A Novel Integrated Pharmacokinetic-Pharmacodynamic Model to Evaluate Combination Therapy and Determine In Vivo Synergism

Abstract

Understanding pharmacokinetic (PK)-pharmacodynamic (PD) relationships is essential in translational research. Existing PK-PD models for combination therapy lack consideration of quantitative contributions from individual drugs, whereas interaction factor is always assigned arbitrarily to one drug and overstretched for the determination of in vivo pharmacologic synergism. Herein, we report a novel generic PK-PD model for combination therapy by considering apparent contributions from individual drugs coadministered. Doxorubicin (Dox) and sorafenib (Sor) were used as model drugs whose PK data were obtained in mice and fit to two-compartment model. Xenograft tumor growth was biphasic in mice, and PD responses were described by three-compartment transit models. This PK-PD model revealed that Sor (contribution factor = 1.62) had much greater influence on overall tumor-growth inhibition than coadministered Dox (contribution factor = 0.644), which explains the mysterious clinical findings on remarkable benefits for patients with cancer when adding Sor to Dox treatment, whereas there were none when adding Dox to Sor therapy. Furthermore, the combination index method was integrated into this predictive PK-PD model for critical determination of in vivo pharmacologic synergism that cannot be correctly defined by the interaction factor in conventional models. In addition, this new PK-PD model was able to identify optimal dosage combination (e.g., doubling experimental Sor dose and reducing Dox dose by 50%) toward much greater degree of tumor-growth inhibition (>90%), which was consistent with stronger synergy (combination index = 0.298). These findings demonstrated the utilities of this new PK-PD model and reiterated the use of valid method for the assessment of in vivo synergism. Significance Statement A novel pharmacokinetic (PK)-pharmacodynamic (PD) model was developed for the assessment of combination treatment by considering contributions from individual drugs, and combination index method was incorporated to critically define in vivo synergism. A greater contribution from sorafenib to tumor-growth inhibition than that of coadministered doxorubicin was identified, offering explanation for previously inexplicable clinical observations. This PK-PD model and strategy shall have broad applications to translational research on identifying optimal dosage combinations with stronger synergy toward improved therapeutic outcomes.

Nanoparticles for Augmenting Therapeutic Potential and Alleviating the Effect of Di(2-ethylhexyl) Phthalate on Gastric Cancer

“…Zhou et al reported that codelivering doxorubicin and a transforming growth factor beta (TGF-β) receptor inhibitor via a nanocarrier effectively inhibits the TGF-β/Smad signaling pathway, resulting in suppressed EMT progression in breast cancer cells . Notably, the distinct pharmacokinetic profiles of different drug components can introduce complexities that may affect the synergistic effects of combined therapy in vivo . In our study, NPs were developed by combining ACS (ARG-conjugated CS) and TFD (TPGS-conjugated FD), and incorporating the amino acid ARG into ACS endowed the NPs with a net positive charge at pH 7.0 .…”

“… 58 Notably, the distinct pharmacokinetic profiles of different drug components can introduce complexities that may affect the synergistic effects of combined therapy in vivo . 59 In our study, NPs were developed by combining ACS (ARG-conjugated CS) and TFD (TPGS-conjugated FD), and incorporating the amino acid ARG into ACS endowed the NPs with a net positive charge at pH 7.0. 60 After acid hydrolysis of the ester bond in TPGS and TFD, the resulting solutions were analyzed by using LC–MS.…”

No Interference of H9 Extract on Trastuzumab Pharmacokinetics in Their Combinations

“…From this perspective, H9 is expected to accelerate HER2-mediated PI3K/AKT inhibition and ameliorate TIC through AMPK activation. Already, these dual-targeting mechanisms of H9 combined with trastuzumab exerted stronger anti-cancer activity by inhibiting PI3K/AKT and activating AMPK than did either drug individually, producing a synergistic effect by inducing apoptosis in mice bearing a breast tumor with combination index (CI) values less than 1 (CI = 0.647) [20,32,37,38].…”

Protein Binding in Translational Antimicrobial Development-Focus on Interspecies Differences

“…The pharmacological effect of a certain drug is dependent on both its pharmacok netic (PK) and pharmacodynamic (PD) properties. The effects of PPB on the PK of antib otics have been studied extensively [10], but whether PPB also affects PD and antimicr bial activity (by reducing the non-protein-bound fraction) continues to be debated [11 This may be due to a lack of standardized in vitro PD models to quantify the impact PPB of antimicrobials [12]. These divergent results may be due to the use of different e perimental media with different protein amounts and types [13,14] or the heterogeneou methods (time-kill curves, MIC assays, dynamic models) used to study the effects of PP in vitro.…”