Summary Basis of Decision for Cubicin ®

3.3.1 Pharmacokinetics

Absorption

Daptomycin pharmacokinetics were generally linear and time-independent at doses of 4 to 12 mg/kg q24h. Steady-state trough concentrations were achieved by the third daily dose. The mean (standard deviation) steady-state trough concentrations attained following administration of 4, 6, 8, 10 and 12 mg/kg q24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9) and 13.7 (5.2) μg/mL, respectively. The mean AUC and Cmin (minimum plasma concentration) of daptomycinduring once-daily dosing with 6, 8, 10 and 12 mg/kg were dose proportional; however, the mean C_max (maximum plasma concentration) was slightly less than dose proportional. Total clearance was unchanged across 4 to 12 mg/kg q24h.

Distribution

Daptomycinis reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding at doses from 4 to 12 mg/kg ranged from 90 to 93%. The apparent volume of distribution (Vd) of daptomycinat steady-state in healthy adult subjects was low, approximately 0.1 L/kg at doses of 4 to 12 mg/kg, consistent with distribution primarily within the extracellular space. Studies conducted in healthy subjects with cantharides-induced blisters demonstrated that daptomycin penetrated into inflammatory exudates. Daptomycin penetrated the inflammatory exudates at a moderate rate with time to maximum concentration (Tmax) occurring approximately three hours later than in plasma. The penetration of daptomycin into the inflammatory exudates was good and the maximum concentration (C_max) achieved in inflammatory fluid was 27.6 µg/mL. The concentration of daptomycin achieved at the inflammatory foci in the skin was well above the MIC90 for the majority of potential Gram-positive pathogens. The population PK study indicated that the volume of distribution increased in subjects with acute bacterial infection relative to uninfected subjects. This is consistent with the pathophysiology of acute bacterial infection which is characterized by an inflammatory response associated with increased vascular permeability and collection of extracellular fluid at the site of infection.

Clinical pharmacology studies indicated that 90-93% of daptomycin binds to plasma proteins. In vitro studies indicated that daptomycin binds to serum albumin in a concentration-independent fashion. The protein binding is relatively weak and readily reversible. Serum protein binding in subjects with varying degrees of renal impairment was comparable to healthy subjects; however, protein binding was decreased in subjects with end-stage renal disease (ESRD) that were on dialysis.

Metabolism

In healthy subjects, no products of daptomycin metabolism or degradation were detected in plasma following administration of radiolabelled drug. After 24 hours, 65% of the radioactivity was recovered in the urine. One-hundred and forty-four (144) hours following administration, 78% of labelled drug was recovered in urine and an additional 5% and 3% of radioactivity was recovered in the feces and the expired air, respectively. In a second non-radiolabelled study, there were four minor metabolites observed in urine samples at low concentrations (each <5% of the daptomycin peak) but none in the plasma samples. Two out of the four metabolites observed in the urine appeared to be Phase-1 oxidative metabolites. It was not reported whether these metabolites were active.

Studies conducted in vitro indicated that daptomycin was not metabolized by human liver microsomes under the conditions tested. Further in vitro studies examined the effect of daptomycin on induction and activity of hepatic cytochrome-P450 isoenzymes. The doses used in these studies were appropriate to the therapeutic concentration. There was no biologically significant inhibition or induction of the enzymes. A possibleenzyme induction of CYP2C9 was observed with 400 µg/ml daptomycin, a concentration that exceeded the expected clinical concentration by 4 to 8x. The effect was not consistently observed in donor tissue.The study presented demonstrated that daptomycin should not adversely influence CYP3A4-mediated metabolism in vivo and that CYP-mediated drug-drug interactions are unlikely.

Excretion

Systemic clearance of daptomycin occurred primarily by renal excretion. In a clinical study using radiolabelled daptomycin, 75-80% of the administered dose was excreted in the urine. The fecal route accounted for an additional 4-6% of the administered dose. Administration of probenecid had no effect on the PK of daptomycin. This suggests that renal tubular secretion, blocked by probenecid, is not a component in explaining daptomycin elimination. Glomerular filtration was the major elimination route for daptomycin.

Special Populations

Three clinical studies examined the PK of daptomycin in subjects with renal impairment. All studies clearly indicated that plasma clearance of daptomycin significantly correlated with creatinine clearance. PK parameters related to renal elimination of daptomycin were significantly influenced in patients with creatinine clearance of <30 mL/min. The drug exposure (AUC) in this group was about 2.5-fold higher as compared to healthy volunteers. In subjects with severe renal impairment, a dosing regime of 4 mg/kg daptomycin once every 48 hours for cSSSI and 6 mg/kg daptomycin every 48 for bacteremia or infective endocarditis has been approved. These doses are derived from PK modelling studies but have not been tested for efficacy or safety. This has been clearly stated in the Product Monograph. Further, it is also stated under Dosage and Administration that "Cubicin should only be used in patients whose creatinine clearance is <30 mL/min when it is considered that the expected clinical benefit outweighs the potential risk and for whom there are no further therapeutic options". In subjects with creatinine clearance >30 mL/min but <50 mL/min, the mean AUC increased by 1.65-fold and the 24-hour serum levels were about 2-fold higher than the control group. In subjects with renal failure, there was a trend towards an increased free fraction of daptomycin but the difference was not statistically significant.

No dose adjustment is required for subjects whose estimated creatinine clearance is >30 mL/min, but for patients whose estimated creatinine clearance is <30 mL/min, a change in the dosage regimen is necessary. As both trough levels and AUC of daptomycin increase in subjects with a creatinine clearance of <50 mL/min, the potential for elevation of serum CPK levels and possible muscle toxicity increases. It is indicated in the Warnings and Precautions section of the Product Monograph that CPK levels should be closely monitored in all patients with some degree of renal insufficiency.

The PK of daptomycin (with the exception of C_max) was significantly different in geriatric subjects; exposure was 58% higher as compared with younger subjects. Renal clearance was lower in geriatric subjects and changes in daptomycin PK may be attributed to changes in renal function. Despite the fact that exposure was higher in geriatric subjects, a 4 mg/kg single-dose of daptomycin was well tolerated and there were no clinically significant changes in hematology, clinical chemistry, or urinalysis. No dosage adjustment is warranted for elderly subjects with normal renal function based on age alone.

There was no effect of mild to moderate hepatic impairment on the PK of daptomycin. The pharmacokinetics of daptomycin in patients with severe hepatic insufficiency have not been evaluated. Compared with non-obese controls, plasma clearance of daptomycin was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects while the AUC increased by approximately 30% and 31%, respectively. The population PK analysis indicated a modest influence of gender on the clearance of daptomycin. The clinical significance of this observation is uncertain. No dosage adjustments are required based on obesity or gender alone.

Drug Interactions

The pharmacokinetics of daptomycin and aztreonam when administered alone or in combination was investigated in healthy volunteers. A comparison of C_max, AUC0-∞ and Fedose indicated that daptomycin and aztreonam do not show a PK drug-drug interaction with each other. The safety profile of 6 mg/kg of daptomycin administered as a single IV dose did not differ when administered in combination with 1000 mg of aztreonam.

A clinical study evaluated the effects of daptomycin at steady state on the single-dose PK of the R- and S-warfarin enantiomers and the pharmacodynamics (PD) of warfarin in healthy subjects. Comparison of C_max and AUC indicated that daptomycin does not have significant effect on the PK of either R- or S-warfarin. In addition, the baseline-corrected INR supports the absence of an effect of daptomycin on the PD of warfarin.The study presented did not examine the PK of daptomycin at the steady state concentration of warfarin. However, the design used in this study minimized the risk of exposure of healthy volunteers to a longer anticoagulant effect, and a single dose of warfarin should be able to detect if there is any interaction with the PK of daptomycin. Comparison of C_max and AUC of daptomycin in this study indicated that the PK of daptomycin was not significantly altered with warfarin administration. Results of safety monitoring during this study did not raise any new safety concerns related to daptomycin administration.

A clinical study evaluated the safety of daptomycin when administered once daily, for 14 consecutive days, in subjects on a stable daily dose of 40 mg of simvastatin. The results indicated that the trough concentration of daptomycin in subjects treated with simvastatin was similar to the concentration observed in other Phase I studies. Multiple-dose administration of daptomycin in subjects receiving concomitant treatment of simvastatin was not associated with a higher incidence of adverse events. Further concomitant administration of daptomycin and simvastatin had no effect on serum CPK levels. There did not appear to be any interaction between simvastatin and daptomycin.

Experience with co-administration of HMG-CoA reductase inhibitors and daptomycin in patients is limited, and also the study design for the interaction study excluded subjects on simvastatin whose CPK levels were >1.5 times the upper limit of normal (ULN). Consideration should be given to temporarily suspending use of HMG-CoA reductase inhibitors in patients receiving daptomycin. A warning has been included in the Product Monograph regarding the use of HMG-CoA reductase inhibitors in patients receiving Cubicin^®.

A clinical study evaluated whether the PK of daptomycin and tobramycin are affected when they are concurrently administered. The results indicated that there was a slight decrease in renal clearance and excretion of daptomycin with concurrent administration of tobramycin. The interaction study of tobramycin and daptomycin was conducted with doses of daptomycin lower than the doses requested for clinical indications. Renal excretion of daptomycin is an important route of elimination. The reviewer is concerned that if therapeutic doses of daptomycin were used in these studies, a possible significant change in renal clearance would have been observed when administered with tobramycin. In the Product Monograph, it is clearly stated that the interaction between these two drugs at clinical dose is not known. Results from the drug interaction studies in animals demonstrated that tobramycin may have a weak potentiating effect on muscle damage caused by daptomycin which is captured in the drug-drug interaction section of the Product Monograph.

3.3.2 Additional Pharmacology Studies

Clinical pharmacology studies were conducted to assess the effect of daptomycin on cardiac repolarization and peripheral nerve conductivity. The study presented found no evidence that exposure to daptomycin at 6 mg/kg once every 24 hours for 14 days caused any clinically meaningful change in cardiac repolarization as measured by QTcB.

The exposure of healthy volunteers to daptomycin at 6 mg/kg once every 24 hours for a period of 14 consecutive days was not associated with either myopathy or neuropathy as judged by objective electrophysiological measures for nerve motor function in the hand or vibration perception threshold (VPT) in the great toe. However, the small fibre sensory function as assessed by a subjective neurological questionnaire revealed the possibility of some degree of peripheral nerve damage. During the 14-day follow-up period more subjects in the daptomycin group (8) compared to the normal saline group (5) reported symptoms of tingling, numbness and weakness. Precautionary statements to monitor for signs and symptoms of neuropathy during therapy with daptomycin have been included in the Product Monograph.

3.3.3 Clinical Efficacy

Complicated Skin and Skin Structure Infections (cSSSI) Treatment

In two similar comparative pivotal two arm cSSSI trials (Studies 9801 and 9901) conducted internationally (US, Europe, South Africa, Israel, Australia), 1092 adults were exposed in approximately equal numbers to either Cubicin^® (daptomycin) or comparator drugs. In each of the two study arms, patients were pre-randomized according to the likelihood or not of exhibiting Staphylococcus aureus resistance to methicillin and/or penicillin intolerance. In the first arm, patients received daptomycin. In the second arm, patients received either semi-synthetic penicillins (i.e., oxacillin, nafcillin, cloxacillin or flucloxacillin) or alternatively, vancomycin if resistance to penicillin or penicillin intolerance was suspected. The control drugs were currently approved for the treatment of cSSSI caused by susceptible pathogens in the countries where they were used. Patients in both study arms could be switched to oral antibiotics after a minimal period of parenteral therapy or immediately to vancomycin in the control arm if resistance was discovered. Aztreonam and/or metronidazole could be administered if infections included Gram-negative and/or anaerobic bacteria.

The primary endpoints of the studies addressed clinical efficacy (improvement, cure) at 7-12 days after treatment with 4 mg/kg daptomycin IV every 24 hours for 7-14 days. Safety was assessed throughout the study period.

A successful microbiologic response for an infecting pathogen was defined as definite eradication (failure to isolate the pathogen from a culture of the primary site of infection at the test-of-cure assessment) or presumed eradication (healing of the primary site of infection with explicit indication that there was "nothing to culture"). Subjects were designated as microbiologic failures if culture data were not available for any other reasons or if one or more of the original infecting Gram-positive pathogens were explicitly isolated (documented persistence). Missing data were designated as presumed persistent failures. Overall, therapeutic success was defined as a subject who had an outcome of clinical success and, if an infecting pathogen had been isolated at baseline, also had a successful microbiologic response. A subject who was a clinical failure, was non-evaluable or was a clinical success with microbiologic failure, was designated as a therapeutic failure.

In Study 9801, one or more Gram-positive pathogens were cultured at baseline in >81% of intent to treat patients (ITT) and in that subgroup of modified intent to treat patients (MITT), Staphylococcus aureus, Streptococcus pyogenes, Streptococcus a galactiae, and Enterococcus faecalis were recovered from approximately 70%, 16.2%, 9.3% and 13.8% of patients, respectively. Overall, 13% of the culture-positive subjects were infected with both Staphylococcus aureus and the β-hemolytic streptococci Streptococcus pyogenes or Steptococcus agalactiae. During the trial period, approximately 32% of ITT patients received protocol-approved antibiotics for Gram-negative and anaerobic organisms, and approximately 40% underwent adjunct procedures such as incisions, drainage or wound debridement.

In Study 9901, one or more Gram-positive pathogens were cultured at baseline in >83% ITT patients and, in those patients S taphylococcus aureus, Streptococcus pyogenes, Streptococcus a galactiae, and Enterococcus faecalis were recovered from approximately 68.9%, 27.1%, 6.6%, and 10.3% respectively. Overall, 20.7% of the culture-positive subjects were infected with both Staphylococcus aureus and the β-hemolytic streptococci Streptococcus pyogenes or Streptococcus agalactiae. During the trial period, approximately 19.8% of ITT patients received protocol-approved antibiotics for Gram-negative and anaerobic organisms, and approximately 19.7% underwent adjunct procedures such as incisions, drainage or wound debridement.

In Study 9801, the overall clinical success rates as determined in integrated analyses were 65.1% in the daptomycin arm and 64.8% in the comparator arm for the MITT population and 76.0% and 76.7%, respectively, for the clinically evaluable (CE) subgroup of the ITT population, demonstrating the non-inferiority of daptomycin to comparators. In Study 9901, the clinical success rates were also comparable for the MITT (84.0% vs. 83.1%) and CE (89.9% vs. 90.4%) groups.

The pooled microbiological successes (organism eradication or presumed eradication ) in the microbiologically evaluable (ME) patient population of studies 9801 and 9901 were similar for daptomycin and comparator arms (74.2% vs. 75.5%). These results were slightly lower in study 9801 (67.8% vs. 67.6%) than Study 9901 (80.1% vs. 81.8%). The pooled microbiological successes in the ME population were comparable for daptomycin and comparator arms relative to the infecting baseline pathogen: methicillin-susceptible Staphylococcus aureus (MSSA) (73.2% vs. 75.8%), methicillin-resistant Staphylococcus aureus (MRSA) (53.6% vs. 58.3%), Streptococcus pyogenes (90.5% vs. 81.8%) and Streptococcus agalactiae (77.8% vs. 65.5%). Microbiological success corroborated clinical success.

Rates of clinical relapse or recurrence at late follow-up (>20 days after end of treatment) were low and there was no evidence of emergence of resistance to daptomycin during or following treatment.

Daptomycin was shown in two pivotal trials to be effective in the treatment of adult cSSSI infections caused by Staphylococcus aureus, Streptococcus agalactiae, and Streptococcus pyogenes. The claim for vancomycin-sensitive Enterococcus faecalis was not considered to be supported by either the trial design or results.

Summaries of fourteen supportive non-pivotal early or developmental trials were also submitted by the sponsor, five of which directly related to cSSSI.

Bacteremia Treatment

One pivotal trial (non-inferiority), a Phase III multicentre, randomized, open-label, comparative study, was used to assess the safety and efficacy of daptomycin compared to conventional therapy in the treatment of subjects with Staphylococcus aureus bacteremia with known or suspected Staphylococcus aureus infective endocarditis (according to modified Duke criteria). Of the 246 patients enrolled, 235 received study medication: 120 patients received daptomycin 6 mg/kg IV once daily, and 115 received comparator (vancomycin 1 gIV every 12 hours or semi-synthetic penicillin 2 g IV every 4 hours, with an initial dose of gentamycin 1 mg/kg IV every 8 hours, for four days). Primary efficacy endpoint success was based on the Independent External Adjudication Committee Outcome at Test-of-Cure (TOC) in the Intent to Treat (ITT) population pooled across diagnostic strata (left-sided infective endocarditis [LIE], complicated right-sided infective endocarditis [RIE], uncomplicated RIE, and complicated bacteremia), and was a composite endpoint based on clinical as well as microbiological success. The main secondary efficacy endpoint was time-to-clearance of bacteremia in the ITT and Per Protocol (PP) populations.

The overall success rates at TOC in the ITT population were 44.2% (53/120) in patients treated with daptomycin,and 41.7% (48/115) in patients treated with comparator. The success rates in the PP population were 54.4% (43/79) in patients treated with daptomycin, and 53.3% (32/60) in patients treated with comparator. Success rates in the overall ITT population showed that daptomycin efficacy was nearly identical irrespective of methicillin-susceptibility of the baseline Staphylococcus aureus infections.

Although the study cohort was representative of patients with Staphylococcus aureus bacteremia and known or suspected IE, multiple exclusion criteria reduced the generalizability of the efficacy results. There were notable study exclusions including, but not limited to, patients with prosthetic valves, pneumonia, known osteomyelitis, meningitis, polymicrobia bloodstream infection, intravascular foreign material not planned for removal within four days of dosing (except vascular stents in place for >6 months or permanent pacemakers), and severe renal failure.

The clinical benefit of daptomycin in clinically and microbiologially evaluable patients with a final diagnosis of IE (53) was supported by limited data for RIE [success in 8/19 (42.1%) vs. 7/16 (43.8%) of patients in the daptomycin vs. comparator arms, respectively]. However, efficacy/clinical benefit of daptomycin was not demonstrated in patients with LIE [1/9 (11.1%) vs. 2/9 (22.2%)].

Efficacy data for diagnostic subgroups were limited and not statistically powered due to a heterogeneous population, discrepancy between entry and final diagnosis of IE, and small numbers. The recommended dose and schedule were justified in patients with normal renal function or mild renal impairment. Poorer outcome was observed in daptomycin patients with moderate renal impairment (creatinine clearance of 30-50 mL/min). Clinical efficacy in patients with severe renal failure was not studied. Efficacy issues have been managed through statements in the Product Monograph.

Two further non-pivotal studies were conducted that addressed bacteremia. The first was a Cubist-sponsored open study comparing daptomycin 4 mg/kg/day, 6 mg/kg/day, and 3 mg/kg twice a day, with a comparator (vancomycin 1 g twice a day or the semi-synthetic penicillins nafcillin or oxacillin 4-13 g/day in divided doses) administered for 7-14 days to Gram-positive bacteremic patients. Robust conclusions were hard to draw but efficacy was comparable for the mid daptomycin dose and comparators (68.8% vs. 73.3% clinical success). Other doses appeared less effective, possibly due to uncontrolled mitigating factors.

The second study was an older Lilly study in which daptomycin 3 mg/kg twice a day following a 6 mg/kg loading dose was compared to conventional treatment for Gram-positive endocarditis/bacteremia. There were only 40 and 14 evaluable patients, and the overall clinical efficacy was 80% vs. 78% for daptomycin vs. comparator, respectively. Daptomycin was not as effective in endocarditis (68.8% vs. 80.0%).

3.3.4 Clinical Safety

Complicated Skin and Skin Structure Infections (cSSSI) Treatment

The integrated analysis of adverse events (AEs) for the two cSSSI pivotal trials showed similar distributions for both daptomycin and comparator groups. The overall AE rate in all patients treated was 51.3% vs. 52.5% for daptomycin vs comparator, with the most frequently occurring AEs being related to the gastrointestinal tract. The majority were mild to moderate and considered unrelated to treatment. Creatine phosphokinase (CPK) increases of 2.1% vs. 1.4% were considered drug-related. The issue of muscle toxicity is considered rare however, and on the whole has not been demonstrated in trials to be particularly problematic. Hypersensitivity and neuropathy were also observed in rare cases, and should be monitored. Precautionary statements are included in the Product Monograph. There did not appear to be any other clinically important trends indicative of daptomycin toxicity. No dose adjustments are considered necessary based on age, race, gender, or degree of hepatic impairment.

In the non-pivotal studies, daptomycin appeared to be well tolerated at the doses proposed for use in cSSSI. Drug-related neurotoxicity and peripheral musculotoxicity appeared to be very rare and reversible even at higher doses. There did not appear to be any drug-induced cardiac toxicity. Experience in patients with underlying severe renal disease, central or peripheral neurological impairments or musculopathies is limited.

Bacteremia Treatment

Safety data from the pivotal study was based on experience in a safety population (n=236) of whom 120 received at least one dose of daptomycin (6 mg/kg every 24 hours). The safety profile was based on varying durations of drug exposure (range 10-42 days, mean 14 days) and a 12-week post-treatment follow-up period. Fourteen patients received >28 days of daptomycin treatment.

The most frequent treatment emergent adverse events (TEAE) observed in the pivotal Phase III clinical study were System Organ Class (SOC): Infections; and Gastrointestinal disorders (including diarrhea, vomiting, constipation, and nausea). Most TEAE were considered unrelated to study drug and were mild to moderate in severity. The most common drug-realted TEAE with daptomycin use were: CPK increase (5%), loose stools (3.3%), blood phosphorous increase (2.5%), dyspepsia (2.5%), and rash (2.5%). Possible/probably drug-related discontinuations were due to elevated CPK [3 (2.5%)], rash [3 (2.5%)], and one report each (<1%) of vomiting, renal failure, thrombocytopenia, and cardiac arrest. Possible/probably drug-related serious adverse events (SAE) included elevated CPK (resolved upon dechallenge), atrial fibrillation/flutter, renal impairment (underlying renal insufficiency), and cardiac arrest leading to death (multiple confounders). Increased SAEs reported in patients with moderate renal impairment who received 6 mg/kg every 24 hours suggest cautious use in this cohort. The safety of daptomycin in patients with severe renal impairment has not been established. Cases of drug-related paresthesia in the daptomycin group were reported uncommonly and resolved despite continued treatment.

Risk management of these potential events includes monitoring clinical response, CPK and renal function, symptoms of myopathy or neuropathy, and discontinuation of drug/temporarily suspending HMG CoA reductase inhibitor or other drugs associated with myopathy. Safety issues have been managed through statements in the Product Monograph.

There are limited long-term safety data available (i.e. >28 days); no unique safety issues were identified in patients with longer courses of therapy.

In the non-pivotal trials, tolerability appeared to be similar for all daptomycin doses and comparators. One patient on 4 mg/kg/day had a slight daptomycin-related CPK elevation (500-750 U/L) during the third week of treatment which was associated with muscle weakness and fatigue. The patient was discontinued from the study and CPK levels promptly recovered.