Pharmacokinetic Optimization of Everolimus Dosing in Oncology: A Randomized Crossover Trial

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of renal cell carcinoma [1], neuroendocrine tumors [2], and hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer [3]. Inhibition of mTOR has been shown to enhance the effectiveness of hormonal-based therapies for breast cancer patients who have become resistant to endocrine therapy [4].

The BOLERO-2 trial showed that the addition of everolimus to exemestane increased progression-free survival in patients with HR-positive, HER2-negative advanced breast cancer compared with placebo [3]. This improvement from 4.1 to 11.1 months resulted in a hazard ratio of 0.38 (95% confidence interval 0.31–0.48, p < 0.0001) in the final analysis [5]. Nonetheless, the everolimus 10 mg once-daily dose in combination with exemestane 25 mg once daily resulted in significant adverse events (AEs) (any grade): 56% of patients developed stomatitis, 36% developed rash, 33% developed fatigue, and 30% developed diarrhea. These events were severe (grade 3) in 8, 1, 3, and 2% of patients, respectively, and a considerable 19% of patients discontinued treatment due to toxicity. Moreover, a meta-analysis of over 900 patients included in various everolimus phase II trials by Ravaud et al. estimated the overall incidence of stomatitis at 57% (any grade) and the incidence of severe (grade 3–4) stomatitis at 6% [6]. Adverse effects, particularly stomatitis, have been shown to be related to pharmacokinetic exposure to everolimus [6, 7]. Specifically, these AEs may be associated with high maximum plasma concentrations (C _max) [8]; thus, reducing C _max while maintaining efficacious trough concentrations (C _min) could be an effective method of optimizing the treatment of everolimus by reducing toxicity yet retaining efficacy.

Generally, the various pharmacokinetic parameters C _min, C _max, and area under the whole blood concentration-time curve (AUC) will be strongly interrelated (i.e. a higher dose will increase all three, and, conversely, a dose reduction will reduce all three). However, in contrast to lowering the once-daily dose (the current strategy to reduce toxicity in clinical practice), switching to a twice-daily schedule could specifically reduce C _max without negatively impacting C _min or AUC, and thereby theoretically reduce toxicity while not reducing efficacy. A strategy to reduce the C _max/C _min ratio could be the use of an extended- or sustained-release formulation [8], or splitting the intake moments from once daily to twice daily.

We hypothesized that given the pharmacological properties of everolimus, the latter approach could reduce the C _max while maintaining the C _min and total exposure, measured as AUC at similar levels. This could lead to reducing the C _max/C _min ratio without the need to develop a new sustained-release formulation, thereby preventing a costly patent extension. To test this hypothesis, we performed a randomized, pharmacokinetic, crossover trial of everolimus 10 mg once daily versus 5 mg twice daily in cancer patients.

The hypothesis of this study was that switching patients from a 10 mg once-daily dose to a 5 mg twice-daily dose would lead to a reduction in C _max, which is probably responsible for most of the dose-limiting toxicities, while still maintaining AUC and C _min, to guarantee similar efficacy. We have shown that splitting everolimus intake results in a large reduction in C _max and a modest, yet statistically significant, increase in C _min (Table 2; Figs. 2, 3). This resulted in an approximately 50% reduction in the C _max/C _min ratio of 6.44 on the once-daily schedule, to 3.18 on the twice-daily schedule (p < 0.001).

No significant difference in total exposure measured as AUC was detected by splitting the dose into a 5 mg twice-daily regimen. This was the intended outcome and was in concordance with the pharmacokinetic data in the phase I study, which showed no dose-dependent change in bioavailability over a dose range of 5–70 mg [10]. Subsequently, these results support the view that a switch from 10 mg once daily to 5 mg twice daily is feasible and could improve specific pharmacokinetic parameters without affecting overall exposure.

Previous studies have shown a large interpatient variability in the pharmacokinetics of everolimus [7, 10‐12]. Our trial confirms this high interpatient variability, with CVs ranging from 28.1 to 53.9% (Table 2). CVs were numerically higher in the twice-daily arm than in the once-daily arm. This difference is most likely driven by the single outlier patient (see Table 4) who had an increased C _max on the twice-daily schedule. As food is known to affect the pharmacokinetics of everolimus [13], patients were instructed to take everolimus with a low-fat meal during the study period. To further reduce a possible effect of this and other environmental factors on the pharmacokinetic variability of everolimus, we used a crossover design for the current study. Using this design, only intrapatient pharmacokinetic variability could possibly influence the outcome.

As shown in Fig. 2, the C _max achieved on the twice-daily schedule in the evening seemed lower compared with the C _max in the morning. This is most likely due to the larger meal size in the evening as food is known to reduce the absorption of everolimus [13]

In the current study, everolimus was well-tolerated in both dose regimens; however, some patients had already received everolimus prior to enrollment. This limits the comparison of toxicity between the two dose regimens as most everolimus-associated AEs occur soon after the initiation of therapy [14]. Moreover, in the current trial, patients were only treated on each dose schedule for a short duration of merely 2 weeks.

Everolimus C _min has been linked to treatment efficacy in several studies. An analysis of 44 renal cell carcinoma patients proposed a threshold for efficacy of 14.1 ng/mL [15]. Although not statistically significant, a difference in progression-free survival of 13.3 versus 3.9 months was seen. In pediatric oncology, everolimus is administered based on whole-blood concentrations, and a C _min window of 5–15 ng/mL is used as the pharmacokinetic target [16]. In pancreatic neuroendocrine tumors, median progression-free survival was 22.7 months in patients with a C _min of 10–30 ng/mL, compared with only 13.8 months in patients with a C _min <10 ng/mL [6]. In a meta-analysis of published phase II trials in various tumor types, a twofold increase in C _min increased the probability of tumor size reduction by 40%, and reduced the risk of progression-free survival events by 10% [6]. These findings underscore the need to maintain C _min levels. Fortunately, the current strategy of 5 mg twice-daily dosing increased C _min compared with once-daily dosing, potentially leading to a better progression-free survival. However, a prospective clinical trial is needed to conclusively demonstrate a reduction in toxicity and improved efficacy for the everolimus twice-daily administration schedule.

A drawback of switching to a twice-daily dose schedule might be that it could reduce treatment compliance. However, the effect of once-daily dosing on adherence has been shown to be modest in other therapeutic areas (e.g. only a 2.9% increase in adherence was seen in a meta-analysis of antiretroviral drugs) [17]. Moreover, it could also be argued that a reduction in toxicity could help maintain treatment adherence and even prevent dose reductions or treatment discontinuation, which are common in everolimus treatment [3, 7].

Limitations of the current study include its limited size and duration and the fact that patients could have already received everolimus prior to enrollment. Although the endpoint of a reduced C _max/C _min ratio has been achieved, the relationship between this ratio and toxicity cannot be assessed based on these data.

An alternative strategy to manage toxicity could be to individualize the everolimus dose based on measured C _min levels, also known as therapeutic drug monitoring. Given the high interpatient variability in exposure [10] and the established exposure–efficacy and exposure–toxicity relationships, this would be a rational approach. Moreover, this has already been implemented in everolimus therapy in transplantation medicine [18] and pediatric oncology [16]. Twice-daily dosing could be combined with therapeutic drug monitoring to further manage the pharmacokinetic exposure in everolimus treatment, and, interestingly, in transplantation medicine, everolimus is already routinely administered in a twice-daily schedule, albeit at a lower total dose [18].

This randomized, pharmacokinetic, crossover study in cancer patients indicates that switching from a 10 mg once-daily to a 5 mg twice-daily dose schedule significantly reduces everolimus C _max without negatively impacting C _min or AUC_24. These results merit further investigation of the everolimus twice-daily schedule in oncology in an effort to reduce everolimus toxicity while maintaining treatment efficacy.