Eravacycline

The mechanism of action of eravacycline involves the disruption of bacterial protein synthesis by binding to the 30S ribosomal subunit thus preventing the incorporation of amino acid residues into elongating peptide chains.

The C-7 and C-9 substitutions in eravacycline are not present in any naturally occurring or semisynthetic tetracyclines and the substitution pattern imparts microbiological activities including retention of in vitro potency against Gram-positive and Gram-negative strains expressing tetracycline-specific resistance mechanism(s) (i.e., efflux mediated by tet(A), tet(B), and tet(K); ribosomal protection as encoded by tet(M) and tet(Q)). Eravacycline is not a substrate for the MepA pump in Staphylococcus aureus that has been described as a resistance mechanism for tigecycline. Eravacycline is also not affected by aminoglycoside inactivating or modifying enzymes.

Mechanism of resistance

Resistance to eravacycline has been observed in Enterococcus harbouring mutations in rpsJ. There is no target-based cross-resistance between eravacycline and other classes of antibiotics such as quinolones, penicillins, cephalosporins, and carbapenems.

Other bacterial resistance mechanisms that could potentially affect eravacycline are associated with upregulated, non-specific intrinsic multidrug-resistant (MDR) efflux.

Susceptibility testing breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for eravacycline are:

Minimum inhibitory concentration breakpoints of eravacycline for different pathogens:

Pharmacokinetic/pharmacodynamic relationship

The area under the plasma concentration-time curve (AUC) divided by the minimum inhibitory concentration (MIC) of eravacycline has been shown to be the best predictor of efficacy in vitro, utilising human steady state exposures in a chemostat and confirmed in vivo in animal models of infection.

Absorption

Eravacycline is administered intravenously and therefore has 100% bioavailability.

The mean pharmacokinetic parameters of eravacycline after single and multiple intravenous infusions (60 minutes) of 1 mg/kg administered to healthy adults every 12 hours are presented in the following table.

Mean (%CV) plasma pharmacokinetic parameters of eravacycline after single and multiple intravenous infusions to healthy adults:

^a Mean (range) represented
^b AUC of Day 1 = AUC_0-12 after the first dose and AUC for Day 10 = steady state AUC_0-12

Distribution

The in vitro binding of eravacycline to human plasma proteins increases with increasing concentrations, with 79%, 86% and 90% (bound) at 0.1, 1 and 10 µg/mL, respectively. The mean (%CV) volume of distribution at steady-state in healthy normal volunteers following 1 mg/kg every 12h is approximately 321 L (6.35), which is greater than total body water.

Biotransformation

Unchanged eravacycline is the major medicinal product-related component in human plasma and human urine. Eravacycline is metabolised primarily by CYP3A4- and FMO-mediated oxidation of the pyrrolidine ring to TP-6208, and by chemical epimerisation at C-4 to TP-498. Additional minor metabolites are formed by glucuronidation, oxidation and hydrolysis. TP-6208 and TP-498 are not considered to be pharmacologically active.

Eravacycline is a substrate for the transporters P-gp, OATP1B1 and OATP1B3 but not for BCRP.

Elimination

Eravacycline is excreted in both urine and faeces. Renal clearance and biliary and direct intestinal excretion account for approximately 35% and 48% of total body clearance after administration of a single intravenous dose of 60 mg ¹⁴C-eravacycline, respectively.

Linearity/non-linearity

The C_max and AUC of eravacycline in healthy adults increase approximately in proportion to an increase in dose. There is approximately a 45% accumulation following intravenous dosing of 1 mg/kg every 12 hours.

Within the range of eravacycline multiple intravenous doses studied clinically, the pharmacokinetic parameters AUC and C_max demonstrate linearity, but with increasing doses the increase in both AUC and C_max are slightly less than dose-proportional.

Potential for drug-drug interactions

Eravacycline and its metabolites are not inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 in vitro. Eravacycline, TP-498 and TP-6208 are not inducers of CYP1A2, CYP2B6 or CYP3A4.

Eravacycline, TP-498 and TP-6208 are not inhibitors of BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1 or MATE2-K transporters. The metabolites TP-498 and TP-6208 are not inhibitors of P-gp in vitro.

Special populations

Renal impairment

The geometric least square mean C_max for eravacycline was increased by 8.8% for subjects with end stage renal disease (ESRD) versus healthy subjects with 90% CI -19.4, 45.2. The geometric least square mean AUC_0-inf for eravacycline was decreased by 4.0% for subjects with ESRD versus healthy subjects with 90% CI-14.0, 12.3.

Hepatic impairment

The geometric mean C_max for eravacycline was increased by 13.9%, 16.3%, and 19.7% for subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe (Child-Pugh Class C) hepatic impairment versus healthy subjects, respectively. The geometric mean AUC_0-inf for eravacycline was increased by 22.9%, 37.9%, and 110.3% for subjects with mild, moderate, and severe hepatic impairment versus healthy subjects, respectively.

Gender

In a population pharmacokinetic analysis of eravacycline, no clinically relevant differences in AUC by gender were observed for eravacycline.

Elderly (≥65 years)

In a population pharmacokinetic analysis of eravacycline, no clinically relevant differences in the pharmacokinetics of eravacycline were observed with respect to age.

Body weight

In a population pharmacokinetic analysis it was shown that eravacycline disposition (clearance and volume) was dependent on body weight. However, the resulting difference in exposure to eravacycline in terms of AUC does not warrant dose adjustments in the weight range studied. No data are available for patients weighing more than 137 kg. The potential influence of severe obesity on eravacycline exposure has not been studied.

In repeated dose toxicity studies in rats, dogs and monkeys, lymphoid depletion/atrophy of lymph nodes, spleen and thymus, decreased erythrocytes, reticulocytes, leukocytes, and platelets (dog and monkey), in association with bone marrow hypocellularity, and adverse gastrointestinal effects (dog and monkey) were observed with eravacycline. These findings were reversible or partially reversible during recovery periods of 3- to 7-weeks.

Bone discolouration (in the absence of histological findings), which was not fully reversible over recovery periods of up to 7-weeks, was observed in rats and monkeys after 13 weeks of dosing.

Intravenous administration of high doses of eravacycline has been associated with cutaneous responses (including hives, scratching, swelling, and/or skin erythema) in rat and dog studies.

In fertility studies in male rats, eravacycline administered at about 5 times the clinical exposure (based on AUC), gave rise to a significantly reduced number of pregnancies. These findings were reversible following a 70-day (10-week) recovery period, equivalent to a spermatogenic cycle in the rat. Findings on the male reproductive organs were also observed in rats in the repeated dose toxicity studies for 14 days or 13 weeks at exposures more than 10- or 5-fold the clinical exposure based on AUC. The observations included degeneration of the seminiferous tubules, oligospermia, and cellular debris in the epididymides, spermatid retention in the seminiferous tubules, increase of spermatid head retention in Sertoli cells, and vacuolation of Sertoli cells and decreased sperm counts. No adverse effects on mating or fertility were observed in female rats.

In embryo-foetal studies, no adverse effects were observed in rats at exposures comparable to clinical exposure or in rabbits at exposures 1.9-fold higher than the clinical exposure (based on AUC) in rats and rabbits respectively. Doses more than 2- or 4-fold higher than the clinical exposure (based on AUC) were associated with maternal toxicity (clinical observations and reduced body weight gain and food consumption), and reduced foetal body weights and delays in skeletal ossification in both species and abortion in the rabbit.

Animal studies indicate that eravacycline crosses the placenta and is found in foetal plasma. Eravacycline (and metabolites) is excreted in the milk of lactating rats.

Eravacycline is not genotoxic. Carcinogenicity studies with eravacycline have not been conducted.

Eravacycline may have the potential to be very persistent in freshwater sediment.