Cubicin
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Cubicin - Scientific Information

Manufacture: Sunovion Pharmaceuticals Inc.
Country: Canada
Condition: Bacteremia, Endocarditis, Methicillin-Resistant Staphylococcus Aureus Infection, Skin and Structure Infection, Skin or Soft Tissue Infection
Class: Miscellaneous antibiotics
Form: Liquid solution, Intravenous (IV)
Ingredients: daptomycin, sodium hydroxide

Pharmaceutical Information

Drug Substance

Common name: daptomycin
Chemical name: N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-Lornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine ε1-lactone
Molecular formula: C72H101N17O26
Molecular mass: 1620.67
Structural formula:

Table 1. Physicochemical properties

Attribute Description
Appearance Clear, dark yellow to light brown solution (bulk drug substance; frozen concentrate). Pale yellow to light brown lyophilized cake (lyophilized drug product).
Solubility (at 25°C)
Water > 1000 mg/mL
Acetonitrile < 0.05 mg/mL
Methanol 34.9 mg/mL
Ethanol 1.20 mg/mL
Isopropyl alcohol 0.11 mg/mL
Partition Coefficient
1-octanol/water -1.32
1-octanol/tris-buffer, pH 7.4 -3.26
pKa (aqueous) 2.9, 3.5, 4.3, 4.7, 10.5
Melting Point 215°C
Specific Rotation (at 25°C)
Water +17.8°
Methanol +11.2°

Clinical Trials

Complicated Skin and Skin Structure Infections (cSSSI)

Study demographics and trial design

The patient demographics and basic trial design for the two pivotal cSSSI studies are summarized in Table 2. Patients were included for skin and skin structure infections complicated by factors implicating deeper soft tissue, significant surgical intervention, comorbidities, hospitalization and/or other factors. The main diagnoses were wound infections, major abscesses and ulcer infections, 57% of which were considered severe in accordance with the SIRS rating scale. Children, pregnant or lactating women and, among others, patients such as those with bacteremia, pneumonia, osteomyelitis, primary muscle disorders or CPK > 50% Upper Limit Normal, third degree burns, shock/hypotension, and severe renal impairment (calculated creatinine clearance < 30 mL/min) were excluded. In the majority of patients with Gram-positive cSSSI, the infections were polymicrobial either due to Gram-positive bacteria, Gram-negative bacteria or anaerobes and 30% of patients received adjunctive surgery. Microbiological analyses were restricted to Gram-positive organisms.

For purposes of the comparator arm, overall analyses, and the grouping of clinically similar patients, all patients were pre-randomized to either vancomycin or anti-staphylococcal semisynthetic penicillins. Vancomycin was chosen in cases of known or suspected MRSA or patient intolerance to penicillins. The anti-staphylococcal semi-synthetic penicillin chosen was dependent upon availability and standard of care in the study country. All patients were then randomized 1:1 to either daptomycin or the comparator arm. Patients could be switched to oral therapies after a minimum of four days of IV treatment if clinical improvement was demonstrated and if a switch was required for other relevant reasons. Patients initially treated with penicillins could be switched to vancomycin if MRSA was cultured after randomization had occurred. Aztreonam and metronidazole could be concurrently administered for the treatment of Gram-negative and anaerobic bacteria respectively.

Overall, the daptomycin and comparator arms were comparable. In study 9801 the large majority of patients were from the US whereas in study 9901 the majority was from South Africa. In the former relative to the latter, study patients tended to be slightly older and included slightly more Caucasians, diabetics, surgical interventions, and vancomycin usage.


Table 2. Summary of Trial Design and Demographics

Study Number (location) Basic Design Primary Efficacy Parameter Antibiotic Treatments Compared (dose and duration) Number of Patients Treated (ITT)* Mean Age in Years (range) Gender (%M/F) Race
(% caucasian/
black/other)
DAP-SST-9801

(US and South Africa)
Multicentre, randomized, parallel group, investigator blinded Clinical outcome in MITT* and CE* patient populations with cSSSI 7-12 days after treatment cessation Daptomycin (4mg/kg/q24h IV x 7-14 days)

versus
264 55.2 (18-91) 54.2/45.8 67.0/18.9/14.4
Comparator: vancomycin (1g q12h IV x 7-14 days) or semisynthetic penicillins** (4-12 g/d IV in divided doses x 7-14 days) 266 55.5 (19-94) 55.6/44.4 62.8/22.6/14.9
DAP-SST-9901

(South Africa, Europe, Australia and Israel)
Multicentre, randomized, parallel group, investigator blinded Clinical outcome in MITT* and CE* patient populations with cSSSI 7-12 days after treatment cessation Daptomycin (4mg/kg/q24h iv x7-14days)

versus
270 47.9 (18-87) 55.6/44.4 50.4/35.2/14.4
Comparator: vancomycin (1g q12h iv x 7-14days) or semisynthetic penicillins*** (4-12 g/d iv in divided doses x 7-14 days) 292 48.6 (17-85) 54.8/45.2 50.0/31.2/18.8
* analytical subpopulations included: ITT: intent to treat population (patients with cSSSI who received at least one dose); MITT: modified intent to treat population (ITT patients with proved Gram-positive bacterial cSSSI at baseline); CE: clinically evaluable population (all ITT patients in whom clinical outcome could be inferred to reflect the effect of the study drug, met clinical criteria for study infection, received correct study drug as randomized for appropriate duration and intensity, had required clinical evaluations and did not receive confounding non-study medications); ME: microbiologically evaluable population (CE patients with a Gram-positive bacterium at baseline); about 82% of ITT patients met MITT criteria and 81% of ITT patients met CE criteria; 84% of CE patients met ME criteria for microbiological evaluability at Test of Cure visit

** anti-staphylococcal semi-synthetic penicillin: nafcicillin, cloxacillin or oxacillin

*** anti-staphylococcal penicillin: flucloxacillin, cloxacillin or oxacillin

Study results

Overall clinical efficacy results are provided in Tables 16 and 17 in terms of the sponsor-defined primary clinical efficacy parameters at the Test Of Cure visit (7-12 days after cessation of antibiotic treatment) for MITT and CE populations.


Table 3. Clinical efficacy outcome (MITT population)

Clinical Response DAP-SST-9801 DAP-SST-9901 Pooled Results
CUBICIN
(N=215)
n (%)
Comparatora
(N=216)
n (%)
CUBICIN
(N=213)
n (%)
Comparatora
(N=255)
n (%)
CUBICIN
(N=428)
n (%)
Comparatora
(N=471)
n (%)
Clinical Success 140 (65.1) 140 (64.8) 179 (84.0) 212 (83.1) 319 (74.5) 352 (74.7)
Cure 90 (41.9) 84 (38.9) 82 (38.5) 109 (42.7) 172 (40.2) 193 (41.0)
Clinical Improvement 50 (23.3) 56 (25.9) 97 (45.5) 103 (40.4) 147 (34.3) 159 (33.8)
Clinical Failure 75 (34.9) 76 (35.2) 34 (16.0) 43 (16.9) 109 (25.5) 119 (25.3)
a Vancomycin or anti-staphylococcal semi-synthetic penicillins

Table 4. Clinical efficacy outcome (CE population)

Clinical Response DAP-SST-9801 DAP-SST-9901 Pooled Results
CUBICIN
(N=208)
n (%)
Comparatora
(N=206)
n (%)
CUBICIN
(N=238)
n (%)
Comparatora
(N=250)
n (%)
CUBICIN
(N=446)
n (%)
Comparatora
(N=456)
n (%)
Clinical Success 158 (76.0) 158 (76.7) 214 (89.9) 226 (90.4) 372 (83.4) 384 (84.2)
Cure 105 (50.5) 96 (46.6) 103 (43.3) 117 (46.8) 208 (46.6) 213 (46.7)
Clinical Improvement 53 (25.5) 62 (30.1) 111(46.6) 109 (43.6) 164(36.8) 171 (37.5)
Clinical Failure 50 (24.0) 48 (23.3) 24 (10.1) 24 (9.6) 74 (16.6) 72 (15.8)
a Vancomycin or anti-staphylococcal semi-synthetic penicillins

The pooled clinical efficacy results, based on sponsor-defined clinical efficacy outcome parameters for the MITT population in studies DAP-SST-9801 and DAP-SST 9901, are provided in Table 18 in terms of infecting bacteria and patient pre-randomization to either antistaphylococcal semi-synthetic penicillins or vancomycin. These two clinical groupings were based upon the likelihood of patients having MRSA or penicillin intolerance and the patients of both groupings received either CUBICIN or the appropriate comparator drug (vancomycin or an anti-staphylococcal semi-synthetic penicillin).


Table 5. Pooled clinical success rates by infecting pathogen and patient prerandomization (MITT population)

Pathogen Pre-randomized to
Semi-synthetic Penicillins
Pre-randomized to
Vancomycin
Drug Received Drug Received
CUBICIN
n/N(%)
Semi-synthetic
Penicillins
n/N (%)
CUBICIN
n/N(%)
Vancomycin
n/N (%)
Staphylococcus aureus
(MSSA)
130/161 (80.7) 128/160 (80.0) 38/50 (76.0) 56/79 (70.9)
Staphylococcus aureus
(MRSA)
3/7 (42.9) 6/9 (66.7) 15/29 (51.7) 20/38 (52.6)
Streptococcus pyogenes 70/79 (88.6) 74/88 (84.1) 9/9 (100.0) 8/15 (53.3)
Streptococcus agalactiae 13/15 (86.7) 15/27 (55.6) 7/9 (77.8) 7/14 (50.0)

Similarly, the pooled microbiological efficacy results (eradication or presumed eradication in the ME population) for studies DAP–SST-9801 and DAP-SST 9901, are provided in Table 6.


Table 6. Pooled microbiological success rates (eradication or presumed eradication) by infecting pathogen and patient pre-randomization (ME population)

Pathogen Pre-randomized to
Semi-synthetic Penicillins
Pre-randomized to
Vancomycin
Drug Received Drug Received
CUBICIN
n/N(%)
Semi-synthetic
Penicillins
n/N (%)
CUBICIN
n/N(%)
Vancomycin
n/N (%)
Staphylococcus aureus
(MSSA)
108/144 (75.0) 108/139 (77.7) 31/41 (75.6) 49/68 (72.1)
Staphylococcus aureus
(MRSA)
2/4 (50.0) 3/6 (50.0) 12/21 (57.1) 18/30 (60.0)
Streptococcus pyogenes 66/72 (91.7) 65/79 (82.3) 9/9 (100.0) 7/9 (77.8)
Streptococcus agalactiae 12/14 (85.7) 12/18 (66.7) 6/7 (85.7) 7/11 (63.6)

Staphylococcus aureus Bacteremia/Staphylococcus aureus Infective Endocarditis (SAB/SAIE) Trial

Study Demographics and Trial Design

The trial design and patient demographics for the Staphylococcus aureus bacteremia/Staphylococcus aureus infective endocarditis (SAB/SAIE) trial are summarized in Table 7 and Table 8.

Adult patients ≥ 18 years of age with clinically documented Staphylococcus aureus bacteremia determined by at least one positive blood culture for Staphylococcus aureus obtained within 2 calendar days prior to the first dose of study drug and irrespective of source were enrolled. The major exclusion criteria were patients with a prosthetic heart valve, cardiac decompensation and/or valve damage, shock or hypotension, severe renal disease, increased AST or ALT, severe neutropenia, or known osteomyelitis. Patients who developed osteomyelitis during treatment were permitted to remain on study. In addition, patients with meningitis, pneumonia, polymicrobial bloodstream infections or with intravascular foreign material not planned for removal within 4 days of dosing (except vascular stents in place > 6 months or permanent pacemakers) were not to be enrolled.

Baseline characteristics in the Intent-to-Treat (ITT) population were well balanced between the two treatment arms. Patients were generally seriously ill and included the elderly, those with systemic inflammatory response syndrome (SIRS), diabetes mellitus, injection drug use, extravascular foreign materials, intravascular foreign materials, percutaneous intravascular devices, presence of a catheter at first positive culture, prior endocarditis, pre-existing valvular heart disease, abnormal chest x-ray, HIV positive, prior endocarditis and surgery, infection and/or trauma within 30 days of onset of the Staphylococcus aureus bacteremia. Eighty-nine patients (38%) had bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA).

Vancomycin was used if the patient had methicillin-resistant Staphylococcus aureus. Vancomycin was used unless or until susceptibility results proved to be methicillin-susceptible whereupon therapy was changed to an anti-staphylococcal semi-synthetic penicillin (SSP) unless contraindicated. The choice of anti-staphylococcal semi-synthetic penicillin was based on the standard therapy in each country.


Table 7. Trial design in the pivotal SAB/SAIE Study

Study Number/
Country
Design Primary Efficacy
Parameter
Treatment Regimen Number of
Patients
Treated
DAP-IE-01-02
United States (40 sites)
Europe (8 sites)
Multi-centre, randomized, openlabel, comparative (non-inferiority) Co-primary composite efficacy endpoint was clinical and microbiological success at test-ofcure visit (6 weeks after last treatment dose), based on an Independent External Adjudication Committee outcome, in the ITT and PP populations* Dose
Daptomycin (6 mg/kg IV q24h)

versus

vancomycin (1 g IV q12h) or semi-synthetic penicillin** (2 g IV q4h)
Gentamicin (1 mg/kg IV q8h): given to all patients in comparator group and those with left-sided infective endocarditis in daptomycin group for the first 4 days (or until blood cultures were negative for 48 hours)

Duration
10-42 days with an option to extend for 14 days. The duration of treatment was to be based on the patient’s diagnosis as determined by the Investigator and the susceptibility of the S. aureus isolate

120




115
* ITT population included all patients who were randomized and received at least one dose of study medication; PP population included those in the ITT population with documented adherence to the protocol

** Anti-staphylococcal semi-synthetic penicillins included nafcillin, oxacillin, cloxacillin or flucloxacillin based on standard therapy in each country

Vancomycin and gentamicin were to be adjusted based on renal function and plasma level according to Investigator’s standard practice and manufacturer’s guidelines


Table 8. Summary of Demographic Characteristics for the SAB/SAIE Study (ITT Population)

Characteristic CUBICIN
(N=120)
Comparator
(N=115)
Total
(N=235)
Median Age (years) (range) 50.5 (21, 87) 55.0 (25, 91) 53.0 (21, 91)
Age, years [N (%)]
≥65
≥75a

30 (25.0%)
19 (15.8%)

37 (32.2%)
15 (13.0%)

67 (28.5%)
34 (14.5%)
Gender, N (%) Male 70 (58.3%) 71 (61.7%) 141 (60.0%)
Female 50 (41.7%) 44 (38.3%) 94 (40.0%)
Race, N (%) Caucasian 75 (62.5%) 81 (70.4%) 156 (66.4%)
BMI, kg/m2 Median (range) 26.90 (17.6, 49.7) 25.67 (17.0, 44.0) 26.47 (17.0, 49.7)
CLcr, mL/minb, Median (range) 86.44 (28.0, 246.9) 83.61 (17.9, 277.0) 84.56 (17.9, 277.0)
CLcr, N (%) <50 mL/minb 19 (15.8%) 22 (19.1%) 41 (17.4%)
a Age category ≥75 years is a subset of the category ≥65 years.

bCalculated by the Sponsor using the Cockcroft-Gault equation.


Upon entry, adult patients were classified for likelihood of endocarditis using the modified Duke criteria (Possible, Definite, or Not Endocarditis). Echocardiography, including transesophageal echocardiogram (TEE), was performed within 5 days following study enrollment. Final diagnoses and outcome assessments at Test of Cure were made by a treatment-blinded Independent External Adjudication Committee (IEAC), using protocol-specified clinical definitions.

Of the 37 patients with an entry diagnosis of Definite Endocarditis, all (100%) had a final diagnosis of infective endocarditis; of the 144 patients with an entry diagnosis of Possible Endocarditis, 15 (10%) had a final diagnosis of infective endocarditis; and, of the 54 patients with an entry diagnosis of Not Endocarditis, 1 (2%) had a final diagnosis of infective endocarditis. There were 182 patients with bacteremia including 121 with complicated and 61 with uncomplicated Staphylococcus aureus bacteremia; and, there were 53 patients with infective endocarditis, including 35 with right-sided and 18 with left-sided endocarditis. A summary of the entry and final diagnostic subgroups (defined below) in the ITT population are presented in Table 9.

Complicated bacteremia was defined as Staphylococcus aureus isolated from blood cultures obtained on at least 2 different calendar days, and/or metastatic foci of infection (deep tissue involvement), and classification of the patient as not having endocarditis according to the modified Duke criteria.

Uncomplicated bacteremia was defined as Staphylococcus aureus isolated from blood culture(s) obtained on a single calendar day, no metastatic foci of infection, no infection of prosthetic material, and classification of the patient as not having endocarditis according to the modified Duke criteria.

Right-sided infective endocarditis (RIE) was definite or possible endocarditis according to the modified Duke criteria and no echocardiographic evidence of predisposing pathology or active involvement of either the mitral or aortic valve. Patients with a final diagnosis of RIE based on these criteria were further classified as either complicated or uncomplicated RIE as described below:

Complicated RIE included patients who met any of the following criteria: were not intravenous drug users; had a positive blood culture for MRSA; had a serum creatinine ≥2.5 mg/dL; or had evidence of extrapulmonary sites of infection.

Uncomplicated RIE included patients who met all of the following criteria: were intravenous drug users; had a positive blood culture for MSSA; had a serum creatinine <2.5 mg/dL; and were without evidence of extrapulmonary sites of infection.

Left-sided infective endocarditis (LIE) was definite or possible endocarditis according to modified Duke criteria and echocardiographic evidence of involvement or predisposing pathology of the mitral or aortic valve.


Table 9. Summary of Entry and Final Diagnostic Subgroups in the SAB/SAIE Trial (ITT Population)

Diagnostic Subgroup CUBICIN
(N=120)
Comparator
(N=115)
Total
(N=235)
IEAC Entry Diagnostic Subgroup [N (%)]
N
Definite IE
Possible IE
Not IE

120
17 (14.2%)
73 (60.8%)
30 (25.0%)

115
20 (17.4%)
71 (61.7%)
24 (20.9%)

235
37 (15.7%)
144 (61.3%)
54 (23.0%)
IEAC Final Diagnostic Subgroup [N (%)]
N
Complicated RIE
Uncomplicated RIE
Complicated bacteremia
Uncomplicated bacteremia
LIE

120
13 (10.8%)
6 (5.0%)
60 (50.0%)
32 (26.7%)
9 (7.5%)

115
12 (10.4%)
4 (3.5%)
61 (53.0%)
29 (25.2%)
9 (7.8%)

235
25 (10.6%)
10 (4.3%)
121 (51.5%)
61 (26.0%)
18 (7.7%)

Study Results

The overall success rates at Test of Cure in the ITT population were 44.2% (53/120) in patients treated with CUBICIN® and 41.7% (48/115) in patients treated with comparator [95% CI 2.4% (-10.2, 15.1)]. The success rates at Test of Cure in the Per Protocol Population were 54.4%(43/79) in patients treated with CUBICIN® and 53.3% (32/60) with comparator [95% CI 1.1% (-15.6, 17.8)].

The success rates in the ITT population are shown in Table 10.


Table 10. Success Rates* at Test of Cure in the pivotal SAB/SAIE Trial (ITT Population)

Population CUBICIN 6
mg/kg n/N (%)
Сomparatora
n/N (%)
Difference:
CUBICIN − Comparator
(Confidence Interval)
Overall 53/120 (44.2%) 48/115 (41.7%) 2.4% (−10.2, 15.1)c
Baseline Pathogen
MSSA 33/74 (44.6%) 34/70 (48.6%) −4.0% (−22.6, 14.6)d
MRSA 20/45 (44.4%) 14/44 (31.8%) 12.6% (−10.2, 35.5)d
>Entry Diagnosisb
Definite or Possible Infective
Endocarditis
41/90 (45.6%) 37/91 (40.7%) 4.9% (−11.6, 21.4)d
Not Infective Endocarditis 12/30 (40.0%) 11/24 (45.8%) −5.8% (−36.2, 24.5)d
>Final Diagnosisf
Complicated Bacteremia 26/60 (43.3%) 23/61 (37.7%) 5.6% (−17.3, 28.6)e
Uncomplicated Bacteremia 18/32 (56.3%) 16/29 (55.2%) 1.1% (−31.7, 33.9)e
Right-Sided Infective Endocarditis
(RIE)
8/19 (42.1%) 7/16 (43.8%) −1.6% (−44.9, 41.6)e
Complicated RIE 5/13 (38.5%) 6/12 (50.0%) −11.5% (−62.4, 39.4)e
Uncomplicated RIE 3/6 (50.0%) 1/4 (25.0%) 25.0% (−51.6, 100.0)e
Left-Sided Infective Endocarditis 1/9 (11.1%) 2/9 (22.2%) −11.1% (−55.9, 33.6)e
* Success: if patient was judged as cured or improved by IEAC, had a negative blood culture, did not receive potentially effective non-study antibiotic that could have altered outcome, and received at least the minimum amount of study medication

a Comparator: vancomycin (1 g IV q12h) or anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin According to the modified Duke criteria

b According to the modified Duke criteria

c 95% Confidence Interval

d 97.5% Confidence Interval (adjusted for multiplicity)

e 99% Confidence Interval (adjusted for multiplicity)

f See definitions above.


Table 11 presents a summary of success rates at Test of Cure by duration of study treatment in the ITT population. Across all patients in the ITT population, success rates increased with increasing duration of treatment in both the CUBICIN® and comparator groups.


Table 11. Summary of Success Rates at Test of Cure in the SAB/SAIE Trial by Duration of Treatment and Final Diagnosis (ITT Population)

Group CUBICIN
6 mg/kg q24h
n/N (%)
Comparator
n/N (%)
1-14
days
15-28
days
29-42
days
>42 days 1-14
days
15-28
days
29-42
days
>42 days
Overall ITT 29/77
(37.7%)
15/29
(51.7%)
7/11
(63.6%)
2/3
(66.7%)
14/52
(26.9%)
21/41
(51.2%)
11/18
(61.1%)
2/4
(50.0%)
Complicated
bacteremia
14/36
(38.9%)
6/14
(42.9%)
4/7
(57.1%)
2/3
(66.7%)
5/30
(16.7%)
10/18
(55.6%)
7/11
(63.6%)
1/2
(50.0%)
Uncomplicated
bacteremia
12/25
(48.0%)
6/7
(85.7%)
0/0
(0%)
0/0
(0%)
9/16
(56.2%)
5/11
(45.5%)
1/1
(100%)
1/1
(100%)
Right-sided
endocarditis
3/9
(33.3%)
3/7
(42.9%)
2/3
(66.7%)
0/0
(0%)
0/4
(0%)
4/6
(66.7%)
3/5
(60.0%)
0/1
(0%)
Left-sided
endocarditis
0/7
(0%)
0/1
(0%)
1/1
(100%)
0/0
(0%)
0/2
(0%)
2/6
(33.3%)
0/1
(0%)
0/0
(0%)
Note: anti-staphylococcal semi-synthetic penicillin (SSP) included nafcillin, oxacillin, cloxacillin, and flucloxacillin.

In the overall ITT population, there was no statistically significant difference in time to clearance of Staphylococcus aureus bacteremia between CUBICIN and comparator. The median time to clearance in patients with MSSA was 4 days and in patients with MRSA was 8 days.

Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was assessed in 19/120 (15.8%) CUBICIN-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (9.6%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with anti-staphylococcal semi-synthetic penicillin). Among all failures, 6 CUBICIN-treated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility on or following therapy). Most patients who failed due to persisting or relapsing Staphylococcus aureus infection had deep-seated infection and did not receive necessary surgical intervention (see WARNINGS AND PRECAUTIONS).

Detailed Pharmacology

Animal Pharmacology

Adult Animals

In animals, daptomycin administration has been associated with effects on skeletal muscle with no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by degenerative/regenerative changes and variable elevations in creatine phosphokinase (CPK). No fibrosis or rhabdomyolysis was evident in repeat dose studies up to the highest doses tested in rats (150 mg/kg/day IV) and dogs (100 mg/kg/day IV). The degree of skeletal myopathy showed no increase when treatment was extended from 1 month to up to 6 months. Severity was dose dependent. All muscle effects, including microscopic changes, were fully reversible within 30 days following cessation of dosing.

In adult animals, effects on peripheral nerve (characterized by axonal degeneration and frequently accompanied by significant losses of patellar reflex, gag reflex and pain perception) were observed at doses higher than those associated with skeletal myopathy. Deficits in the dogs' patellar reflexes were seen within 2 weeks of the start of treatment at 40 mg/kg IV (9 times the human Cmax at the 6 mg/kg IV q24h dose), with some clinical improvement noted within 2 weeks of the cessation of dosing. However, at 75 mg/kg/day IV for 1 month, 7/8 dogs failed to regain full patellar reflex responses within the duration of a 3-month recovery period. In a separate study in dogs receiving doses of 75 and 100 mg/kg/day IV for 2 weeks, minimal residual histological changes were noted at 6 months after cessation of dosing. However, recovery of peripheral nerve function was evident.

Acute IV administration of daptomycin to male mice was associated with dose-related effects on the central nervous system that were minimal at dose levels below 100 mg/kg but significant at 200 mg/kg. These effects included decreased motor activity, leg weakness, tremors, grasping loss, decreased abdominal tone, piloerection, decreased frequency of acetic acid-induced writhing, and increased hexobarbital-induced sleep time. Animal model studies have demonstrated that there is an increased penetration of daptomycin into the cerebrospinal fluid through inflamed meninges.

Daptomycin has been shown to penetrate into rabbit meninges (non-inflamed, 2%; inflamed 6%).

In another study of general pharmacological properties at doses up to 150 mg/kg IV, daptomycin caused no changes in gross behavior of rats at 15 mg/kg. Slight hypoactivity and abnormal posture were observed at 50 mg/kg. At 150 mg/kg, changes included hypoactivity, abnormal posture and gait, ptosis, decreased limb tone, increased defecation, and decreased food consumption and body weight. Most effects were transient and reversed within 24 hours postdose. After pre-treatment at this dose, daptomycin also potentiated thiopental-Na anesthesia by 4 to 8-fold and inhibited motor coordination.

Tissue distribution studies in rats have shown that daptomycin is retained in the kidney.

The effect of concurrent administration of daptomycin and simvastatin on skeletal muscle was studied in a repeat dose study in CD rats. A total of four groups of male rats (15 rats per group) were treated as follows: Group 1: vehicle, days 0-27; Group 2: daptomycin 20 mg/kg/day IV, days 14-27; Group 3: Simvastatin 10 mg/kg/day Oral, days 0-27; and Group 4: Simvastatin 10 mg/kg/day Oral, days 0-27 and daptomycin 20mg/kg/day IV, days 14-27. Blood for serum chemistry was obtained on days 13 (prior to the initiation of daptomycin treatment) and 27. Following 14 days of treatment with 10 mg/kg/day of simvastatin in combination with 20 mg/kg/day of daptomycin, a slight, statistically significant increase was detected in the levels of aspartate aminotransferase but not creatine phosphokinase (Table 12). However, it is noteworthy that following thirteen days of treatment with simvastatin alone (prior to the administration of daptomycin), slight, statistically significant elevations in mean serum levels of creatine phosphokinase and aspartate aminotransferase were detected in Group 4 animals as compared to Group 3 animals (see Table 12). Because the magnitude of the difference in CPK and AST between Group 4 and Group 3 (10/20 and 10/0 mg/kg/day simvastatin/daptomycin, respectively) on day 27 (1.4 and 1.4-fold respectively) was comparable to that noted on day 13, the difference is most likely related to the pre-existing (day 13) elevation and not due to the addition of daptomycin administration to simvastatin.

The microscopic examination of skeletal muscle at the end of study revealed minimal degenerative and/or regenerative changes in animals from all groups. Although the incidence was slightly higher for daptomycin (with or without simvastatin) as compared to vehicle or simvastatin alone treated groups, there was no increase in the incidence or severity of muscle effects in the daptomycin alone group as compared to daptomycin in combination with simvastatin.

Together, these data support the conclusion that no effect of drug interaction on skeletal muscle was observed upon co-administration of daptomycin and simvastatin to rats at clinically relevant doses.


Table 12. Summary of Creatine Phosphokinase (CPK) and Aspartate Aminotransferase (AST) Levels in Rats Following Administration of Oral Simvastatin With and Without Intravenous Daptomycin

Daily Dosea Control Vehicle + Vehicle Daptomycin 20mg/kg/day + Vehicle Simvastatin 10 mg/kg/day + Vehicle Simvastatin 10mg/kg/day + Daptomycin 20 mg/kg/day
Group 1 Group 2 Group 3 Group 4
CPK (IU/L)
Day 13b 331.4 435.7 352.5 590.2c
Day 27 509.1(54%)e 568.5 (30%)e 777.0 (121%)e 1083 (84%)e
AST (U/L)
Day 13b 99.2 99.3 97.7 121.7d
Day 27 104.5 (5%)e 107.1 (8%)e 121.3 (24%)e 169.5d (39%)e
a Dose administration of simvastatin was initiated 14 days prior to addition of daptomycin treatment. Simvastatin was administered from Treatment Days 0 to 27; Daptomycin was administered from Treatment Days 14-27.

b Values for Day 13 preceded initiation of daptomycin treatment.

c Significantly different from Groups 1 and 3 but not Group 2 by Duncan’s test (p<0.05)

d Significantly different from Groups 1, 2 and 3 by Duncan’s test (p<0.05)

e Numbers in parentheses represent the percentage increase in CPK or AST values from Day 13 to 27


The effect of concurrent administration of daptomycin and tobramycin with respect to nephrotoxicity and neuromuscular toxicity was studied in rats. Daptomycin dose levels were 1, 5, and 20 mg/kg IV q24h. The tobramycin dose was 10 mg/kg SC b.i.d. Tobramycin treatment alone was associated with mild nephropathy. In comparison to the control group, absolute and relative kidney weights were increased in all groups receiving tobramycin. In addition, an increased incidence and severity of cortical tubular regeneration was observed in all tobramycintreated groups. Concurrent administration of daptomycin had no effect on the tobramycininduced nephropathy. Mild skeletal muscle degeneration and/or regeneration were observed in the high dose daptomycin group when given alone. When daptomycin was administered concurrently with tobramycin, skeletal muscle degeneration and/or regeneration were observed at dose levels of daptomycin ≥ 5 mg/kg. An increase in the incidence of the muscle damage in relation to tobramycin dose suggests that daptomycin-induced myopathy may be potentiated by co-administration of tobramycin. This increase is most likely related to the nephrotoxic effects of tobramycin, which may have resulted in reduced renal clearance of daptomycin and higher systemic exposure. No microscopic damage to the sciatic nerve was apparent.

The effect of concurrent administration of daptomycin and gentamicin with respect to nephrotoxicity was investigated in dogs. Gentamicin dose levels were 9 or 30 mg/kg/day IM (3 or 10 mg/kg q8h). The daptomycin dose was 30 mg/kg/day IV (10 mg/kg.q8h). When daptomycin was administered with high dose gentamicin, blood urea nitrogen and creatinine levels were 2-fold greater and potassium levels were slightly decreased (approximately 17%) as compared to the values observed with gentamicin alone. High dose gentamicin alone produced slight to minimal renal tubular necrosis and tubular epithelial regeneration. In animals receiving high dose gentamicin in combination with daptomycin, the severity of these lesions was graded as minimal to moderate. Thus, when a high dose of gentamicin was given in combination with daptomycin, the severity of the nephrotoxic lesions was increased and changes in clinical chemistry parameters indicative of renal effects were observed. In contrast, the administration of daptomycin with a low dose of gentamicin did not produce a functionally meaningful difference in the severity of nephrotoxicity. Daptomycin, given alone at 30 mg/kg/day did not induce nephrotoxicity.

Juvenile Animals

Target organs of daptomycin-related effects in 7-week-old juvenile dogs were skeletal muscle and nerve, the same target organs as in adult dogs. In juvenile dogs, nerve effects were noted at lower daptomycin blood concentrations than in adult dogs following 28 days of dosing. In contrast to adult dogs, juvenile dogs showed evidence of effects in nerves of the spinal cord as well as peripheral nerves after 28 days of dosing. No nerve effects were noted in juvenile dogs following 14 days of dosing at doses up to 75 mg/kg/day.

Administration of daptomycin to 7-week-old juvenile dogs for 28 days at doses of 50 mg/kg/day produced minimal degenerative effects on the peripheral nerve and spinal cord in several animals. A dose of 150 mg/kg/day for 28 days produced minimal degeneration in the peripheral nerve and spinal cord as well as minimal to mild degeneration of the skeletal muscle in a majority of animals, accompanied by slight to severe muscle weakness evident in most dogs. Following a 28-day recovery phase, microscopic examination revealed apparent recovery of the skeletal muscle and the ulnar nerve effects, but nerve degeneration in the sciatic nerve and spinal cord was still observed in all 150 mg/kg/day dogs (see TOXICOLOGY).

Following once-daily administration of daptomycin to juvenile dogs for 28 days, microscopic effects in nerve tissue were noted at a Cmax value of 417 μg/mL, which is approximately 3-fold less than the Cmax value associated with nerve effects in adult dogs treated once daily with daptomycin for 28 days (1308 μg/mL).

Neonatal Animals

Neonatal Animals Administration of daptomycin to postnatal day (PND) 4 neonatal dogs at 50 and 75 mg/kg/day (Cmax and AUCinf values of ≥321 μg/mL and ≥1470 μg•h/mL, respectively) produced marked clinical signs of twitching, muscle rigidity in the limbs, impaired use of limbs, and a decrease in body weights and overall body condition necessitating early discontinuation by PND 19. A dose of 25 mg/kg/day from PND 4 to PND 31 (Cmax and AUCinf values of 147 μg/mL and 717 μg•h/mL, respectively) produced mild reversible clinical signs of twitching and one incidence of muscle rigidity with no effects on body weight. No histopathological effect related to daptomycin was observed (including peripheral and central nervous system and skeletal muscle) at any dose. No effects were observed in dogs administered daptomycin at 10 mg/kg/day, the NOAEL, following 28 days of treatment with associated Cmax and AUCinf values of 62 μg/mL and 247 μg•h/mL, respectively.

Human Pharmacology

Pharmacodynamics

In a placebo-controlled study in healthy volunteers, there was no evidence that exposure to CUBICIN (daptomycin for injection) at 6 mg/kg IV q24h x 14d caused any meaningful changes in cardiac repolarization as measured by QTcB. In nerve motor function studies, CUBICIN administration did not cause any significant changes in the set of objective measures indicative of neuropathy or myopathy. CUBICIN administration was associated with a significant increase in the number of affirmative responses to the neurological questionnaire designed to assess symptoms and deficits associated with small fiber sensory function. During the 14-day follow-up period more subjects in the CUBICIN group (8) compared to the normal saline group (5) reported symptoms of tingling, numbness and weakness.

In an ascending dose study, CUBICIN was well-tolerated at doses up to 12 mg/kg for up to 14 days. No significant adverse effects, including effects on skeletal muscle and peripheral nerves, were observed during the study period in any dose group.

Pharmacokinetics

The pharmacokinetic profile of CUBICIN in humans is highly predictable following intravenous administration. Single and multiple doses of CUBICIN, up to 12 mg/kg/day for up to 14 consecutive days have been studied in healthy subjects (see Table 9, ACTION AND CLINICAL PHARMACOLOGY).

The pharmacokinetics and concentrations of CUBICIN in cantharides-induced skin blisters and in plasma were determined over a 24-hour period following a single IV infusion of 4 mg/kg in healthy volunteers. CUBICIN penetrated the inflammatory exudate moderately rapidly, with mean 1- and 2- hour concentrations of 9.4 μg/mL and 14.5 μg/mL, respectively. Tmax in the inflammatory fluid occurred approximately 3 hours later than in plasma (3.7 hours vs. 0.5 hours) with a Cmax of 27.6 μg/mL. The mean Cmax in the plasma was 77.5 μg/mL. The elimination half-life of CUBICIN from the inflammatory exudate was highly variable, ranging from 6.3 hours to 30.9 hours, with a mean of 17.3 hours. The mean AUC0-24h in the inflammatory exudate was 318.2 μg•hr/mL. Mean plasma elimination half-life was 7.74 hours with mean plasma AUC0-24h of 468.0 μg•hr/mL, representing approximately 88% of the mean AUC0-∞ (529.7 μg•hr/mL). The penetration of CUBICIN into inflammatory exudate, calculated as AUC0-24h exudate/AUC0-24h plasma, was 68.4%.

A study was conducted to evaluate the pharmacokinetics of CUBICIN over a period of 3 weeks in subjects with End Stage Renal Disease (ESRD) on hemodialysis three times weekly using both high-flux (Baxter CT190G) and low-flux (Fresenius F8) dialysis membranes. CUBICIN was administered as an 8 mg/kg loading dose followed by 6 mg/kg 3 times per week.

The AUC values on Day 17 appear higher in the low-flux group at 2586 μg x h/mL compared with the high-flux group at 1716 μg x h/mL (Table 13). However, examination of the individual AUC’s of the 4 subjects in the low-flux group and 3 subjects in the high-flux group indicated that the low flux cohort’s AUCs were consistently higher across all time points than those of the subjects in the high-flux cohort. Thus, there was little evidence of excessive accumulation in the low flux group compared with the high flux group.

Due to high variability in CUBICIN pharmacokinetics between subjects under hemodialysis using low-flux and high-flux membranes, no statistically significant differences were detectable. However, the pre- to post-dialysis decrease in daptomycin levels was greater on the high-flux membrane (41%) compared to the low-flux membrane (5 to 7%).


Table 13. Pharmacokinetic Parameters of CUBICIN Following Single (Day 1) and Repeat (3 times/week) Dosing in Subjects with ESRD

Membrane
Type
Day N Pharmacokinetic Parameters Mean (CV%)
Cmax
(μg/mL)
Cmin
(μg/mL)
AUCa
(μg x h/mL)
T½
(h)
CL
(mL/h/kg)
Vss
L/kg
Low-Flux 1 6 91 (31) - 1697 (33) 38.5 (21.3) 2.8 (40.7) 0.14 (17.8)
8 5 86 (33) 17 (9) 1916 (45) 42.3 (26.9) 3.5 (54.4) 0.18 (28.3)
17 4 103 (26) 29 (11) 2586 (35) 55.9 (36.1) 2.2 (35.4) 0.16 (21.0)
High-Flux 1 7 107 (39) - 1945 (34) 35.7 (11.3) 2.8 (51.6) 0.14 (54.2)
8 6 81 (38) 14 (6) 1672 (36) 38.1 (16.6) 3.7 (50.0) 0.19 (54.6)
17 3 94 (17) 22 (3) 1716 (27) 45.3 (37.8) 3.6 (44.1) 0.27 (85.1)
Subjects received 8 mg/kg on Day 1, followed by 6 mg/kg 3 times per week.

a AUC (0-t): Area under the concentration versus time curve from 0 to end of dosing interval

Microbiology

Daptomycin has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria only. Daptomycin inserts directly into the cytoplasmic membrane of both growing and stationary phase Gram-positive bacteria resulting in dissipation of the membrane potential and efflux of potassium ions, which causes inhibition of protein, DNA and RNA synthesis and bacterial cell death with negligible lysis. The antibacterial activity of daptomycin requires the presence of free calcium, therefore, the determination of in vitro susceptibility of bacteria to daptomycin requires that broth media be supplemented with physiological levels of free (ionized) calcium at a concentration of 50 μg/mL. Daptomycin retains activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (see INDICATIONS AND CLINICAL USE). Daptomycin is not active against Gram-negative bacteria.

Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive organisms in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC ratios (minimum bactericidal concentration/minimum inhibitory concentration) using broth dilution methodology.

Daptomycin’s activity in vitro is inhibited in the presence of pulmonary surfactant. In mouse and hamster models of broncho-alveolar pneumonia (BAP), daptomycin lacked efficacy.

In vitro studies have investigated daptomycin interactions with other antibiotics. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin occurred with aminoglycosides, β-lactam antibiotics and rifampin against some isolates of staphylococci including some methicillin-resistant isolates.

Daptomycin has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections.


Table 14. Daptomycin MIC50 and MIC90 for Susceptible Aerobic and Facultative Gram- Positive Bacteria in vitro and in Clinical Infections

Microoganism # of clinical isolates MIC (μg/mL)
MIC50 MIC90 Range
Staphylococcus aureus (including methicillin-resistant strains) 3848 0.25 0.5 ≤0.06 – 2
Streptococcus agalactiae 187 0.12 0.25 ≤0.06 - 0.5
Streptococcus pyogenes 170 ≤0.06 ≤0.06 ≤0.06 - 0.12

The following in vitro data are available (Table 15), but their clinical significance is unknown. Greater than 90% of the following microorganisms demonstrate an in vitro MIC less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus. The efficacy of daptomycin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.


Table 15. Daptomycin MIC50 and MIC90 for Susceptible Aerobic and Facultative Gram-Positive Microorganisms in vitro

Microoganism # of clinical isolates MIC (μg/mL)
MIC50 MIC90 Range
Corynebacterium jeikeium 68 0.25 0.5 0.06 – 1
Enterococcus faecalis (vancomycin-resistant strains) 34 0.5 2 0.25 – 2
Enterococcus faecalis (vancomycin-susceptible strains) 917 0.5 1 ≤0.06 - 4
Enterococcus faecium (including vancomycin-resistant strains) 398 2 4 0.25 - 4
Staphylococcus epidermidis (including methicillin-resistant strains) 164 0.5 0.5 0.12 - 1
Staphylococcus haemolyticus 102 0.25 0.5 0.03 - 1
Streptococcus dysgalactiae subsp. equisimilis 102 ≤0.03 0.06 ≤0.03 - 0.12

Resistance

At this time, no mechanism of resistance to daptomycin has been identified. There have been reports of Staphylococcus aureus isolates exhibiting decreased or intermediate vancomycin susceptibility demonstrating decreased daptomycin susceptibility.

Non-susceptible isolates of Staphylococcus aureus have been recovered from patients in clinical trials. These include one patient enrolled in a Phase 2 study, one who received CUBICIN in a compassionate use study, and seven from the SAB/SAIE trial.

Cases of daptomycin resistance have been reported in staphylococci during post-marketing.

Susceptibility Testing Methods

Susceptibility testing by dilution methods requires the use of daptomycin susceptibility powder. The testing also requires the presence of physiological levels of free calcium ions (50 μg/mL of calcium, using calcium chloride) in Mueller-Hinton broth.

Dilution Technique

Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure based on a broth dilution method or equivalent using standardized inoculum and concentrations of daptomycin. The use of the agar dilution method is not recommended with daptomycin. The MICs should be interpreted according to the criteria in Table 16.


Table 16. Susceptibility Interpretive Criteria for Daptomycin

Pathogen Broth Dilution MIC
(μg/mL)a
S I R
Staphylococcus aureus (methicillin-susceptible and methicillin-resistant) ≤ 1 (b) (b)
Streptococcus pyogenes and Streptococcus agalactiae ≤ 1 (b) (b)
a The MIC interpretive criteria for S. aureus are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 μg/mL; the MIC interpretive criteria for Streptococcus spp. other than S. pneumoniae are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 μg/mL, supplemented with 2 to 5% lysed horse blood, inoculated with a direct colony suspension and incubated in ambient air at 35°C for 20 to 24 hours.

b Limited data on daptomycin resistant strains precludes defining any categories other than "Susceptible". Strains yielding test results suggestive of a "Non-Susceptible" category should be retested, and if the result is confirmed, the isolate should be submitted to a reference laboratory for confirmation of results using CLSI reference broth microdilution method.


A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.

Diffusion Technique

Quantitative methods that require measurements of zone diameters have not been shown to provide reproducible estimates of the susceptibility of bacteria to daptomycin. The use of a disk diffusion method is not recommended with daptomycin.

Quality Control

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the procedures. Standard daptomycin powder should provide the range of values noted in Table 30. Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.


Table 17. Acceptable Quality Control Ranges for Daptomycin to be used in Validation of Susceptibility Test Results

QC Strain Acceptable Quality Control Ranges
Broth Dilution MIC
(μg/mL)a
Staphylococcus aureus ATCC 29213 12-01-00
Streptococcus pneumoniae ATCC 49619b 0.06-0.5
a The quality control ranges for S. aureus are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 μg/mL; the quality control ranges for S. pneumoniae are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 μg/mL, supplemented with 2 to 5% lysed horse blood, inoculated with a direct colony suspension and incubated in ambient air at 35°C for 20 to 24 hours.

b This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae.

Toxicology

Single-Dose Toxicity Studies

Acute toxicity testing identified the neuromuscular system (nervous system and/or skeletal muscle) as the target organ of daptomycin toxicity, and uncovered potential differences in sensitivity among the species tested (i.e., mouse, rat, dog, and monkey). Studies performed are listed in Table 31 below.


Table 18. Results of Single-Dose Toxicity Studies

Species/Strains Route Dose Levels
(mg/kg)
Max. Non-Lethal
Dose (mg/kg)
Noteworthy Findings
Mouse/ICR IV 0, 700, 900, 1100, 1400 <700 0: Transient generalized leg weakness
700: 1M and 5F died
≥700: Generalized leg weakness, hypoactivity, ataxia, tremors, ptosis, and death
Rat/Fischer IV 0, 110, 140, 180, 225 110 0: Transient generalized leg weakness
110: Transient generalized leg weakness, hypoactivity
140: 4M and 1F died ≥140: Leg weakness, ataxia, hindlimb paralysis, tremors, clonic convulsions, and death
Dog/Beagle IV 25, 200 200 ≥25: Slight (2-3X) increases in serum creatine phosphokinase (CPK) within 24 h post-dose and generally returned to normal within 48 h after dosing
200: 10% decrease in body weight in 1 of 4 dogs, and slight reduction in appetite in 2 of 4 dogs
Monkey/Rhesus IV 25, 200 25 25: Slight, transient lethargy and paleness of the facial skin in 2 of 4 animals; CPK increased >10-fold at 3 h post-dose and returned to normal within 48 h
200: 1M and 2F died. Death preceded by extreme lethargy, ataxia, and severe muscle weakness; slight axonal degeneration of the sciatic nerve in one of the deaths; CPK increased >10-fold at 3 h post-dose and did not return to normal until Day 7 after dosing
Rat/Fischer SC 0, 350, 700 700 0: Transient generalized leg weakness
≥ 350: Transient generalized leg weakness; sores/scabs at injection sites
IV: intravenous; SC: subcutaneous; M: male; F: female; h: hour.

Repeat-Dose Toxicity Studies

The results of repeat-dose and investigative studies consistently demonstrated daptomycin’s primary target organ to be skeletal muscle in adult rats and dogs, with effects observed in peripheral nerve at higher dose levels in both species (Table 19). Skeletal myopathy was usually accompanied by serum creatine phosphokinase (CPK) elevations in adult dogs, which preceded clinical effects and correlated with the severity of microscopic lesions. Nephrotoxicity and gastrointestinal effects observed in rats appear to be species-specific because these effects were not evident in either dogs or monkeys up to the highest doses tested (75 mg/kg/day and 10 mg/kg/day in dogs and monkeys, respectively). Recovery from skeletal myopathy was more rapid than recovery from daptomycin-related peripheral neuropathy. Recovery of peripheral nerve function was evident within 3 to 6 months post-dosing, although very minimal histological changes were observed 6 months after dosing cessation.

In contrast to adult dogs, juvenile dogs showed evidence of effects in nerves of the spinal cord as well as peripheral nerves after 28 days of dosing (Table 19 and see DETAILED PHARMACOLOGY, Animal Pharmacology, Juvenile Animals). The effects were noted at lower daptomycin doses and at lower daptomycin blood concentrations than in adult dogs. The data suggests that as compared to adult populations, juvenile populations may be more sensitive to daptomycin-related nerve effects.


Table 19. Summary of Findings on Repeat-Dose Toxicity and Investigative Studies*

Species/Strain Study
Duration
Dose Range
(mg/kg/day)
Noteworthy Findings (Dose levels affected)
Rat/Fischer 2 weeks; 1, 3, and 6 months 1 to 150
  • Skeletal Muscle (≥ 5 mg/kg): Mild myofiber degeneration/regeneration (e.g., diaphragm, quadriceps, pectoral, biceps femoris); electron microscopy revealed intracellular edema of endothelial cells and infiltration of macrophages and monocytes. Both Type I and Type II fibers affected. Effects were reversible within 30 days following cessation of dosing.
  • Nervous System (≥ 100 mg/kg): Peripheral neuropathy such as slight axonal degeneration of the sciatic nerve.
  • Kidney (≥ 10 mg/kg): Increased kidney weight; vacuolar degeneration/regeneration of renal cortical tubular epithelium; cytoplasmic bodies observed upon electron microscopy. Effects were reversible.
  • GI Tract (≥ 20 mg/kg): Cecal changes (dilatation and increased weight) attributable to changes in enterobacterial flora typical of prolonged antibiotic treatment. Effects were reversible after an 8-week recovery phase.
Dog/Beagle 2 weeks; 1, 3, and 6 months 1 to 100
  • Skeletal Muscle (≥ 10 mg/kg): Reversible myofiber degeneration/regeneration (degenerative effects limited to ≤ 0.1% of fibers). CPK/AST/ALT elevations. Skeletal muscle effects are independent of Cmax and appear primarily related to dosing frequency (time between doses) and/or AUC.
  • Nervous System (≥ 40 mg/kg; based upon 6 months of dosing): Abnormal patellar reflex, decreased sensory and motor nerve conduction velocities, minimal microscopic axonal degeneration observed following 6 months of dosing (at 40 mg/kg/day). In shorter term studies (14 days to 3 months duration), nerve effects were observed at doses (≥ 75 mg/kg. Moderate to severe clinical signs (abnormal posture/gait, impaired coordination, inability to stand, sternal recumbency) and functional (electrophysiology) deficits were evident. Microscopic effects were detected in peripheral nerves, dorsal ganglia, nerve roots (including left and right ventral and dorsal roots) and spinal nerves. Cmax appeared the key determinant for peripheral nerve effects. Recovery of peripheral nerve function was evident within 3 to 6 months post-dosing (consistent with the lack of effect upon the neuronal cell body), although histological changes (dorsal roots, ventral roots and spinal nerves) were evident 6 months after dosing. In all but one case, the axonal degeneration observed in these tissues was graded as very minimal and described as rare, scattered vacuoles.
Juvenile Dog/Beagle 2 weeks and 1 month 1 to 150
  • Skeletal Muscle (≥ 150 mg/kg): Reversible degeneration of skeletal muscle. In contrast to adult dogs, CPK levels were not increased in juvenile dogs.
  • Nervous System (≥ 50 mg/kg; based upon 6 months of dosing): Minimal to slight axonal degeneration of peripheral nerve fiber (sciatic, ulnar) and spinal cord (cervical, thoracic, lumbar, dorsal nerve root) observed. Peripheral nerve (sciatic) and spinal cord (cervical, thoracic, lumbar) effects were not reversed following a 4-week recovery phase.
Monkey/Rhesus 1 month 1 to 10 No effects were observed up to 10 mg/kg, the highest dose tested.
* Daptomycin was administered by bolus IV injection in all studies; one study also investigated administration via 30-minute IV infusion. For most studies, daptomycin was administered once daily (q24h), except for select investigative studies in which it was also administered on a three times daily (q8h) regimen.

GI: gastrointestinal; CPK: creatine phosphokinase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; AUC: area under the curve; Cmax: maximum serum concentration following dosing.

Genotoxicity

Daptomycin was not mutagenic or clastogenic in a battery of genotoxicity tests, including the Ames assay, a mammalian cell gene mutation assay, a test for chromosomal aberrations in Chinese hamster ovary cells, an in vivo micronucleus assay, an in vitro DNA repair assay, and an in vivo sister chromatid exchange assay in Chinese hamsters.

Carcinogenicity

Carcinogenicity studies have not been conducted.

Reproduction and Development Toxicity

Reproductive and developmental toxicity studies of daptomycin were conducted in rats (up to 150 mg/kg) and rabbits (up to 75 mg/kg) by once-daily bolus IV injection. Studies were conducted at daptomycin dose levels up to and including those that caused parental toxicity (see Repeat-Dose Toxicity Studies).

Daptomycin administration to the F0 generation was not associated with any reproductive toxicity, such as adverse effects on mating, fertility, parturition, and lactation. Further, there were no findings to suggest that daptomycin treatment of the F0 generation resulted in any developmental toxicities in the F1 generation. No test article-related mortality, teratogenic potential, alterations in growth, or functional toxicities was noted in any of the studies. Effects on progeny were limited to a slight (~10%), transient decrease in body weight at a dose level of 150 mg/kg in rats; this effect was reversible within 14 days postpartum. No other effects on the growth, behavior, or reproductive performance of the offspring were noted.