Chemical formula: C₈₆H₉₇Cl₃N₁₀O₂₆ Molecular mass: 1,793.101 g/mol PubChem compound: 16136912
Oritavancin has three mechanisms of action: (i) inhibition of the transglycosylation (polymerization) step of cell wall biosynthesis by binding to the stem peptide of peptidoglycan precursors; (ii) inhibition of the transpeptidation (crosslinking) step of cell wall biosynthesis by binding to the peptide bridging segments of the cell wall; and (iii) disruption of bacterial membrane integrity, leading to depolarization, permeabilization, and rapid cell death.
Gram-negative organisms are intrinsically resistant to all glycopeptides, including oritavancin.
Resistance to oritavancin was observed in vitro in vancomycin-resistant isolates of Staphylococcus aureus. There is no known cross-resistance between oritavancin and non-glycopeptide classes of antibiotics.
Oritavancin exhibits reduced in vitro activity against certain Gram-positive organisms of the genera Lactobacillus, Leuconostoc and Pediococcus that are intrinsically resistant to glycopeptides.
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:
Susceptibility Interpretive Criteria for Oritavancin:
| Organism group | MIC breakpoints (mg/L) | |
|---|---|---|
| S ≤ | R > | |
| Staphylococcus aureus | 0.125 | 0.125 |
| Beta-haemolytic streptococci, ομάδες A, B, C, G | 0.25 | 0.25 |
| Viridans group streptococc (S. anginosus group only) | 0.25 | 0.25 |
S=Susceptible, R=Resistant
The area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratio of oritavancin for the infecting organism has been shown to be the parameter that best correlates with efficacy.
Oritavancin exhibits linear pharmacokinetics at a dose up to 1,200 mg. The mean (CV%) maximum oritavancin concentration (Cmax) and AUC0-∞ in patients receiving a single 1,200 mg dose in ABSSSI patients is 138 (23) μg/ml and 2,800 (28.6) μg•h/mL respectively.
Oritavancin is approximately 85% bound to human plasma proteins. Based on population PK analysis, the population mean total volume of distribution is estimated to be approximately 87.6 L, indicating oritavancin is extensively distributed into the tissues.
Exposures (AUC0-24) of oritavancin in skin blister fluid were 20% of those in plasma after a single 800 mg dose in healthy subjects.
No metabolites were observed in plasma or bile from oritavancin treated dogs and rats, respectively. Additionally, in vitro human liver microsome studies indicated that oritavancin is not metabolized.
No mass balance study has been conducted in humans. In humans, less than 1% to 5% of the dose was recovered as parent drug in faeces and urine respectively after 2 weeks of collection indicating that oritavancin is slowly excreted unchanged.
The mean terminal elimination plasma half-life of oritavancin is 245 hours (14.9% CV) based on population PK analysis of ABSSSI patients receiving a single 1,200 mg dose. The population mean total clearance is estimated at 0.445 L/h (27.2 % CV).
In a population PK analysis, a relationship between height and clearance was identified, where clearance increased with increasing height. Dose modification based on height is not necessary.
The pharmacokinetics of oritavancin was examined in the single dose Phase 3 ABSSSI studies in patients with normal renal function, CrCL ≥90 mL/min (n=213), mild renal impairment, CrCL 60-89 mL/min (n=59), moderate renal impairment, CrCL 30-59 mL/min (n=22), and severe renal impairment CrCL <30 mL/min (n=3). Population pharmacokinetic analysis indicated that renal impairment had no clinically relevant effect on the exposure of oritavancin. No dedicated studies in dialysis patients have been conducted.
Dosage adjustment of oritavancin is not needed in patients with mild or moderate renal impairment. The pharmacokinetics of oritavancin in patients with severe renal impairment has not been evaluated.
The pharmacokinetics of oritavancin were evaluated in a study of subjects with moderate hepatic impairment (Child-Pugh Class B, n=20) and compared with healthy subjects (n=20) matched for gender, age and weight. There were no relevant changes in pharmacokinetics of oritavancin in subjects with moderate hepatic impairment.
Dosage adjustment of oritavancin is not needed in patients with mild and moderate hepatic impairment. The pharmacokinetics of oritavancin in patients with severe hepatic impairment has not been studied.
Population PK analysis from the single dose Phase 3 ABSSSI studies in patients indicated that gender, age, weight, or race had no clinically relevant effect on the exposure of oritavancin. No dosage adjustment is warranted in these subpopulations.
The primary adverse effect of oritavancin administration to rats and dogs was a dose related accumulation of eosinophilic granules in tissue macrophages including hepatocytes, renal cortical epithelial cells, adrenal cells and macrophages of the reticulo endothelial system. The appearance of the eosinophilic granules did not occur following single dose administration and did not significantly affect innate macrophage function in vitro at intracellular levels anticipated from a single 1,200 mg dose.
Moderate, dose-related increases in liver enzymes (alanine transaminase and aspartate transaminase) were observed in rats and dogs and were shown to be reversible upon cessation of treatment. Biochemistry changes associated with kidney function including decreases in urine-specific gravity and pH and slight increases in blood urea nitrogen and sporadic increases in creatinine were present in both rat and dog after treatment of two weeks. Extramedullary haematopoiesis in the spleen was observed in rats. This histopathological finding correlated with an enlargement and an increase in the weight of the spleen. The exposure in rats at the no observed adverse effect level (NOAEL) was less to only slightly higher than the human exposure based on the AUC.
Histamine-like infusion reactions following immediately or shortly after dosing with oritavancin occurred in both rats and dogs. These reactions were associated with mortality at lower dosages in male than in female rats in single dose studies; however, the same gender-related differences were not observed in other species. Studies in neonatal rats and dogs for 30 days showed the same tissue effects as those seen in adult animals including sensitivity to the oritavancin-mediated histamine-like infusion reactions. Mortality was observed in neonatal rats at slightly lower dosage levels than in adults.
A standard battery of in vitro and in vivo tests on the genotoxic potential did not reveal any clinically relevant findings. Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of oritavancin.
When administered intravenously at doses up to 30 mg/kg, oritavancin did not affect the fertility or reproductive performance of male and female rats. Studies in pregnant rats and rabbits do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. There was no evidence of transplacental transfer of oritavancin in pregnant rats. The exposure in rats at the NOAEL was less to only slightly higher than the human exposure based on the AUC.
Following a single intravenous infusion in lactating rats, radio-labelled [14C]oritavancin was excreted in milk and absorbed by nursing pups.
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