Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials
ATC code: J01XX09
Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only.
The mechanism of action involves binding (in the presence of calcium ions) to bacterial membranes of both growing and stationary phase cells causing depolarisation and leading to a rapid inhibition of protein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis.
Daptomycin exhibits rapid, concentration dependent bactericidal activity against Gram positive organisms in vitro and in in vivo animal models. In animal models AUC/MIC and Cmax/MIC correlate with efficacy and predicted bacterial kill in vivo at single doses equivalent to human doses of 4 mg/kg and 6 mg/kg once daily.
Strains with decreased susceptibility to daptomycin have been reported especially during the treatment of patients with difficult-to-treat infections and/or following administration for prolonged periods. In particular, there have been reports of treatment failures in patients infected with Staphylococcus aureus, Enterococcus faecalis or Enterococcus faecium, including bacteraemic patients, that have been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin during therapy.
The mechanism(s) of daptomycin resistance is (are) not fully understood.
Minimum inhibitory concentration (MIC) breakpoint established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except S. pneumoniae) are Susceptible ≤ 1 mg/l and Resistant > 1 mg/l.
The prevalence of resistance may vary geographically and over time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Commonly Susceptible Species:
Staphylococcus aureus*
Staphylococcus haemolyticus
Coagulase negative staphylococci:
Streptococcus agalactiae*
Streptococcus dysgalactiae subsp equisimilis*
Streptococcus pyogenes*
Group G streptococci:
Clostridium perfringens
Peptostreptococcus spp
Inherently resistant organisms:
Gram negative organisms
* denotes species against which it is considered that activity has been satisfactorily demonstrated in clinical studies.
In two clinical trials in complicated skin and soft tissues infections, 36% of patients treated with Cubicin met the criteria for systemic inflammatory response syndrome (SIRS). The most common type of infection treated was wound infection (38% of patients), while 21% had major abscesses. These limitations of the patients population treated should be taken into account when deciding to use Cubicin.
In a randomised controlled open-label study in 235 patients with Staphylococcus aureus bacteraemia (i.e, at least one positive blood culture of Staphylococcus aureus prior to receiving the first dose) 19 of 120 patients treated with Cubicin met the criteria for RIE. Of these 19 patients 11 were infected with methicillin-susceptible and 8 with methicillin-resistant Staphylococcus aureus. The success rates in RIE patients are shown in the table below.
| Population | Daptomycin | Comparator | Differences in Success |
|---|---|---|---|
| n/N (%) | n/N (%) | Rates (95% Cl) | |
| ITT (intention to treat) Population | |||
| RIE | 8/19 (42.1%) | 7/16 (43.8%) | -1.6% (-34.6, 31.3) |
| PP (per protocol) Population | |||
| RIE | 6/12 (50.0%) | 4/8 (50.0%) | 0.0% (-44.7, 44.7) |
Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was observed in 19/120 (15.8%) patients treated with Cubicin, 9/53 (16.7%) patients treated with vancomycin and 2/62 (3.2%) patients treated with an anti-staphylococcal semi-synthetic penicillin. Among these failures six patients treated with Cubicin and one patient treated with vancomycin were infected with Staphylococcus aureus that developed increasing MICs of daptomycin on or following therapy (see “Mechanisms of resistance” above). Most patients who failed due to persisting or relapsing Staphylococcus aureus infection had deep-seated infection and did not receive necessary surgical intervention.
The safety and efficacy of daptomycin was evaluated in paediatric patients aged 1 to 17 years (Study DAP-PEDS-07-03) with cSSTI caused by Gram positive pathogens. Patients were enrolled in a stepwise approach into well-defined age groups and given age-dependent doses once daily for up to 14 days, as follows:
The primary objective of Study DAP-PEDS-07-03 was to assess the safety of treatment. Secondary objectives included an assessment of efficacy of age-dependent doses of intravenous daptomycin in comparison with standard-of-care therapy. The key efficacy endpoint was the sponsor-defined clinical outcome at test-of-cure (TOC), which was defined by a blinded medical director. A total of 389 subjects were treated in the study, including 256 subjects who received daptomycin and 133 subjects who received standard-of-care. In all populations the clinical success rates were comparable between the daptomycin and SOC treatment arms, supporting the primary efficacy analysis in the ITT population.
Summary of sponsor-defined clinical outcome at TOC:
| Clinical Success in Paediatric cSSTI | |||
|---|---|---|---|
| Daptomycin n/N (%) | Comparator n/N (%) | % difference | |
| Intent-to-treat | 227/257 (88.3%) | 114/132 (86.4%) | 2.0 |
| Modified intent-to-treat | 186/210 (88.6%) | 92/105 (87.6%) | 0.9 |
| Clinically evaluable | 204/207 (98.6%) | 99/99 (100%) | -1.5 |
| Microbiologically evaluable (ME) | 164/167 (98.2%) | 78/78 (100%) | -1.8 |
The overall therapeutic response rate also was similar for the daptomycin and SOC treatment arms for infections caused by MRSA, MSSA and Streptococcus pyogenes (see table below; ME population); response rates were > 94% for both treatment arms across these common pathogens.
Summary of overall therapeutic response by type of baseline pathogen (ME population):
| Pathogen | Overall Successa rate in Paediatric cSSTI n/N (%) | |
|---|---|---|
| Daptomycin | Comparator | |
| Methicillin-susceptible Staphylococcus aureus (MSSA) | 68/69 (99%) | 28/29 (97%) |
| Methicillin-resistant Staphylococcus aureus (MRSA) | 63/66 (96%) | 34/34 (100%) |
| Streptococcus pyogenes | 17/18 (94%) | 5/5 (100%) |
a Subjects achieving clinical success (Clinical Response of “Cure” or “Improved”) and microbiological success (pathogen–level response of “Eradicated” or “Presumed Eradicated”) are classified as overall therapeutic success.
The safety and efficacy of daptomycin was evaluated in paediatric patients aged 1 to 17 years (Study DAP-PEDBAC-11-02) with bacteraemia caused by Staphylococcus aureus. Patients were randomized in a 2:1 ratio into the following age groups and given age-dependent doses once daily for up to 42 days, as follows:
The primary objective of Study DAP-PEDBAC-11-02 was to assess the safety of intravenous daptomycin versus SOC antibiotics. Secondary objectives included: Clinical outcome based on the blinded Evaluator’s assessment of clinical response (success [cure, improved], failure, or nonevaluable) at the TOC Visit; and Microbiological response (success, failure, or non-evaluable) based
on evaluation of Baseline infecting pathogen at TOC.
A total of 81 subjects were treated in the study, including 55 subjects who received daptomycin and 26 subjects who received standard-of-care. No patients 1 to <2 years of age were enrolled in the study. In all populations the clinical success rates were comparable in the daptomycin versus the SOC treatment arm.
Summary of Blinded Evaluator defined clinical outcome at TOC:
| Clinical Success in Paediatric SAB | |||
|---|---|---|---|
| Daptomycin n/N (%) | Comparator n/N (%) | % difference | |
| Modified intent-to-treat (MITT) | 46/52 (88.5%) | 19/24 (79.2%) | 9.3% |
| Microbiologically modified intent-to-treat (mMITT) | 45/51 (88.2%) | 17/22 (77.3%) | 11.0% |
| Clinically evaluable (CE) | 36/40 (90.0%) | 9/12 (75.0%) | 15.0% |
The microbiological outcome at TOC for the daptomycin and SOC treatment arms for infections caused by MRSA and MSSA are presented in the table below (mMITT population).
| Pathogen | Microbiological Success rate in Paediatric SAB n/N (%) | |
|---|---|---|
| Daptomycin | Comparator | |
| Methicillin-susceptible Staphylococcus aureus (MSSA) | 43/44 (97.7%) | 19/19 (100.0%) |
| Methicillin-resistant Staphylococcus aureus (MRSA) | 6/7 (85.7%) | 3/3 (100.0%) |
Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kg administered as a single daily dose by 30-minute intravenous infusion for up to 14 days in healthy volunteers. Steady-state concentrations are achieved by the third daily dose.
Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUC and Cmax) was demonstrated in healthy subjects following administration of daptomycin as a 30-minute intravenous infusion or as a 2-minute intravenous injection.
Animal studies showed that daptomycin is not absorbed to any significant extent after oral administration.
The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately 0.1 l/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycin appears to only minimally penetrate the blood-brain barrier and the placental barrier following single and multiple doses.
Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In healthy volunteers and patients treated with daptomycin, protein binding averaged about 90% including subjects with renal impairment.
In in vitro studies, daptomycin was not metabolised by human liver microsomes. In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.
After infusion of 14C-daptomycin in healthy adults, the plasma radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma, and minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.
Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid and daptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no active tubular secretion of daptomycin.
Following intravenous administration, plasma clearance of daptomycin is approximately 7 to 9 ml/h/kg and its renal clearance is 4 to 7 ml/h/kg.
In a mass balance study using radiolabelled material, 78% of the administered dose was recovered from the urine based on total radioactivity, whilst urinary recovery of unchanged daptomycin was approximately 50% of the dose. About 5% of the administered radiolabel was excreted in the faeces.
Following administration of a single 4 mg/kg intravenous dose of Cubicin over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-∞ was approximately 58% higher in elderly subjects (≥75 years of age) compared with those in healthy young subjects (18 to 30 years of age). There were no differences in Cmax. The differences noted are most likely due to the normal reduction in renal function observed in the geriatric population.
No dose adjustment is necessary based on age alone. However, renal function should be assessed and the dose should be reduced if there is evidence of severe renal impairment.
The pharmacokinetics of daptomycin in paediatric subjects was evaluated in 3 single-dose pharmacokinetic studies. After a single 4 mg/kg dose of Cubicin, total clearance normalized by weight and elimination half-life of daptomycin in adolescents (12-17 years of age) with Gram-positive infection were similar to adults. After a single 4 mg/kg dose of Cubicin, total clearance of daptomycin in children 7-11 years of age with Gram-positive infection was higher than in adolescents, whereas elimination half-life was shorter. After a single 4, 8, or 10 mg/kg dose of Cubicin, total clearance and elimination half-life of daptomycin in children 2-6 years of age were similar at different doses; total clearance was higher and elimination half-life was shorter than in adolescents. After a single 6 mg/kg dose of Cubicin, the clearance and elimination half-life of daptomycin in children 13-24 months of age were similar to children 2-6 years of age who received a single 4-10 mg/kg dose. The results of these studies show that exposures (AUC) in paediatric patients across all doses are generally lower than those in adults at comparable doses.
A Phase 4 study (DAP-PEDS-07-03) was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in paediatric patients (1 to 17 years old, inclusive) with cSSTI caused by Grampositive pathogens. Daptomycin pharmacokinetics in patients in this study are summarized in Table 2. Following administration of multiple doses, daptomycin exposure was similar across different age groups after dose adjustment based on body weight and age. Plasma exposures achieved with these doses were consistent with those achieved in the adult cSSTI study (following 4 mg/kg once daily in adults).
Table 2. Mean (Standard Deviation) of Daptomycin Pharmacokinetics in Paediatric cSSTI Patients (1 to 17 Years of Age) in Study DAP-PEDS-07-03:
| Age Range | 12-17 years (N=6) | 7-11 years (N=2)a | 2-6 years (N=7) | 1 to <2 years (N=30)b |
|---|---|---|---|---|
| Dose Infusion Time | 5 mg/kg 30 minutes | 7 mg/kg 30 minutes | 9 mg/kg 60 minutes | 10 mg/kg 60 minutes |
| AUC0-24hr (μg×hr/ml) | 387 (81) | 438 | 439 (102) | 466 |
| Cmax (μg/ml) | 62.4 (10.4) | 64.9, 74.4 | 81.9 (21.6) | 79.2 |
| Apparent t1/2 (hr) | 5.3 (1.6) | 4.6 | 3.8 (0.3) | 5.04 |
| CL/wt (ml/hr/kg) | 13.3 (2.9) | 16.0 | 21.4 (5.0) | 21.5 |
Pharmacokinetic parameter values estimated by noncompartmental analysis
a Individual values reported as only two patients in this age group provided pharmacokinetic samples to enable pharmacokinetic analysis; AUC, apparent t1/2 and CL/wt could be determined for only one of the two patients
b Pharmacokinetic analysis conducted on the pooled pharmacokinetic profile with mean concentrations across subjects at each time point
A Phase 4 study (DAP-PEDBAC-11-02) was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in paediatric patients (1 to 17 years old, inclusive) with SAB. Daptomycin pharmacokinetics inpatients in this study are summarized in Table 3. Following administration of multiple doses, daptomycin exposure was similar across different age groups after dose adjustment based on body weight and age. Plasma exposures achieved with these doses were consistent with those achieved in the adult SAB study (following 6 mg/kg once daily in adults).
Table 3. Mean (Standard Deviation) of Daptomycin Pharmacokinetics in Paediatric SAB Patients (1 to 17 Years of Age) in Study DAP-PEDBAC-11-02:
| Age Range | 12-17 years (N=13) | 7-11 years (N=19) | 1 to 6 years (N=19)* |
|---|---|---|---|
| Dose Infusion Time | 7 mg/kg 30 minutes | 9 mg/kg 30 minutes | 12 mg/kg 60 minutes |
| AUC0-24hr (μg×hr/ml) | 656 (334) | 579 (116) | 620 (109) |
| Cmax (μg/ml) | 104 (35.5) | 104 (14.5) | 106 (12.8) |
| Apparent t1/2 (hr) | 7.5 (2.3) | 6.0 (0.8) | 5.1 (0.6) |
| CL/wt (ml/hr/kg) | 12.4 (3.9) | 15.9 (2.8) | 19.9 (3.4) |
Pharmacokinetic parameter values estimated using a model-based approach with sparsely collected pharmacokinetic samples from individual patients in the study.
* Mean (Standard Deviation) calculated for patients 2 to 6 years of age, since no patients 1 to <2 years of age were enrolled in the study. Simulation using a population pharmacokinetic model demonstrated that the AUCss (area under the concentrationtime curve at steady state) of daptomycin in paediatric patients 1 to <2 years of age receiving 12 mg/kg once daily would be comparable to that in adult patients receiving 6 mg/kg once daily.
Relative to non-obese subjects daptomycin systemic exposure measured by AUC was about 28% higher in moderately obese subjects (Body Mass Index of 25-40 kg/m²) and 42% higher in extremely obese subjects (Body Mass Index of >40 kg/m²). However, no dose adjustment is considered to be necessary based on obesity alone.
No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed.
Following administration of a single 4 mg/kg or 6 mg/kg intravenous dose of daptomycin over a 30-minute period to subjects with various degrees of renal impairment, total daptomycin clearance (CL) decreased and systemic exposure (AUC) increased as renal function (creatinine clearance) decreased.
Based on pharmacokinetic data and modelling, the daptomycin AUC during the first day after administration of a 6 mg/kg dose to patients on HD or CAPD was 2-fold higher than that observed in patients with normal renal function who received the same dose. On the second day after administration of a 6 mg/kg dose to HD and CAPD patients the daptomcyin AUC was approximately 1.3-fold higher than that observed after a second 6 mg/kg dose in patients with normal renal function. On this basis, it is recommended that patients on HD or CAPD receive daptomycin once every 48 hours at the dose recommended for the type of infection being treated (see section 4.2).
The dosage regimen for Cubicin in paediatric patients with renal impairment has not been established.
The pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic impairment (Child-Pugh B classification of hepatic impairment) compared with healthy volunteers matched for gender, age and weight following a single 4 mg/kg dose. No dosage adjustment is necessary when administering daptomycin in patients with moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh C classification) have not been evaluated.
In studies of clinically-relevant duration (14-28 days), daptomycin administration was associated with minimal to mild degenerative/regenerative changes in skeletal muscle in the rat and dog. Microscopic changes in skeletal muscle were minimal (approximately 0.05% of myofibres affected) and at the higher doses were accompanied by elevations in CPK. No fibrosis or rhabdomyolysis was observed. Depending on the study duration, all muscle effects, including microscopic changes, were fully reversible within 1-3 months following cessation of dosing. No functional or pathological changes in smooth or cardiac muscle were observed.
The lowest observable effect level (LOEL) for myopathy in rats and dogs occurred at exposure levels of 0.8 to 2.3-fold the human therapeutic levels at 6 mg/kg (30-minute intravenous infusion) for patients with normal renal function. As the pharmacokinetics (see section 5.2) is comparable, the safety margins for both methods of administration are very similar.
A study in dogs demonstrated that skeletal myopathy was reduced upon once daily administration as compared to fractionated dosing at same total daily dose, suggesting that myopathic effects in animals were primarily related to time between doses.
Effects on peripheral nerves were observed at higher doses than those associated with skeletal muscle effects in adult rats and dogs, and were primarily related to plasma Cmax. Peripheral nerve changes were characterised by minimal to slight axonal degeneration and were frequently accompanied by functional changes. Reversal of both the microscopic and functional effects was complete within 6 months post-dose. Safety margins for peripheral nerve effects in rats and dogs are 8- and 6-fold, respectively, based on comparison of Cmax values at the No Observed Effect Level (NOEL) with the Cmax achieved on dosing with 30-minute intravenous infusion of 6 mg/kg once daily in patients with normal renal function.
The findings of in vitro and some in vivo studies designed to investigate the mechanism of daptomycin myotoxicity indicate that the plasma membrane of differentiated spontaneously contracting muscle cells is the target of toxicity. The specific cell surface component directly targeted has not been identified. Mitochondrial loss/damage was also observed; however the role and significance of this finding in the overall pathology are unknown. This finding was not associated with an effect on muscle contraction.
In contrast to adult dogs, juvenile dogs appeared to be more sensitive to peripheral nerve lesions as compared to skeletal myopathy. Juvenile dogs developed peripheral and spinal nerve lesions at doses lower than those associated with skeletal muscle toxicity.
Reproductive toxicity testing showed no evidence of effects on fertility, embryofetal, or postnatal development. However, daptomycin can cross the placenta in pregnant rats (see section 5.2). Excretion of daptomycin into milk of lactating animals has not been studied.
Long-term carcinogenicity studies in rodents were not conducted. Daptomycin was not mutagenic or clastogenic in a battery of in vivo and in vitro genotoxicity tests.
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