Some Thoughts about Eravacycline Based on the Phase 2 cIAI Study

eravacycline
eravacycline

Solomkin et al. conclude that the efficacy and safety of eravacycline compares favorably to the control drug, ertapenem.[1]  This top-level assessment is made with the usual caveats (insufficient statistical power, small sample size), but a few points deserve comment.

Eravacycline is a fluorocycline; as a tetracycline derivative it follows into the footsteps of doxycycline, tigecycline (Tygacil® / Wyeth) and omadacycline (Paratek).  Hence, broad-spectrum activity against Acinetobacter and ESBL producers would be expected, in addition to broad coverage of Gram-positive, Gram-negative, atypical and anaerobe pathogens as is typical for the entire tetracycline class.

A recognized liability of the tetracycline class is its propensity to cause nausea, vomiting and abdominal pain.  Doxycycline is not easy on the stomach, and neither is tigecycline.  Not a side-effect profile that surgeons or patients that just underwent major abdominal surgery like to deal with.  It is a significant side effect, not just a nuisance.

In the case of tigecycline, this amounts to a dose-limiting toxicity [2] which resulted in suboptimal dosing to the point of underdosing.  As we know, tigecycline was inferior to SOC in VAP patients, with increased mortality as a result.  The dose in the HAP/VAP trial was 100 mg IV (loading dose) followed by 50 mg IV q12h and probably too low.  The same dose was used for cSSSI, cIAI and CAP, infections with a rather high success rate for antibiotics old and new.

If we have learned anything from 3 prior failures (the ceftibiprole, doripenem, tigecycline), it is the fact that HAP/VAP is a tough proving ground for antibiotics.

So, we will want to know precisely how eravacycline stacks up against SOC at tolerated dose levels.  This is an AUC over MIC drug, so it is hoped that optimal dosing (based on PK/PD modeling) is not compromised by safety/tolerability issues.

In the Phase 2 trial, a numerically higher rate of GI side effects was seen with the higher once-a-day dosing scheme compared to the lower dose and the comparator.  However, given the uneven randomization scheme (2:2:1) and small number of control cases on SOC (N=30), efficacy comparisons are problematic.  This was a dose selection study first and foremost, not a comparison to SOC study.

Hence, both the efficacy and safety of eravacycline will require confirmation in pivotal Phase 3 trials which are now underway for cIAI and cUTI.

In the Phase 2 trial eravacycline was dosed at either 1.5 mg/kg q24h or at 1.0 mg/kg q12h.  In the Phase 3 IGNITE program, eravacycline is dosed with the better tolerated 1.0 mg/kg q12h regimen.[3]  Such weight-based dosing may be a clever move on part of Tetraphase as it allows for some degree of dose normalization not doable with a fixed dose schedule.

However, it will make the IV to PO transition quite difficult, assuming FDA insist on bioequivalent PO dosing for step-down therapy.

Abbreviations:
HAP/VAP               Hospital acquired, Ventilator-Associated Pneumonia
SOC                      Standard of Care
AUC                      Area under the plasma concentration curve
PK/PD                   Pharmacokinetic/pharmacodynamic


References:

[1] J. Solomkin.  http://aac.asm.org/content/early/2013/12/10/AAC.01614-13.full.pdf
[2] G. Muralidharan.  Pharmacokinetics of Tigecycline after Single and Multiple Doses in Healthy Subjects.  Antimicrob. Agents Chemother. 2005; 49:220
[3] http://ir.tphase.com/releasedetail.cfm?ReleaseID=862238

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