Ratiometric dosing of anticancer drug combinations: Controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice

Abstract

Anticancer drug combinations can act synergistically or antagonistically against tumor cells in vitro depending on the ratios of the individual agents comprising the combination. The importance of drug ratios in vivo, however, has heretofore not been investigated, and combination chemotherapy treatment regimens continue to be developed based on the maximum tolerated dose of the individual agents. We systematically examined three different drug combinations representing a range of anticancer drug classes with distinct molecular mechanisms (irinotecan/floxuridine, cytarabine/daunorubicin, and cisplatin/daunorubicin) for drug ratio -dependent synergy. In each case, synergistic interactions were observed in vitro at certain drug/drug molar ratio ranges (1:1, 5:1, and 10:1, respectively), whereas other ratios were additive or antagonistic. We were able to maintain fixed drug ratios in plasma of mice for 24 hours after i.v. injection for all three combinations by controlling and overcoming the inherent dissimilar pharmacokinetics of individual drugs through encapsulation in liposomal carrier systems. The liposomes not only maintained drug ratios in the plasma after injection, but also delivered the formulated drug ratio directly to tumor tissue. In vivo maintenance of drug ratios shown to be synergistic in vitro provided increased efficacy in preclinical tumor models, whereas attenuated antitumor activity was observed when antagonistic drug ratios were maintained. Fixing synergistic drug ratios in pharmaceutical carriers provides an avenue by which anticancer drug combinations can be optimized prospectively for maximum therapeutic activity during preclinical development and differs from current practice in which dosing regimens are developed empirically in late-stage clinical trials based on tolerability.

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…Three different drug combinations taken from various drug classes (irinotecan/floxuridine, cytarabine/daunorubicin, and cisplatin/daunorubicin) were evaluated for ratio-dependent synergy. It was found that only specific drug ratios (1:1, 5:1, 10:1, respectively) yielded in vitro synergy, otherwise the interactions were deemed additive or antagonistic [146].…”

The role of protein kinase C in the synergistic interaction of safingol and irinotecan in colon cancer cells

“…One challenge remains with the use of such fixed ratio drug combinations, whereby the synergistic drug ratio may not be achieved at the site of action due to the differences in the pharmacokinetic behavior of the individual drugs (43). Recently, the use of drug delivery systems such as liposomes or polymeric nanoparticles could co-deliver and maintain synergistic drug ratios of therapeutic agents at the tumor site (28). Improved therapeutic efficacy could be achieved through such sophisticated formulations in animal models, and phase I/II clinical trials have begun to evaluate these novel formulations (44,45).…”

Combination Chemotherapy in Cancer: Principles, Evaluation and Drug Delivery Strategies

“…Ultimately, one can only determine whether a new combination provides a statistically significant increase in a specific end point such as response rate, time to progression or survival . Preclinical drug interaction studies allow a more rational design of clinical combination chemotherapy protocols, which are generally based on the empiric assumption that maximal efficacy will be achieved by co-administering each drug at their maximum tolerated doses (MTDs) (Mayer & Janoff, 2007;Harasym et al, 2007;Mayer et al, 2006). This "more-is-better" philosophy applied to anticancer combinations may result in higher toxicity with minimal therapeutic benefit due to concentration-dependent drug interactions (Mayer et al, 2006;Ramsey et al, 2005).…”

“…Undoubtedly, there are several molecular and pharmacological factors that determine the effectiveness of drug combinations. A rationallydesigned fixed drug combination is required since certain drug ratios can be synergistic, while others are additive or even antagonistic (Mayer & Janoff, 2007;Mayer et al, 2006). The design of preclinical drug combination studies on established cell lines, primary cell cultures or animal models has to take into account several factors such as drug concentration, exposure time, drug administration schedule and analytic method for evaluating the drug interaction (Zoli et al, 2001).…”