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Fighting Superbugs: Supporting FDA Approval of a New Antibiotic

One of the most rewarding parts of leading Certara’s consulting services is recognizing how our work supports new drug approvals to positively impact patients’ health. In this blog post, I’ll discuss how Certara helped Cubist obtain FDA approval for Zerbaxa™ (ceftolozane/tazobactam), a new antibacterial drug to treat adults with complicated infections.

The growing threat of antibiotic resistance

According to a report from the Centers for Disease Control and Prevention (CDC), in the United States, at least two million people become infected with antibiotic resistant bacteria and at least 23,000 people die annually as a direct result of these infections. At the same time, the pipeline for novel antibacterial drugs remains alarmingly low. To create incentives for the pharmaceutical industry to invest in developing new antibacterial drugs, the Generating Antibiotic Incentives Now, or GAIN, provision was signed into law as part of the Food and Drug Administration Safety and Innovation Act in 2012. This legislation extends by five years the exclusivity period during which antibiotics that treat serious or life-threatening infections can be sold without competition from generics.

A new weapon in the battle against gram-negative bacteria

Increased drug resistance in gram-negative pathogens such as Pseudomonas aeruginosa and extended-spectrumβ-lactimase (ESBL)- producing Enterobacteriaceae have been linked to especially deadly infections. Zerbaxa has been approved for treating adults with complicated urinary tract infections (cUTI), including pyelonephritis, and complicated intra-abdominal infections (cIAI) caused by gram-negative bacteria.

Zerbaxa is a novel combination of the cephalosporin, ceftolozane, and the established β-lactimase inhibitor (BLI) tazobactam (TAZ). TAZ potentiates the activity of ceftolozane against the majority of ESBL-producing gram-negative bacilli and some AmpC-overexpressed Enterobacteriaceae, as well as against important anaerobic pathogens such as Bacteroides fragilis.

Certara scientists support the approval of Zerbaxa

A team of senior Certara scientists supported the preclinical and clinical development, and ultimately, the regulatory approval of Zerbaxa in several key ways. Early in Zerbaxa’s development, we helped to characterize its toxicokinetic profile in dogs. Once Zerbaxa moved into clinical trials, we helped describe its pharmacokinetic profile in healthy volunteers when the drug was given in a strength (mg) fixed at a 2:1 ratio for ceftolozane relative to TAZ. This work showed that ceftolozane clearance was similar whether administered alone or in combination with tazobactam, suggesting tazobactam had no effect on the clearance of ceftolozane.

The pharmacokinetics of Zerbaxa appeared to be dose proportional and linear across a wide range of doses. Both drugs were primarily excreted renally. The results of this study supported continuing the clinical development of the drug. Read more about this work by Certara’s MyMy Trinh and her colleagues in the Antimicrobial Agents and Chemotherapy article, Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult subjects following single and multiple ascending doses.

The sponsor now had an initial understanding of Zerbaxa’s PK profile in healthy adults. Next, they enlisted the help of my colleague, Dr. Samer Mouksassi, to help them with two critical tasks to help inform the objectives of the upcoming clinical trials:

  • Build a population pharmacokinetic (PK) model for Zerbaxa in healthy adult volunteers AND patients with renal impairment and complicated bacterial infections
  • Identify the major determinants of variability for Zerbaxa’s PK

Based on data from Phase 1 and 2 studies, Dr. Mouksassi and his colleagues used Certara’s industry-leading Pop PK/PD software, Phoenix NLME, to perform population PK analysis and identify the major sources of variability. Zerbaxa PK was described by a linear two-compartment model with first-order drug elimination. As expected, drug clearance was highly correlated with renal function. The final PK models adequately described the plasma concentration of Zerbaxa.

These models formed the basis for predicting the probability of target attainment in diverse populations with varying demographics, renal function, and infection status. In addition, these results suggested that Zerbaxa could be an alternative to the currently recommended treatments for cUTI and cIAI in patients with varying degrees of renal impairment, especially in cases of drug-resistant infections. Monte Carlo simulations derived with the population PK/PD model can also be utilized to further guide dosing recommendations for Zerbaxa in various populations, for different pathogens of interest, and for other indications such as nosocomial pneumonia infection. For more information, read the recently published Journal of Clinical Pharmacology article, “Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections.”

All information presented derive from public source materials.

Learn more about how modeling and simulation informs drug development for infectious diseases

This webinar described the application of early development strategies to enable development of two new antiviral drugs for children using limited adult data. Extensive use of translational science and quantitative modeling and simulation methods were key underpinnings to facilitate the successful execution of these programs.

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By: Michael Eckstut

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