissue infections known or suspected to be due to
`Gram-positive organisms. Subjects were randomized to receive either IV daptomycin 4 mg/kg q24h
`(n=277 randomized) or comparator drug (n=294 randomized) for 7 to 14 days. Comparators consisted of
`vancomycin and antistaphylococcal penicillins (nafcillin, oxacillin, cloxacillin, and flucloxacillin).
`Subjects with a CLCR of 70 to 30 mL/min were to receive a modified dosing regimenfor daptomycin (4
`mg/kg loading dose, followed by 3 mg/kg q36 hr); subjects wi