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For patients with amyotrophic lateral sclerosis who take oral riluzole tablets, approximately 50% experience alanine transaminase (ALT) levels above upper limit of normal (ULN), 8% above 3× ULN, and 2% above 5× ULN. BHV-0223 is a novel 40 mg rapidly sublingually disintegrating (Zydis) formulation of riluzole, bioequivalent to conventional riluzole 50 mg oral tablets, that averts the need for swallowing tablets and mitigates first-pass hepatic metabolism, thereby potentially reducing risk of liver toxicity. DILIsym is a validated multiscale computational model that supports evaluation of liver toxicity risks. DILIsym was used to compare the hepatotoxicity potential of oral riluzole tablets (50 mg BID) versus BHV-0223 (40 mg BID) by integrating clinical data and in vitro toxicity data. In a simulated population (SimPops), ALT levels > 3× ULN were predicted in 3.9% (11/285) versus 1.4% (4/285) of individuals with oral riluzole tablets and sublingual BHV-0223, respectively. This represents a relative risk reduction of 64% associated with BHV-0223 versus conventional riluzole tablets. Mechanistic investigations revealed that oxidative stress was responsible for the predicted ALT elevations. The validity of the DILIsym representation of riluzole and assumptions is supported by its ability to predict rates of ALT elevations for riluzole oral tablets comparable with that observed in clinical data. Combining a mechanistic, quantitative representation of hepatotoxicity with interindividual variability in both susceptibility and liver exposure suggests that sublingual BHV-0223 confers diminished rates of liver toxicity compared with oral tablets of riluzole, consistent with having a lower overall dose of riluzole and bypassing first-pass liver metabolism., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology.)

Biologically based dose-response (BBDR) modeling of environmental pollutants can be utilized to inform the mode of action (MOA) by which compounds elicit adverse health effects. Chemicals that produce tumors are typically labeled as either genotoxic or nongenotoxic. Though both the genotoxic and the nongenotoxic MOA may be operative as a function of dose, it is important to note that the label informs but does not define a MOA. One commonly proposed MOA for nongenotoxic carcinogens is characterized by the key events cytotoxicity and regenerative proliferation. The increased division rate associated with such proliferation can cause an increase in the probability of mutations, which may result in tumor formation. We included these steps in a generalized computational pharmacodynamic (PD) model incorporating cytotoxicity as a MOA for three carcinogens (chloroform, CHCl(3); carbon tetrachloride, CCL(4); and N,N-dimethylformamide, DMF). For each compound, the BBDR model is composed of a chemical-specific physiologically based pharmacokinetic model linked to a PD model of cytotoxicity and cellular proliferation. The rate of proliferation is then linked to a clonal growth model to predict tumor incidences. Comparisons of the BBDR simulations and parameterizations across chemicals suggested that significant variation among the models for the three chemicals arises in a few parameters expected to be chemical specific (such as metabolism and cellular injury rate constants). Optimization of model parameters to tumor data for CCL(4) and DMF resulted in similar estimates for all parameters related to cytotoxicity and tumor incidences. However, optimization of the CHCl(3) data resulted in a higher estimate for one parameter (BD) related to death of initiated cells. This implies that additional steps beyond cytotoxicity leading to induced cellular proliferation can be quantitatively different among chemicals that share cytotoxicity as a hypothesized carcinogenic MOA.