Purpose The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, clinical safety, and current regulatory status of solithromycin are reviewed.
Summary Solithromycin is a novel ketolide antibiotic developed for the treatment of community-acquired bacterial pneumonia (CABP). Its pharmacologic, pharmacokinetic, and pharmacodynamic properties provide activity against a broad range of intracellular organisms, including retained activity against pathogens displaying various mechanisms of macrolide resistance. Phase III clinical trials of solithromycin demonstrated noninferiority of both oral and i.v.-to-oral regimens of 5–7 days’ duration compared with moxifloxacin for patients with moderately severe CABP. Nearly one third of patients receiving i.v. solithromycin experienced infusion-site reactions. Although no liver-related adverse events were reported in patients receiving oral solithromycin, more patients receiving i.v.-to-oral solithromycin experienced asymptomatic, transient transaminitis, with alanine transaminase levels of >3 to >5 times the upper limit, compared with those treated with moxifloxacin. These results led the Food and Drug Administration to conclude that the solithromycin new drug application was not approvable as filed, adding that the risk of hepatotoxicity had not yet been adequately characterized. The agency further recommended a comparative study of patients with CABP to include approximately 9,000 patients exposed to solithromycin in order to exclude drug-induced liver injury events occurring at a rate of 1 in 3,000 with 95% probability.
Conclusion Solithromycin is a novel ketolide antibiotic with activity against a broad spectrum of intracellular organisms, including those displaying macrolide resistance. While demonstrating noninferiority to a current first-line agent in the treatment of CABP, concerns for drug-induced liver injury and infusion-site reactions have placed its regulatory future in doubt.
Macrolide resistance is increasing among pathogens causing community-acquired bacterial pneumonia (CABP), prompting investigation into new antimicrobial therapies.
Solithromycin is a novel macrolide–ketolide with unique properties that confer activity against key CABP pathogens, including drug-resistant isolates.
Concerns related to hepatotoxicity have put solithromycin’s ultimate approval and marketing in doubt.
Community-acquired bacterial pneumonia (CABP) is a major contributor to morbidity and mortality worldwide and poses a significant economic burden across healthcare systems.1–3 A well-known association exists between the incidence of CABP and increasing age, with a sharp rise occurring in patients age 65 years or older.4,5 Analyses of Medicare beneficiaries revealed a high incidence of CABP (4,482 per 100,000 person-years) and a high rate of associated hospitalizations (1.2 per episode), a mortality rate of 5.6% at 30 days, and a mean cost per episode of $8,606 (estimated annual cost, $13 billion).2,6 Furthermore, there is a high rate of recurrence in patients who survive an episode of CABP, and epidemiologic studies have found that the annual incidence of CABP has increased over the past 2 decades.1,7
There is substantial evidence that the initial choice of antimicrobial therapy in CABP has a significant impact on mortality. Gleason and colleagues8 noted that among a variety of different empirical CABP treatment regimens, those consisting of a nonpseudomonal third-generation cephalosporin plus a macrolide were associated with a 34% reduction in 30-day mortality compared with a nonpseudomonal, third-generation cephalosporin-only regimen. This finding was corroborated by Brown and colleagues,9 who noted significant reductions in mortality, length of stay, and total hospital charges for patients treated empirically for CABP with combination therapy that included a macrolide. These and other studies have elucidated the key importance of empirical coverage of Streptococcus pneumoniae and the atypical bacterial pathogens in CABP, forming the basis of the inclusion of macrolides in empirical CABP treatment recommendations for adults issued by the Infectious Diseases Society of America (IDSA).10,11
Subsequent data have highlighted the benefit of adherence to IDSA guideline recommendations for antimicrobial CABP therapy, including macrolide-based regimens, in reducing mortality and hospital readmissions.12–14 However, there is growing concern about macrolide resistance with the rising volume of macrolide prescriptions. Macrolide resistance in S. pneumoniae has been reported in 48% of isolates in North America, and patients with macrolide-resistant atypical pathogens, particularly Mycoplasma pneumoniae (up to 15% of isolates in North America), have a significantly longer duration of symptoms and hospitalization and increased rates of antibiotic use.15–21 These and other rising resistance rates have driven a widespread effort to incentivize and accelerate the development of new antimicrobial drugs.22,23
Solithromycin is a next-generation macrolide–ketolide under development in oral and i.v. formulations for the treatment of CABP. This article reviews solithromycin’s pharmacology, pharmacokinetics, pharmacodynamics, use in the treatment of CABP and other possible indications, and current regulatory status.
Literature searches of PubMed, EMBASE, and Google Scholar were performed for peer-reviewed publications through February 7, 2017, using the search terms solithromycin and CEM 101.
Resistance. Macrolides, including solithromycin, exert their antimicrobial effect by binding the large (50S) ribosomal subunit and inhibiting protein synthesis.24,25 Recognition of the pharmacologic advantages proffered by new-generation macrolides necessitates an understanding of mechanisms of macrolide resistance, of which 3 are known.16 The first and most prominent is constitutive or macrolide-inducible ribosomal target-site modification by methylation or mutation. Methylation of the 23S component of the 50S ribosomal subunit at the A2058 residue is performed by Erm proteins and produces a resistance profile referred to as the MLSB phenotype (so named for resistance to macrolides, lincosamides, and type B streptogramins).26,27 Mutations in domain V of rRNA and ribosomal proteins L4 and L22 have also been shown to confer macrolide resistance.28,29 The second mechanism of macrolide resistance is macrolide-inducible active efflux, which is conferred by expression of ATP-binding-cassette transporter proteins encoded by the plasmid-borne msr(A) gene.30 The final mechanism of resistance is macrolide inactivation by esterases and phosphotransferases encoded by mph(C).31
Chemistry. Solithromycin is part of a newer generation of macrolides called ketolides.32 Ketolides use a keto function replacement for the C-3 carbon cladinose (found in older macrolides, including erythromycin and azithromycin) that produces improved activity against erm-expressing bacteria by allowing for tighter binding to the ribosome.33–35 Solithromycin, like the prototypical clinical ketolide telithromycin, incorporates an alkyl–aryl side chain at the C-11 and C-12 carbons, but solithromycin’s longer side chain displays better anchoring in the ribosomal binding site compared with telithromycin. Solithromycin also contains a fluorine atom linked to the C-2 carbon of the lactone ring, making it the first fluoroketolide.36
Ribosomal and receptor interactions. Crystallographic and biochemical characterization of solithromycin binding to the 23S ribosomal component indicate that its alkyl–aryl side chain may form a hydrogen bond with residues in the loop of helix 35 in domain II of the 23S rRNA, producing a tighter interaction with the binding site.36 Furthermore, solithromycin demonstrated the characteristic ability of ketolides to bind the Ermmethylated A2058 residue with greater efficiency than did telithromycin. Solithromycin’s improved ribosomal binding compared with telithromycin is likely due to enhanced binding capacity conferred by the extended alkyl–aryl side chain and the unique addition of the C-2 fluorine.
In addition to ribosomal interactions, investigations into off-target actions of the macrolides have helped to elucidate how certain adverse effects are pharmacologically mediated—particularly hepatotoxicity associated with the ketolides (discussed in greater detail below). Telithromycin was shown to have inhibitory effects at various nicotinic acetylcholine receptors, including the α7 receptors expressed by branches of the vagus nerve terminating in the liver (as well as by hepatic macrophages).37,38 A lack of significant inhibitory effect at the α7 receptor was noted with solithromycin when compared with telithromycin, likely due to the lack of a pyridine moiety in the solithromycin alkyl–aryl side chain.38 As stimulation of these receptors has demonstrated protective effects against proinflammatory cytokines such as tumor necrosis factor α, their inhibition may help to explain telithromycin’s propensity for causing liver injury.39,40
Spectrum of activity
In vitro activity. The in vitro activity of solithromycin has been examined in a wide range of microorganisms.21,41–55 The minimum inhibitory concentration (MIC) results of these studies are displayed in Table 1. Solithromycin has demonstrated excellent in vitro activity against key CABP pathogens, including S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma species, Chlamydophila pneumoniae, and Legionella pneumophila. This activity appears to be retained in many resistant organisms, including erythromycin-resistant Group B Streptococcus56; macrolide-resistant S. pneumoniae isolates, including the emerging multidrug-resistant serotype 19A and resistant isolates expressing both methylation- and mutation-mediated resistance mechanisms57,58; and telithromycin-resistant β-hemolytic streptococci,43 as well as a number of azithromycin-resistant Mycoplasma genitalium isolates.59 Solithromycin also has in vitro activity against macrolide-resistant Neisseria gonorrhoeae isolates; the potential use of solithromycin for gonococcal disease is discussed below.44 Further, solithromycin has demonstrated in vitro antimalarial activity, including multi-drug-resistant Plasmodium falciparum lines.60 At the time of this review, there are no proposed susceptibility breakpoints for solithromycin against any of the organisms listed above.
In vivo activity. Solithromycin was tested in a murine systemic infection model in which mice were treated with the drug via oral gavage 1 hour after infection with S. pneumoniae or Streptococcus pyogenes.49 The 50% protective dose for solithromycin was lower than that for clarithromycin for both S. pneumoniae (14.4 mg/kg versus 26.9 mg/kg) and S. pyogenes (8.9 mg/kg versus 24.3 mg/kg). An additional study of systemic infections in mice infected with S. pneumoniae, S. pyogenes, or Staphylococcus aureus showed solithromycin activity to be comparable to or exceeding that of other macrolides and ketolides, but an approximately threefold higher dose of solithromycin was required to achieve 50% survival in mice infected with macrolide-resistant S. pneumoniae compared with macrolide-sensitive strains.61 In a neutropenic murine model, mice with pulmonary S. pneumoniae infection required lower doses of solithromycin to achieve at least a 2 log10 reduction in pulmonary bacterial counts for both macrolide-susceptible and macrolide-resistant strains compared with azithromycin, clarithromycin, and telithromycin.61 A neutropenic rat model of pulmonary infection with H. influenzae noted a reduced bacterial burden in lung tissue at 24 and 48 hours after treatment with solithromycin, but azithromycin was most active against the H. influenzae strains.61 In a chinchilla model of otitis media with S. pneumoniae and nontypeable H. influenzae, the authors noted middle ear fluid concentrations of solithromycin exceeded plasma concentrations, with rapid sterilization of the middle ear fluid noted in strains of both pathogens with MICs of ≤0.5 μg/mL.62
Absorption and distribution. In a study of 49 nonpregnant healthy volunteers age 19–55 years, the administration of single oral doses of 50, 100, 200, 400, 800, 1,200, and 1,600 mg of solithromycin produced mean maximum plasma concentration (Cmax) values of 0.0223–1.964 μg/mL in a greater than dose-proportional manner up to the 1,200-mg dose, with a median time to Cmax achievement (tmax) of 1.5–6.0 hours from administration.63 Similar to the Cmax, the area under the concentration–time curve from time 0 to time t and to infinity (AUC0–t and AUC0–∞, respectively) increased in a greater than dose-proportional manner up to the 1,200-mg dose. There was substantial variability, from 24% to 85%, among AUC values across the dosing groups. The mean elimination half-life (t1/2) ranged from 3.16 to 7.42 hours between the 50- and 1,600-mg doses.63
In the same study, a separate group of 24 fed and fasted adults were administered single oral doses of solithromycin 400 mg to assess the effects of food on the drug. There appeared to be little difference between the patient groups in concentration–time profiles. Fed:fasted ratios of least-squares means for ln-transformed Cmax, AUC0–t, and AUC0–∞ were 107%, 97.1%, and 97.8%, respectively, and mean t1/2 values were 5.02 and 5.37 hours for fed and fasted patients, respectively. Finally, the authors administered multiple escalating oral doses of solithromycin to 35 volunteers starting at 200 mg and increasing in 200-mg increments up to 600 mg, with escalation determination based on completed follow-up assessments and safety analyses. Repeated once-daily oral administration for 7 days produced greater than dose-proportional increases in plasma exposure across the dosing range (200–600 mg), with the mean AUC over the final dosing interval increasing from 2.3 to 18.4 μg·hr/mL. The median tmax ranged from 3.5 to 4.0 hours and remained constant between days 1 and 7, and mean t1/2 increased from 5.8 to 8.7 hours across the 200- to 600-mg dosing range.
A study involving healthy adults age 18–55 years compared steady-state concentrations of solithromycin in plasma with those in the epithelial lining fluid (ELF) and alveolar macrophages.64 Solithromycin 400 mg was administered orally once daily to 30 volunteers for 5 days, with intermittent plasma and bronchoalveolar lavage samples obtained for solithromycin concentration determination. Solithromycin concentrations were 2.4- to 28.6-fold higher in ELF and 44- to 515-fold higher in alveolar macrophages compared with plasma on day 5 and were significantly higher in ELF and alveolar macrophages than in plasma at all sampling times. Mean plasma solithromycin concentrations on day 5 were low, ranging from 0.730 mg/L 3 hours after administration to 0.086 mg/L 24 hours after administration.
Finally, solithromycin was studied in adolescent patients age 12–17 years with suspected or confirmed bacterial infections.65 Solithromycin 12 mg/kg (up to 800 mg) on day 1 and 6 mg/kg (up to 400 mg) on days 2–5 were administered orally to 13 patients for up to 5 days, and paired plasma and dried blood spot samples were obtained intermittently. Values for Cmax and AUC for 0–24 hours were within the range of observed values in adults, and dried blood spot and plasma concentrations showed a linear relationship with one another. In October 2016, a clinical trial investigating the pharmacokinetics and safety of solithromycin as add-on therapy for suspected or confirmed bacterial infections in children and adolescents was completed; the results are forthcoming.66
No human clinical studies have evaluated the use of solithromycin in pregnant patients. Two ovine experiments noted that solithromycin was readily distributed to the amniotic cavity and fetal tissue, but the effects on the fetus were not studied.67,68 An ex vivo study in human placentas delivered by cesarean section indicated substantial solithromycin transfer across the placenta.69 Further study is needed to determine the drug’s effects on the fetus and utility in intrauterine and fetal infections during pregnancy.
Metabolism and excretion. Solithromycin is primarily metabolized by cytochrome P-450 (CYP) isozyme 3A4 (CYP3A4), with minimal contribution by other CYP isozymes, and also displays CYP3A4 autoinhibition.61,70 In addition, solithromycin is both a substrate and an inhibitor of P-glycoprotein (Pgp). The two primary solithromycin metabolites, N-acetylated solithromycin and hydroxyl destriazolyl-phenylamino solithromycin, retain the macrolide core and are therefore active, but each accounts for less than 7% of drug exposure. Drug interaction studies indicated that solithromycin is a strong CYP3A4 inhibitor, with significant effects on concentrations of CYP3A4-metabolized drugs.61,70 However, use with other CYP3A4 inhibitors appears to have little effect on solithromycin concentrations, likely due to its autoinhibitory activity. Concomitant administration with strong CYP3A4 and Pgp inducers produced reductions of >97% in solithromycin Cmax and AUC, demonstrating that such combinations are contraindicated.61,70 Concomitant administration of solithromycin with the Pgp substrate digoxin produced significant increases in plasma digoxin AUC and Cmax, indicating a need for careful monitoring of such combinations. Approximately 77% of a radioactive dose of 14C-labeled solithromycin was recovered in the feces, while only 14% was eliminated via the urine, mostly as inactive metabolites.61,70
The pharmacodynamics of macrolides, including solithromycin, are significantly influenced by the intracellular accumulation imbued by their large volumes of distribution.71,72 This accumulation, coupled with a slow speed of bactericidal activity and a postantibiotic leukocyte enhancement effect, produces a mixed time-dependent and AUC-to-MIC ratio-dependent pharmacodynamic profile.73 Human exposure–response analyses from pooled clinical trial data indicate that solithromycin has an AUC-to-MIC ratio-based antimicrobial profile.61 Lemaire and colleagues74 investigated the intracellular pharmacodynamics of solithromycin in THP-1 cells—a human myelomonocytic cell line with macrophage-like activity—that were infected with S. aureus, Listeria monocytogenes, and L. pneumophila. It was noted that accumulation of solithromycin in THP-1 cells within 24 hours was approximately 350-fold higher compared with extracellular concentrations and was significantly higher than that of azithromycin. Solithromycin demonstrated higher potency than azithromycin, with an intracellular 50% effective concentration of 0.0068 mg/L compared with azithromycin’s 0.11 mg/L and apparent bacteriostatic concentrations of 0.022 mg/L for solithromycin versus >50 mg/L for azithromycin. Although a marked decrease in potency was noted for all drugs studied when the broth pH was adjusted from 7.4 to 5.5, solithromycin retained the most activity. The range of MICs for S. aureus from pH 7.4 to 5.5 was approximately 0.5–256 mg/L for azithromycin compared with approximately 0.0625–1 mg/L for solithromycin. As the intracellular compartments in which macrolides accumulate (lysosomes and related vacuoles) are acidic,75 this improved intracellular activity in an acidic environment, coupled with the enhanced target site–binding properties discussed above, may explain solithromycin’s improved antimicrobial profile against atypical bacterial pathogens compared with the profiles of other macrolides.
Clinical efficacy in CABP
A Phase II, randomized, double-blind, multicenter study compared the efficacy and safety of 5-day regimens of oral solithromycin and oral levofloxacin in 132 patients with moderately severe CABP76; the subsequent Phase III trials used moxifloxacin as the comparator.77,78 Clinical success was observed in 84.6% of solithromycin-treated patients and 86.6% of levofloxacin-treated patients in the intention-to-treat (ITT) population, with similar between-group rates of early clinical response found in post hoc analyses. Early clinical response is a recently described endpoint prescribed by the Food and Drug Administration (FDA) for new CABP studies and includes an improvement at 72 hours after treatment initiation in at least 2 symptoms (including cough, dyspnea, pleuritic chest pain, and sputum production) and no worsening of any other symptoms.79 The Phase III studies described below are the first to incorporate this new endpoint.
Two Phase III trials have assessed the use of solithromycin for CABP. SOLITAIRE-ORAL was a global, double-blind, randomized, active-controlled, noninferiority trial comparing the efficacy and safety of oral solithromycin with oral moxifloxacin.77 Adults with clinically and radiographically confirmed moderately severe CABP (pneumonia severity index [PORT] scores of >50 but ≤105) were randomized to receive solithromycin orally once daily (800 mg on day 1, 400 mg on days 2–5, and placebo on days 6 and 7) or moxifloxacin orally once daily (400 mg on days 1–7), based on the results of the aforementioned Phase II trial and moxifloxacin’s labeling. The primary outcome was early clinical response at 72 hours of treatment in the ITT population. The noninferiority margin was set at –10%. A total of 860 patients were enrolled from 114 centers in North America, Latin America, Europe, and South Africa, 34% of whom were age 65 years or older. The most frequently identified bacterial isolates were S. pneumoniae (23%) and H. influenzae (16%). Atypical pathogens (Legionella or Mycoplasma species) were identified in 24% of patients. Efficacy outcomes are outlined in Table 2. The authors concluded that oral solithromycin was noninferior to moxifloxacin for the treatment of CABP.
SOLITAIRE-IV, the second Phase III trial of solithromycin, was a global, randomized, double-blind, active-controlled, noninferiority study evaluating the safety and efficacy of i.v.-to-oral regimens of solithromycin and moxifloxacin.78 Similar criteria to those used in SOLITAIRE-ORAL were used for study enrollment, with the exceptions of a wider PORT score range (>50 to ≤130) and mandatory enrollment of ≤25% of patients with less-severe disease (PORT class II) and ≥25% of patients with more-severe disease (PORT class IV). Patients were randomized to receive solithromycin (400 mg i.v. every 24 hours, switching to 800 mg orally once daily for the first dose, then 400 mg once daily) or moxifloxacin (400 mg i.v. every 24 hours, switching to 400 mg orally once daily) for 7 days. Patients could complete 7 days of i.v. therapy or be switched to oral therapy at the investigator’s discretion. Both patients and investigators were blinded to the study drug formulation. The primary outcome was early clinical response at 72 hours in the ITT population. Similar to SOLITAIRE-ORAL, the noninferiority margin was set at –10%. A total of 863 patients were enrolled from 147 centers in Eastern Europe, Europe, Asia-Pacific countries, North America, South Africa, and Latin America, 45% of whom were age 65 years or older. The mean treatment duration was identical between the solithromycin and moxifloxacin groups for both i.v. (3 days) and oral (4 days) therapy. The proportions of patients receiving 7 days of i.v. therapy for solithromycin and moxifloxacin were 22.0% and 25.6%, respectively. Efficacy outcomes are outlined in Table 3. The authors concluded that i.v.-to-oral solithromycin regimens were noninferior to i.v. moxifloxacin.
A Phase II/III randomized, open-label, active-control, multicenter study is being conducted to assess the safety and efficacy of solithromycin in children and adolescents with CABP, with a projected study completion date of January 2018.80
Other potential uses
Nonalcoholic fatty liver disease. Solithromycin use was associated with a significantly reduced mean liver weight and liver:body weight ratio, reduced whole blood glucose levels, and significantly improved histological score in a diabetic murine model of nonalcoholic steatohepatitis (NASH).81 An ongoing Phase II proof-of-principle study is evaluating the effects of solithromycin on hepatic histology and biomarkers in patients with NASH and is expected to be completed in 2017.82 Due to significant hepatotoxicity concerns, the study protocol was amended to use a lower dose of solithromycin.
Gonococcal disease. As discussed previously, solithromycin has demonstrated in vitro activity against N. gonorrhoeae, including macrolide-resistant strains. In a Phase II non-comparative trial of adults with uncomplicated urogenital gonorrhea, 59 patients were given a single dose of oral solithromycin (1,000 or 1,200 mg).83 Cultures for N. gonorrhoeae were negative for all sites of culture-proven infection after administration of either the 1,000- or 1,200-mg dose. Adverse gastrointestinal events were most common and were less common with the 1,000-mg dose versus the 1,200-mg dose, including self-limited loose stools (61% versus 42%), mild nausea (32% versus 14%), and mild vomiting (26% versus 3%). There are additional gonorrhea-related clinical trials of solithromycin, including a recently completed Phase I study of genitourinary and pharyngeal pharmacokinetics of solithromycin84 and an ongoing Phase III study comparing oral solithromycin with intramuscular ceftriaxone plus oral azithromycin for the treatment of urogenital gonorrhea (SOLITAIRE-U).85
Chronic obstructive pulmonary disease. Macrolides have demonstrated in vitro antiinflammatory properties and have been investigated for use in chronic inflammatory airway diseases.86 A Phase II, randomized, double-blind, placebo-controlled, crossover study was initiated to evaluate the effects of solithromycin on airway inflammation in patients with chronic obstructive pulmonary disease (COPD).87 Enrollment in this study was initially suspended pending modifications to the dosing regimen but has since been terminated due to concerns about significant hepatotoxicity.61
Safety and tolerability
General. Each of the clinical trials described above included analyses of safety and tolerability. No deaths or serious adverse events were reported in the Phase I studies63–65; the most commonly reported adverse events were headache, diarrhea, and nausea. In the Phase II study of solithromycin, the most commonly reported adverse event was mild diarrhea (21%).76 The remaining adverse events occurred in fewer than 9% of patients, and 3 of these events (headache, increased hepatic enzymes, and rash) were considered treatment related.
The adverse events reported in the SOLITAIRE trials are summarized in Table 4. In the SOLITAIRE-ORAL study, 37% of solithromycin-treated and 36% of moxifloxacin-treated patients reported at least 1 treatment-emergent adverse event, of which 10% and 13% were considered to be treatment related, respectively.77 Serious adverse events occurred in 7% of solithromycin-treated and 6% of moxifloxacin-treated patients, none of which were considered to be treatment related. The most commonly reported adverse events associated with solithromycin and moxifloxacin were headache (4% and 3%, respectively), diarrhea (4% and 6%, respectively), and nausea (4% for both drugs). Adverse events leading to discontinuation that were clearly related to the study drug were reported in 1% of patients in each group and consisted of nausea (n = 2), vomiting (n = 1), and allergic dermatitis (n = 1). Clostridium difficile colitis was not reported in any of the solithromycin-treated group and was reported in 2 moxifloxacin-treated patients (<1%). Six patients in each group died, but none of these deaths were attributed to the study drugs.
In SOLITAIRE-IV, 52% of solithromycin-treated patients and 35% of moxifloxacin-treated patients experienced treatment-emergent adverse events.78 Infusion-site events (e.g., pain, phlebitis, erythema) accounted almost entirely for this observed difference and occurred in 31.3% of solithromycin-treated patients and 5.4% of moxifloxacin-treated patients and led to treatment discontinuation in 2% and 0.2% of patients, respectively. When excluding infusion-site events, treatment-emergent adverse events occurred at a similar rate in patients treated with solithromycin (34.5%) and moxifloxacin (32.9%). Serious adverse events occurred with solithromycin (6.9% of patients) and moxifloxacin (5.4% of patients), 2 (0.5%) of which (urticaria and anaphylaxis) were considered related to solithromycin. The most common noninfusion-site adverse events for solithromycin and moxifloxacin were diarrhea (4.4% and 5.9%, respectively), headache (3.5% and 4.2%), and nausea (3.2% and 1.6%). No patients in the solithromycin group developed C. difficile colitis but 1 patient did in the moxifloxacin-treated group. The rates of adverse events in patients who received 5–7 days of i.v. study drug were comparable to those in the overall study population. Differentiation, if any, in the rates of adverse events between the i.v. and oral treatment periods was not reported.
Q-T interval prolongation. Earlier macrolide generations have been associated with prolongation of the Q-T interval and corresponding arrhythmias.88 A Phase I study was performed to assess solithromycin’s effect on the Q-T interval.89 Forty-eight healthy volunteers age 18–55 years and without clinically significant electrocardiogram abnormalities were randomly assigned to receive single doses of solithromycin (800 mg i.v.), moxifloxacin (400 mg orally), or placebo for the corresponding agent in a double-dummy three-way crossover design. No effects on the Q-T interval corrected with Fridericia’s method (Q-TcF) or individually corrected (Q-Tc) interval were noted. The potential effect of multiple doses cannot be determined from the results of this study; however, the 2 SOLITAIRE trials provided useful safety data on the cardiac effects of solithromycin with repeated exposure.77,78
In SOLITAIRE-ORAL, post-baseline Q-TcF interval increases of >30 and >60 milliseconds were noted in 17.1% and 2.3% of solithromycin-treated patients and 30.5% and 5.8% of moxifloxacin-treated patients, respectively, with mean Q-TcF interval increases of 4.5 milliseconds with solithromycin and 12.2 milliseconds with moxifloxacin after 7 days of therapy.77 In SOLITAIRE-IV, post-baseline Q-TcF interval increases of >30 and >60 milliseconds were noted in 16.3% and 4.1% of solithromycin-treated patients and 25.4% and 6.3% of moxifloxacin-treated patients, respectively, with mean Q-TcF interval increases of 6.5 milliseconds with solithromycin and 12.6 milliseconds with moxifloxacin at the end of treatment. Effects of Q-T interval prolongation were not reported in the other clinical trials discussed.63,64,65,67
Hepatotoxicity. In pooled Phase I study data, 7.5% of patients had alanine transaminase (ALT) levels above the upper limit of normal (ULN), and 2 patients discontinued solithromycin due to ALT levels of >5 times the ULN.61 One solithromycin-treated patient in the Phase II trial had a peak ALT concentration of >3 times the ULN; 2 such elevations were noted in the levofloxacin group.76
Rates of elevated ALT levels in individual Phase III trials have been included in Table 4. When Phase III trial data were pooled, overall ALT concentrations of >3 times, >5 times, and >10 times the ULN were noted in 7.2%, 2.4%, and 0.1% of solithromycin-treated patients versus 3.6%, 1.0%, and 0.2% of moxifloxacin-treated patients, respectively. As noted in Table 4, this effect was particularly pronounced in SOLITAIRE-IV. In SOLITAIRE-ORAL, most peak ALT levels were seen at 4 days of treatment (when liver function testing was first performed), with about 30% occurring after treatment completion (between days 6 and 15).77 In contrast, half of ALT peak levels were seen within 5 days of treatment initiation and half between days 6 and 15 in SOLITAIRE-IV.78 Two of these patients discontinued therapy prematurely due to transaminitis.
Importantly, substantial proportions of patients enrolled in the ongoing NASH and now-terminated COPD studies described above experienced hepatotoxicity, including 3 (75%) of 4 COPD and 1 (17%) of 6 NASH patients.61 Hepatotoxic effects observed in patients with COPD included elevated values of multiple liver function tests (n = 1), including ALT levels of up to >10 times the ULN, with mild icterus and pruritus; a peak ALT concentration of 7.3 times the ULN (n = 1); and a peak ALT level of 4.1 times the ULN (n = 1). In the NASH study, 1 patient experienced an ALT elevation of 4.5 times the ULN. Importantly, these studies involved significantly higher exposure to solithromycin than in the CABP trials76,77,78 (28 days of treatment in the COPD trial87 and 13 weeks in the NASH trial82).
Dosing and administration
Solithromycin has been studied in i.v. and oral formulations. The Phase III data presented herein support the use of oral or i.v.-to-oral solithromycin regimens at the discretion of the provider as an effective treatment for CABP.77,78 Oral regimens, including i.v.-to-oral, used an oral loading dose of 800 mg on day 1 of oral therapy, with lower maintenance doses of 400 mg on subsequent days (with the loading dose given to patients transitioning from i.v. to oral administration), based on the nonlinear pharmacokinetics demonstrated in Phase I studies and reported autoinhibition of metabolism.63,70 However, it was proposed that use of an oral loading dose in i.v.-to-oral regimens is unnecessary for effective therapy and may have increased toxicity.61 I.V. regimens consist of 400 mg once daily without a loading dose. The duration of therapy in clinical trials ranged from 5 to 7 days based on patients’ severity of illness. Administration of solithromycin in a fed or fasted state does not appear to have significant impact on oral bioavailability.63 Solithromycin for injection is administered over 60 minutes after dilution with 0.45% or 0.9% sodium chloride injection or lactated Ringer’s injection.61 Solithromycin elimination occurs primarily through hepatic transformation and excretion in the feces, and administration in mild, moderate, and severe hepatic dysfunction without dose adjustment did not appear to have a significant impact on solithromycin exposure or the rate of adverse events.61,70
Current regulatory status
The FDA Antimicrobial Drugs Advisory Committee reviewed the new drug application (NDA) for solithromycin on November 4, 2016.61 The committee unanimously agreed that solithromycin was an effective treatment for CABP but stated that the risk of hepatotoxicity had not yet been adequately characterized. Ultimately, by a 7–6 decision, the committee recommended that the NDA for solithromycin be approved, with recommendations (1) to add a warning against use for longer than 7 days in duration, (2) to eliminate the oral loading dose in patients transitioning from i.v. to oral therapy, and (3) to carefully select patients receiving solithromycin to avoid the possibility of increased exposure through renal dysfunction or drug–drug interactions.
On December 29, 2016, Cempra—the manufacturer of solithromycin—announced that FDA had issued a complete response letter stating that the NDA was not approvable in its current form.90 FDA noted that the risk of hepatotoxicity had not yet been adequately characterized and recommended a comparative study of patients with CABP to include approximately 9,000 patients exposed to solithromycin in order to exclude drug-induced liver injury events occurring at a rate of 1 in 3,000 with 95% probability. Further, FDA noted deficiencies in both of the solithromycin manufacturing facilities.
Place in therapy
Solithromycin’s efficacy, simple dosing, and short treatment duration make it an attractive option for CABP. Considering the rising rate of macrolide resistance in CABP-causing pathogens, particularly atypical bacteria, and its broad range of activity in these organisms, solithromycin has the potential to take on a primary role in the empirical treatment of CABP.15–20 However, significant safety concerns with solithromycin have tempered this enthusiasm. In preapproval clinical trials, the first ketolide, telithromycin, caused mild-to-moderate increases in ALT at a higher frequency in treatment groups relative to comparator agents.91–97 After telithromycin’s commercial launch, a number of reports of hepatotoxicity, including 3 cases of serious liver injury, 1 of which resulted in death, led FDA to issue warnings about liver toxicity with the drug’s use, a restricted indication,98 and a boxed warning. It seems unlikely that solithromycin, even if approved, would be widely adopted for the treatment of CABP in the absence of compelling, large-scale safety data. As solithromycin is not approved, no information is available on the proposed cost of therapy.
Other uses of solithromycin, such as for the treatment of gonococcal disease, NASH, and pediatric CABP, warrant consideration, as the toxicity profile may vary significantly in these populations. In addition, Cempra has announced the development of an ophthalmic formulation of solithromycin, which may have utility in the treatment of ocular diseases caused by susceptible pathogens while avoiding systemic toxicity.90,99
Solithromycin is a novel ketolide antibiotic developed for the treatment of CABP; however, concerns related to hepatotoxicity have put its ultimate approval and marketing in doubt.
Dr. Aitken serves on advisory boards for Cempra, Theravance, Allergan, and Astellas Pharma and on the speaker’s bureau for Merck. The authors have declared no other potential conflicts of interest.
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