Chemical formula: C₁₈H₁₂ClF₃N₄O₄ Molecular mass: 440.76 g/mol PubChem compound: 487101
Delafloxacin inhibits bacterial topoisomerase IV and DNA gyrase (topoisomerase II), enzymes required for bacterial DNA replication, transcription, repair, and recombination.
Resistance to fluoroquinolones, including delafloxacin, can occur due to mutations in defined regions of the target bacterial enzymes topoisomerase IV and DNA gyrase referred to as Quinolone-Resistance Determining Regions (QRDRs), or through other resistance mechanisms such as efflux mechanisms.
Cross-resistance between delafloxacin and other fluoroquinolones may be observed, although some isolates resistant to other fluoroquinolone may retain susceptibility to delafloxacin.
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for delafloxacin are as follows:
| Organism | MIC breakpoints (mg/L) | |
|---|---|---|
| Susceptible (S ≤) | Resistant (R >) | |
| Staphylococcus aureus (ABSSSI) | 0.25 | 0.25 |
| Staphylococcus aureus (CAP) | 0.016 | 0.016 |
| Streptococcus pneumoniae | 0.06 | 0.06 |
| Streptococcus pyogenes | 0.03 | 0.03 |
| Streptococcus dysgalactiae | 0.03 | 0.03 |
| Streptococcus agalactiae | 0.03 | 0.03 |
| Streptococcus anginosus group | 0.03 | 0.03 |
| Escherichia coli | 0.125 | 0.125 |
| Haemophilus influenzae | 0.004 | 0.004 |
The fAUC24/MIC ratio, as for other quinolone antibiotics, resulted in the pharmacokinetic/ pharmacodynamic parameter most closely associated with the efficacy of delafloxacin.
Following oral administration of 450 mg of delafloxacin every 12 hours, steady state concentrations are achieved after approximately 5 days with about 36% accumulation after multiple administrations. The half-life of oral delafloxacin is approximately 14 hours.
Following intravenous use of 300 mg delafloxacin every 12 hours, steady state concentrations are achieved after approximately 3-5 days with about 10% accumulation after multiple administrations. The half-life of IV delafloxacin is approximately 10 hours.
Delafloxacin pharmacokinetic is comparable in patients with ABSSSI or CAP and healthy volunteers.
Peak plasma delafloxacin concentrations are achieved within about 1 hour after oral administration under fasting conditions.
Peak plasma delafloxacin concentrations are achieved at the end of the 1 hour intravenous infusion.
The 450-mg tablet and 300-mg IV formulations are bioequivalent with regard to total exposure (AUC). Delafloxacin may be administered with or without food as total systemic exposure (AUC∞) is unchanged between fasted and fed (high-fat, high-calorie) conditions.
The steady state volume of distribution of delafloxacin is about 40 L which approximates total body water. The plasma protein binding of delafloxacin is approximately 84%; it primarily binds to albumin. Plasma protein binding of delafloxacin is not significantly affected by the degree of renal impairment.
Following IV administration of 7 doses of 300 mg of delafloxacin to 30 healthy volunteers, the mean delafloxacin AUC0-12 (3.6 hr*µg/mL) in alveolar macrophages was 83% of the free-plasma AUC0-12, and the mean delafloxacin AUC0-12 (2.8 hr*µg/mL) in epithelial lining fluid was 65% of the free-plasma AUC0-12.
Glucuronidation of delafloxacin is the primary metabolic pathway with oxidative metabolism representing <1% of an administered dose. The glucuronidation of delafloxacin is mediated mainly by UGT1A1,UGT1A3 and UGT2B15. Unchanged parent drug is the predominant component in plasma. There are no significant circulating metabolites (mean=9.6%) in humans.
In vitro data indicate that delafloxacin at clinically relevant concentrations does not inhibit cytochrome P450 CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 nor UDP glucuronosyltransferases isoforms UGT1A1 and UGT2B7. Delafloxacin does not induce CYP1A2, CYP2B6, CYP2C9, CYP2C8, CYP2C19 or CYP3A4/5. Likewise at clinically relevant concentrations delafloxacin does not inhibit the transporters MDR1, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2K and BSEP. Delafloxacin is a probable substrate of BCRP.
After single intravenous dose of 14C-labeled delafloxacin, 65% of the radioactivity is excreted in the urine and 28% is excreted in the faeces. Delafloxacin is excreted both unchanged and as glucuronide metabolites in urine. The radioactivity recovered from faeces is unchanged delafloxacin.
Pharmacokinetic parameters are not altered in obese patients (BMI ≥30 kg/m²).
No clinically meaningful changes in delafloxacin pharmacokinetics when administered orally in patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B and C) compared to matched healthy control subjects. Therefore, no dosage adjustment is necessary.
No clinically meaningful changes in delafloxacin Cmax and AUC∞ were observed, following administration of a single 300 mg intravenous dose of delafloxacin into patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B and C) compared to matched healthy control subjects.
Following a single oral (400 mg) administration to patients with mild, moderate or severe renal impairment, mean total exposure (AUCt) was about 1.5-fold higher for subjects with moderate and severe renal impairment compared with healthy subjects, whereas total systemic exposures were comparable to subjects with mild renal impairment. Peak exposure (Cmax) was not statistically significantly different between renal impaired and healthy subjects.
Following single intravenous (300 mg) administration to patients with mild, moderate, or severe renal impairment or ESRD on haemodialysis with and without haemodialysis after dosing, mean total exposure (AUCt) were 1.3, 1.7, 2.1, 3.5 and 4.1-fold higher than values for matched control subjects. Peak concentrations for the mild and moderate renal impairment patients were similar to that of healthy subjects, whereas peak concentrations were 2.1-fold, 5.9-fold and 6.4-fold higher for patients with severe renal impairment and ESRD on haemodialysis with and without haemodialysis after dosing, respectively.
In patients with moderate, or severe renal impairment or ESRD on haemodialysis, accumulation of the intravenous vehicle sulfobutylbetadex sodium occurs. The mean systemic exposure (AUC) increased 2.2-fold, 5.3-fold, 8.5-fold and 29.8-fold for patients with moderate impairment, severe impairment and ESRD with and without haemodialysis after dosing, respectively compared to the normal control group. The mean peak exposure (Cmax) increased about 2-fold, 5-fold and 7-fold for patients with severe impairment and ESRD with and without haemodialysis after dosing, respectively compared to the normal control group.
The pharmacokinetics of delafloxacin is not significantly altered with age; therefore, dose adjustment is not necessary based on age.
No clinical trials have been conducted with delafloxacin in paediatric patients.
Clinically significant gender-related differences in delafloxacin pharmacokinetics have not been observed in healthy subjects or in patients with ABSSSI or CAP. No dose adjustment is recommended based on gender.
In repeat dose toxicity studies in rats and dogs, gastrointestinal effects were the main findings: these included dilated cecum (oral only), abnormal stool, and decreased food intake and/or body weight in rats, and emesis, salivation and abnormal stool/diarrhoea in dogs. In addition increases in serum ALT and ALP, and reduced total protein and globulin values were recorded at the end of the treatment period in the pivotal 4-week IV dog study at the high dose (75 mg/kg) in individual dogs. Importantly, gastrointestinal effects and slightly elevated liver enzymes in dogs were not associated with histopathological changes of gastrointestinal and annexed tissues (pancreas, liver). No adverse effects were seen in rats at exposures about 2-fold higher than humans, or in dogs at exposures approximately equal to humans.
In embryo-fetal development studies carried out in rats and rabbits, delafloxacin was devoid of teratogenic effects but induced foetal growth retardation and ossification delays at levels of dose producing maternal toxicity. In rats foetal effects occurred at a level of exposure exceeding about 2-fold that observed in humans based on the AUC, but in rabbits, a species known to be extremely sensitive to maternal toxicity of antibacterial drugs, the effects on foetuses were recorded at levels of exposure well below that observed in humans. As delafloxacin is excreted in milk, severe toxicity was observed in newborn rats during lactation when mothers were treated during pregnancy and lactation with delafloxacin at a dose producing a systemic exposure about 5-fold higher than observed in humans. However, no such effects and no other developmental abnormalities occurred in the progeny of mothers exposed up to a level about 2-fold higher than observed in humans. No effects were detected on rat male and female fertility at a level of exposure about 5-fold higher than that observed in humans.
Long-term carcinogenicity studies have not been conducted with delafloxacin.
No genotoxicity hazard was identified in vitro and it was negative in vivo at the highest possible dose ≥15 times the estimated human plasma exposure based on AUC.
Environmental risk assessment studies have shown that delafloxacin may pose a risk to aquatic compartment(s).
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