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How PBPK Can Help Solve Fatal Poisonings

My mom― a clinician scientist herself― would often say this about the power of pharmacology:

Every medicine has its price.

While most patients benefit from their medications, cases of fatal drug poisonings are tragedies wherein patients pay the ultimate price. Forensic toxicology probes cases of fatal poisonings where the cause of death is unknown. This field uses many tools to examine causes of death. Autopsies and toxicological screens are well-known tools. In the dawning era of personalized medicine, forensic detectives can leverage modeling and simulation to reveal the circumstances leading to a fatal drug concentration.

Physiologically-based pharmacokinetic (PBPK) models describe the behavior of drugs in the different body tissues. Depending on the route of administration, the course of the drug can be tracked through the blood and tissues. Each tissue is considered to be a physiological compartment. The concentration of the drug in each compartment is determined by combining systems data, drug data, and trial design information. The systems data includes demographic, physiological, and biochemical data for the individuals in the study population. The drug data consists of its physicochemical properties, its binding characteristics, and information on its metabolism and solubility. The trial design information comprises the dose, administration route, dosing schedule, and co-administered drugs.

In this blog post, forensic toxicologist, Dr. Jakob Ross Jornil from Aarhus University’s Department of Forensic Medicine, in Denmark, joined me to talk about how he’s using PBPK models to help him solve drug poisoning cases and provide insights to prevent these tragedies from re-occurring.

Jakob Jornil
Dr. Jakob Jornil

Suzanne Minton: From your vantage point, what’s the biggest difference between fictional portrayals of forensic science and reality?

Jakob Jornil: I’m not an expert in the fictional portraits of forensic toxicology, but from my point of view, most of them are pretty unrealistic. Forensic toxicology is an interesting field, but there aren’t many cliffhangers in my work.

I recently read a book, The Arc of the Swallow by S.J. Gazen that was very realistic. The writer consulted with experts and did a good job portraying forensic toxicology.

Suzanne Minton: You have access to the Simcyp Simulator through Aarhus University’s membership in the Simcyp Consortium. Most people think of pharmaceutical companies using PBPK models to inform drug development. Can you talk about the uses of the Simcyp Simulator beyond drug development?

Jakob Jornil: I’ve been using the Simcyp Simulator as my pharmacokinetic “Swiss Army knife” for forensic toxicology. In many cases, overly high blood concentrations of a drug can be a major source of toxicity. PBPK models can help us gain insight into the mechanisms that could have caused that high concentration from the doses given.

I use the Simcyp Simulator to estimate the impact of genetics on drug exposure. For example, if I have adequate data on the drug’s properties and know that the victim’s cytochrome P450 enzyme (CYP) genotypes, then I can use PBPK modeling to determine the importance of various genotypes on drug metabolism. If the deceased was a poor metabolizer (PM) of a certain CYP isoform, was that why his drug blood concentration was so high? We can perform simulations to see if the genotype was the important factor or whether we should examine other causes.

Modeling provides quantitative insights into the importance of PM status, for example, for interpreting genotype-drug concentration correlations. Without modeling some people may over-interpret the importance of genotyping results. They might think that a victim’s PM status is the sole reason for their high drug concentration, but they have no quantitative information on the importance of the genotype. Other reasons might be important as well― co-medications, low activity of several CYP enzymes, dehydration, organ impairment, etc. These additional factors could also be examined by modeling.

Suzanne Minton: How do you see the use of PBPK for forensics toxicology evolving in the future?

Jakob Jornil: Using PBPK as part of toxicological assessment enables scientists to probe important mechanisms. This technology is a relatively new for the field of forensics. By informing toxicological assessments, PBPK modeling can elucidate the reasons behind a fatal drug poisoning. This information can also guide clinicians’ prescribing practices to avoid future serious adverse events.

Suzanne Minton: That’s a really good point! Obviously, it’s too late to help drug poisoning victims, but we can bolster patient safety to prevent similar cases.

In addition to using the Simcyp Simulator, you also use our Cardiac Safety Simulator. Can you discuss how you use mechanistic modeling to assess drug cardiotoxicity?

Jakob Jornil: A doctoral student at our department is collaborating with Sebastian Polak at Certara regarding the Cardiac Safety Simulator. Predicting arrhythmias with the Cardiac Safety Simulator has a lot of potential use in forensic science.

While we’re still just taking our first steps into this area, this technology has enormous potential for understanding the effects of high concentrations of new compounds on the heart. A hot topic in forensic toxicology is the problem of new psychoactive substances, (NPS). Marketed as “bath salts, designer drugs, or herbal highs,” these substances are not legally regulated. So, people are taking drugs that have undergone zero safety testing. Due to the paucity of information on the toxicity, abuse liability, and risks associated with these substances, they threaten public health and safety.

When fatal NPS poisonings occur, we have no idea what intrinsic or extrinsic factors precipitated the death. We have no idea of the particular NPS’ toxicological concentration limits. Usually, we guessed at the underlying causes of toxicity because conducting human experiments would be unethical.

Thus, studies in virtual patients may be our only way of assessing toxicity. The Cardiac Safety Simulator could help us determine whether a drug-induced cardiac arrhythmia could have caused the fatality. We are really excited about using the Cardiac Safety Simulator, and hopefully, we’ll use it for more in the future.

Suzanne Minton: What are some of your current goals for your research?

Jakob Jornil: Currently, the goal for my colleagues and me is to quantify hepatic CYP enzymes in postmortem tissue. We would like to use that information in our simulations to support our forensic casework. So we could use actual CYP expression in the liver to determine if the high drug concentration was caused by low activity of one or more CYP enzymes.

Suzanne Minton: Is there anything else that you’d like the readers of our blog to know about you and your research?

Jakob Jornil: Not many researchers in forensic toxicology use PBPK. From my point of view, combining the Simcyp Simulator with forensic toxicology is a “happy marriage” with so many possibilities. I hope that over time the forensic toxicology community will embrace this approach. The Simcyp Simulator allows me to examine very complex problems that I wouldn’t be able to explore otherwise.

Suzanne Minton: Jakob, it was a pleasure talking with you. Thank you so much!

To learn more about Dr. Jornil’s research, please visit his university website.

Learn more about using PBPK for forensic toxicology by reading our case study “CSI Simcyp: How PBPK Models Provided Insight into a Fatal Drug Poisoning.”

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By: Suzanne Minton

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