By Klaus Romero and Amin Rostami

May 29, 2018 | Clinical Informatics News Best Practices Award Finalist | In February, three entries were announced the winners of the Clinical Informatics News Best Practices Awards. Each year these awards are given with the goal of recognizing the projects that raise the bar on innovation in clinical trials. While only three projects are rewarded, we can’t help but recognize the remaining six finalists for their efforts in improving the clinical trial process for both patients and researchers. Here is one of those finalists. – The Editors

Tuberculosis (TB) is one of the top 10 causes of death worldwide. In 2016, 10.4 million people fell ill with TB and 1.7 million died from the disease, according to the World Health Organization (WHO). Furthermore, 40% of HIV deaths in 2016 were due to TB.

Compounding this global healthcare crisis, most TB drugs are more than 40 years old, have significant side effects and drug interactions, and require a long treatment period. In addition, WHO reports that there were an estimated 600,000 new cases with resistance to rifampicin (the most effective first-line drug) globally in 2016 and 490,000 of them had multidrug-resistant TB. Clearly, new drugs are needed to treat this disease.

To support these drug development efforts, Certara in collaboration with the Critical Path to TB Drug Regimens (CPTR) introduced a pharmacokinetic/pharmacodynamic (PK/PD) lung model for its Simcyp Population-based Simulator v16, which can predict how drugs will be dispersed in the lungs at different stages of TB infection.

The Simcyp Simulator combines drug-specific physicochemical data with in vitro absorption and disposition data so that it can predict drug behavior in virtual patient populations. Its algorithms also account for demographic (gender, age, body size, ethnicity), societal (environmental effects and diet) and genetic differences (in enzymes, etc.) between populations.

The Simcyp Simulator is a highly sophisticated platform for determining first-in-human dose selection, designing more efficient and effective clinical studies, evaluating new drug formulations, and predicting drug-drug interactions (DDIs) and PK outcomes in clinical populations. These include vulnerable populations such as pediatric patients, pregnant women, and patients with impaired organ function.

Certara initially developed a mechanistic, permeability-limited, physiologically-based pharmacokinetic (PBPK) lung model for the Simcyp Simulator. This model represented the lung and airways as seven compartments. Therefore, it could predict drug disposition in the plasma, lung, and epithelial lining fluid (ELF), and the potential impact of disease progression on drug kinetics at different stages of TB infection.

The first version of this lung model examined only passive drug movement within the compartments. However, as some of the compounds being tested as potential TB therapies, such as the antibiotic moxifloxacin, are moved by drug transporters like P-glycoprotein (P-gp), a more advanced model was required. The in vitro intrinsic clearance of moxifloxacin was estimated using the Simcyp in vitro analysis (SIVA) toolkit and extrapolated to the in vivo scenario. By including P-gp transport in its moxifloxacin model, Certara was able to improve the predictive accuracy of the ELF:plasma ratio for this drug.

Refining the Model

Pulmonary TB is characterized by the formation of granulomas—heterogeneous lesions comprised of a necrotic core surrounded by a macrophage- and neutrophil-rich cellular rim.

To treat pulmonary infections effectively, TB drugs (which are usually administered orally) must pass through the intestine into the systemic circulation and reach the mycobacteria in the lung granulomas.

Therefore, Certara set out to develop an enhanced lung model that would reflect drug distribution and PD effect in the plasma, lung, and TB granulomas. This increased focus is particularly important as lack of correlation between the drug dose and concentration in the plasma, lung, and granulomas is thought to contribute to the long treatment duration and failure of many novel TB drug regimens.

The result was a mechanistic, permeability-limited PK/PD granuloma model with compartments representing macrophages, interstitial fluid, caseum, and blood.

Certara’s enhanced lung model also permits four drugs, with different dosing regimen, to be studied concurrently. This is particularly useful because the most common dosing regimen for TB employs four drugs.

Equally important, the Simcyp Simulator has been accepted by the US Food and Drug Administration (FDA), European Medicines Agency, Japanese Pharmaceuticals and Medical Devices Agency, and China’s Food and Drug Administration. It has been leveraged to inform more than 100 label claims for new drug approvals from US FDA in the past few years.

Results Generated

The Critical Path Institute has already used this Simcyp Simulator model to evaluate the PK of multiple investigational drugs and different dosing strategies in virtual TB patients and assess their DDI liability.

Conclusions/Implications

Sponsors can now leverage in vitro and in silico data to better understand TB drug disposition and penetration in plasma, lung tissue, ELF, and TB granulomas. Researchers can also simulate drug dose, disease state, and concomitant medications. Therefore, sponsors can use this enhanced Simcyp Simulator lung model to determine which TB drug dosing regimens will produce therapeutic concentrations at target sites in the lungs, and thus expedite development of new treatments. It could also potentially support personalized dosing for TB patients.

Amin Rostami is Chief Scientific Officer at Certara, the global leader in model-informed drug development and regulatory science. He is also Professor of Systems Pharmacology and Co-director of the Centre for Applied Pharmacokinetic Research at the University of Manchester, UK.

Klaus Romero is Director of Clinical Pharmacology and Quantitative Medicine at The Critical Path Institute.