Skeptical at the idea of ravenous brain-eating undead? You don’t have to take my word for it. The Centers for Disease Control and Prevention (CDC) Office of Public Health Preparedness and Response recognizes this threat. Their Zombie Preparedness website provides information on getting ready for all kinds of disasters.
Modeling and simulation (M&S) technology can help fight the Walking Dead. Zombie plague, like other serious infectious diseases, presents unique challenges to drug development. One challenge is that exposing humans to these pathogens in drug efficacy studies is unethical. M&S methods include “top down” approaches such as PK/PD modeling and simulation and “bottom up” approaches such as PBPK modeling and simulation. These approaches can use animal studies and simulate clinical trials to help prove a drug’s safety and efficacy in untestable clinical scenarios.
Scary bugs, hard to develop drugs
The FDA provides a guidance on the “Animal Rule.” This is a pathway for approval when human efficacy studies are not ethical or feasible. To optimize dosing, sponsors use an animal model to characterize the PK. This animal model must have pharmacodynamic endpoints that relate to the desired human endpoints. In recent years, we have helped develop treatments for two deadly infectious diseases: botulism and smallpox.
Gaining FDA approval for a botulism antitoxin
Botulism is a rare, and sometimes, fatal illness. It is caused by toxins produced by the Clostridium botulinum bacteria. Early symptoms include double vision, blurred vision, drooping eyelids, slurred speech, difficulty swallowing, dry mouth and muscle weakness. The symptoms may progress to paralysis of the respiratory muscles, arms, legs, and trunk. Left untreated, botulism can cause death.
There are five main kinds of botulism:
- Foodborne, caused by eating infected food
- Wound botulism, caused by a wound infected with Clostridium botulinum
- Infant botulism is caused by consuming the spores of the bacterium. The bacteria then grow in the intestines and release the toxin. This is why you never give infants honey to eat.
- Adult intestinal toxemia, which occurs by the same route as infant botulism
- Iatrogenic botulism due to accidental overdose of botulinum toxin
Using modeling and simulation to optimize dosing for a botulism treatment
Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)-(Equine) (BAT) is an antitoxin consisting of immune globulin fragments. BAT is derived from horses immunized with C. botulinum toxins. It treats symptoms following exposure to botulinum neurotoxin (BoNT) serotypes A, B, C, D, E, F or G.
To support the human dosing regimen of BAT, I performed pharmacokinetic (PK) and pharmacodynamic (PD) modeling. The models used available data from guinea pigs, non-human primates (NHP) and humans. We developed a PK compartmental model in humans, guinea pigs and rhesus macaques. Then, an exposure-response model was constructed to understand the relationship between BAT exposure and response to BoNT. This model used available post-exposure prophylaxis study information from guinea pigs and rhesus macaque.
Exposure to BAT in humans was simulated using the PK model for candidate scenarios. Survival probability in humans was predicted based on the established exposure-response model. We predicted that the probability of survival in humans following exposure to all BoNT serotypes was more than 93.1% following administration of one vial of BAT.
The FDA approved Botulism Toxin Heptavalent to treat patients showing botulism symptoms following exposure to the neurotoxin. BAT is the first instance of a plasma derivative gaining FDA approval under the Animal Rule. For more information, please check out my poster, “Exposure-Response Modeling and Simulation to Support Human Dosing for Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) – (Equine) or BAT.”
Dose optimization for a treatment that protects against smallpox in humans
Smallpox plagued humanity for millennia. The mortality rate for this viral disease was as high as 30%. Long-term complications of smallpox included disfiguring pockmarks and blindness.
This highly contagious illness is caused by the variola virus, a member of the orthopox virus family. There is no specific treatment for smallpox. The only way to prevent it is through vaccination.
Through heroic public health efforts, smallpox was globally eradicated in the late 1970s. However, concerns remain about its potential use as an agent of bioterrorism. The CDC has detailed its plans to protect the public from smallpox in its response plan and guidelines.
Tecovirimat is a small-molecule therapeutic for smallpox prevention. We sought to determine its human efficacious dose. To do so, we used efficacy studies in NHPs and PK/PD analysis. The efficacy analysis used data from studies that evaluated treatment following infection of NHPs with monkeypox virus (MPXV).
Monkeypox virus is related to smallpox. Cynomolgus monkeys infected with MPXV develop a smallpox-like disease. We performed population PK modeling to extrapolate from NHPs the effect of infection on tecovirimat PK to humans. The models were developed using the non-linear mixed effects modeling software, Phoenix NLME.
Using these M&S technology-enabled strategies, we identified a dose of tecovirimat that should protect over 95% of the population. The US government has amassed tecovirimat in the strategic national stockpile. For more information, please read this paper by my colleagues, Nathalie Gosselin, Samer Mouksassi, Nastya Kassir, and JF Marier, in Antimicrobial Agents and Chemotherapy, “Pharmacokinetic and Pharmacodynamic Modeling To Determine the Dose of ST-246 To Protect against Smallpox in Humans.”
All information presented derive from public source materials.
Join the modeling and simulation revolution
The use of M&S in drug development has evolved from being a research nicety to a regulatory necessity. Today, modeling and simulation is leveraged to some extent, across most development programs to understand and optimize key decisions related to safety, efficacy, dosing, special populations, and others. Further, the use of M&S as a percentage of an entire drug development program is growing, as the advances in both computing power and our understanding of biological sciences increases, thus propelling both the need and value of the technology.
This white paper provides a compilation of best practices to systematically leverage the many benefits of M&S across a drug development program. I hope that you’ll read it and let me know what you think in the comments section!