A novel integrated PK/PD model to assess combination therapy: Determination of the synergistic antitumor efficacy between doxorubicin and sorafenib

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Understanding pharmacokinetic/pharmacodynamic (PK/PD) relationship is essential to identify optimal dosage regimens to achieve desired therapeutic outcomes. Existing PK/PD model for combination therapy lacks consideration of quantitative contributions from individual drugs while the “interaction factor” (y) may be arbitrarily assigned to one drug or the other. As such, distinct estimation and prediction results will be obtained, which will be confusing. In this study, we developed a novel integrated PK/PD model to characterize and predict combination therapy by considering contributions (e.g., a and β) from individual drugs (A and B, respectively), and established a new formula to define the “combination factor” (δ) concerning synergistic, additive, or antagonist effects. Doxorubicin (Dox; drug A) and sorafenib (Sor; drug B) were used as model drugs to validate this new approach. Dox (i.v.) and Sor (p.o.) PK data were obtained in BALB/c mice, and both were fit well to two‐compartment PK models. Physiological xenograft tumor growth was described by Simeoni model, and inhibition of tumor growth was attributable to the exposure to single drug (k2A×CA(t) or k2B×CB(t)), or combination (a×k2A×CA(t) + β×k2B×CB(t)). This PK/PD model was able to describe all experimental data, and reveal a greater antitumor potency for Dox (k2A = 13.8 L/mg/day) than Sor (k2B = 0.0267 L/mg/day), as well as a clear synergism (d = 1.24) for Dox plus Sor combination therapy with current dosage regimen. Interestingly, model simulation showed that increase of Sor doses for combination therapy preferably produces greater degrees of tumor suppression. Moreover, combination therapy with 2‐fold higher of tested Sor dose and half of Dox dose may lead to optimal synergistic antitumor effect. These results indicate that this new PK/PD model can be utilized to evaluate combination therapy in a definite manner.Support or Funding InformationThis study was supported by grants R01CA225958 and R01GM133888 from the National Institutes of Health