A Fresh Look at Echinocandin Dosing

Home , Anidulafungin, Caspofungin, Echinocandin, Micafungin

J Antimicrob Chemother 2018; 73 Suppl 1: i44–i50 doi:10.1093/jac/dkx448

We can do better: a fresh look at echinocandin dosing

Justin C. Bader1, Sujata M. Bhavnani1, David R. Andes2 and Paul G. Ambrose1*

1Institute for Clinical Pharmacodynamics (ICPD), Schenectady, NY, USA; 2University of Wisconsin, Madison, WI, USA

*Corresponding author. Institute for Clinical Pharmacodynamics (ICPD), 242 Broadway, Schenectady, NY 12305, USA. Tel: !1-518-631-8101; Fax: !1-518-631-8199; E-mail: [email protected]

First-line antifungal therapies are limited to azoles, polyenes and echinocandins, the former two of which are associated with high occurrences of severe treatment-emergent adverse events or frequent drug interactions. Among antifungals, echinocandins present a unique value proposition given their lower rates of toxic events as compared with azoles and polyenes. However, with the emergence of echinocandin-resistant Candida species and the fact that a pharmacometric approach to the development of anti-infective agents was not a mainstream practice at the time these agents were developed, we question whether echinocandins are being dosed optimally. This review presents pharmacokinetic/pharmacodynamic (PK/PD) evaluations for approved echinocandins (anidulafungin, caspofungin and micafungin) and rezafungin (previously CD101), an investigational agent. PK/PD-optimized regimens were evaluated to extend the utility of approved echinocandins when treating patients with resistant isolates. Although the beneﬁts of these regimens were apparent, it was also clear that anidulafungin and micafungin, regardless of dosing adjustments, are unlikely to provide therapeutic exposures sufﬁcient to treat highly resistant isolates. Day 1 probabilities of PK/PD target attainment of 5.2% and 85.1%, respectively, were achieved at the C. glabrata MIC90 (0.12 mg/L) and MIC97 (0.06 mg/L) values, respectively, for these agents. However, evaluations of rezafungin demonstrated high probabilities of target attainment over 4 weeks of therapy (100%) after administration of a single-dose regimen at the MIC90 of 0.06 mg/L. This signals that although existing therapies are not optimal to treat resistant organisms, more potent new echinocandins (relative to achievable drug exposures) may be on the horizon.

Introduction glucan synthesis, their primary structural component, through inhibition of the 1,3-b-D-glucan synthase enzyme. These agents Clinicians today are provided a limited armamentarium regarding provide a safe and effective alternative to more traditional polyene the therapies available to treat mycoses. Treatments are effec- and azole therapies. The first of these agents, caspofungin, tively limited to three drug classes: azoles, echinocandins and received approval from the US FDA in 2001, which was later fol- polyenes. Of these, the polyenes act by forming membrane pores lowed by approvals for micafungin and anidulafungin in 2005 and through binding to ergosterol, a key structural component in fun- 2006, respectively. In the nearly two decades these agents have gal cell membranes. Thus, membrane permeability is increased, been available, no changes have been made to their recom- causing the leakage of intracellular potassium and other mole- mended dosing regimens.4 cules. Azoles destabilize fungal cell membranes by preventing Given that a pharmacometric approach to the development of C-14a demethylation of lanosterol through binding to fungal cyto- anti-infective agents was not a mainstream practice at the time chrome P-450 enzymes, resulting in decreased ergosterol produc- echinocandins were developed, the dosing of echinocandins may tion. However, the mechanisms by which these agents act present not be optimized for pharmacokinetics/pharmacodynamics a double-edged sword. Non-specific binding of polyenes to choles- (PK/PD). Moreover, the use of echinocandins5 has steadily 1 terol in mammalian cell membranes and of azoles to human increased and the prevalence of echinocandin resistance among cytochrome P-450 enzymes2 may result in drug-related toxicities. Candida species,6–14 though still relatively rare, has also increased Development of therapies specific for fungi has been challenging since these agents were introduced to the clinic. These trends are given that, unlike bacteria, fungi are eukaryotic organisms. Thus, especially troubling in light of recent clinical studies which have the targets for these agents are more likely to resemble those indicated that treatment failures and patient mortality increase found in humans.3 with caspofungin MIC.15,16 Thus, we are left questioning whether Echinocandins are unique in that they target the cell wall. Given current dosing recommendations for these agents provide thera- that this component is absent from mammalian cells, echinocan- peutic drug concentrations in patients with infections due to resist- dins are less likely to interact with human cells and therefore result ant Candida. Herein, we will delve into this question and consider in fewer toxic events as compared with azoles and polyenes. echinocandin dosing strategies, both traditional and novel. But we These agents reduce the integrity of fungal cell walls by disrupting must first review how antimicrobial dosing regimens are derived.

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r2 = 0.94 r2 = 0.97 2 2 2

1 1 1 cfu/kidney cfu/kidney cfu/kidney 10 10 10 0 0 0

–1 –1 –1 Change in log Change in log Change in log –2 –2 –2 100 1000 10 000 100 000 1 10100 1000 10 000 0 25 50 75 100 C T AUC:MIC ratio max:MIC ratio % max>MIC

Figure 1. Relationships between change in log10 cfu from baseline at 24 h and anidulafungin total-drug AUC:MIC ratio, Cmax:MIC ratio and %T.MIC. This ﬁgure is based on data from Andes et al.19

Dose fractionation: the first step towards dosing regimens. Total doses of 1.25, 5, 20, 80 or 320 mg/kg regimen selection were administered over 96 h as one, two, four, or six divided doses (i.e. doses were given every 96, 48, 24 or 16 h, respectively).19 In essence, an optimized dosing regimen is one which best balan- Using Hill-type models, relationships between the change in fungal ces the competing needs for high efficacy and low toxicity. Early density in homogenized tissue relative to baseline and the three investigations for dose selection are ideally performed pre- PK/PD indices discussed previously were evaluated. As shown in clinically. In vivo and in vitro infection models are utilized to charac- Figure 1, these data demonstrated that fungal density was most terize the relationship between drug exposures and fungal density closely associated with anidulafungin AUC:MIC and Cmax:MIC (primarily measured as log10 cfu). Critical to our understanding of ratios, indicating that this agent exhibits a concentration- this relationship is recognizing the fact that not all antifungal dependent pattern of fungicidal activity. The ideal regimen for this agents exhibit the same patterns of fungicidal activity.17 agent is one that optimizes anidulafungin exposures to maximize Some drugs exhibit what is known as concentration-dependent fungal killing while minimizing drug-induced toxicities. activity, meaning that, as drug concentrations increase, so too do 18 the rate and extent of pathogen killing. This pattern of activity is Front-loading: answering the unexplored best captured by expressing drug exposures indexed to a pathogen’s degree of susceptibility to the agent in question. The PK/PD questions of efficacy indices frequently assessed to evaluate such agents are the While data from dose-fractionation studies lay the foundation for AUC:MIC and Cmax:MIC ratios. Conversely, for some drugs the rate the determination of target exposures and provide preliminary and extent of bacterial killing are not increased over a wide range guidance for the selection of maintenance therapy (i.e. the data of drug concentrations. The activity of these agents is time inform dosing frequency and magnitude), these studies are not dependent and their effects are largely dependent upon the time designed to support the selection of the optimal duration of ther- during which exposures remain above a target threshold. This is apy. Moreover, they cannot assess what impact a loading dose will best captured by the percentage of time that drug concentrations have on efficacy. remain above a pathogen’s MIC (%T.MIC). Collectively, the However, Okusanya et al.20 elegantly demonstrated how these AUC:MIC ratio, Cmax:MIC ratio and %T.MIC are the three most factors impact efficacy of azithromycin in an evaluation of gerbils common PK/PD indices used to characterize the relationship with Haemophilus influenzae middle ear infections. A front-loading between exposure and efficacy. experiment design was utilized, in which each animal was Determining the PK/PD index most associated with efficacy for administered intermittent bolus doses to simulate human a given antifungal allows investigators to determine the magni- concentration–time profiles for one of three azithromycin dosing tudes of these indices associated with different levels of bacterial regimens containing the same total dose: (i) a 500 mg loading reduction (i.e. PK/PD targets for efficacy). Such information can be dose on Day 1 followed by 250 mg daily; (ii) 500 mg daily for used to identify PK/PD-optimized dosing regimens for develop- 3 days; or (iii) a single 1500 mg dose on Day 1. Plasma concentra- ment. The determination of the PK/PD index is made by conducting tions and cfu counts were measured pre-dose and at 1, 2, 3, 4, 5, 6, dose-fractionation studies, whereby fungicidal activity is evaluated 12, 24, 48 and 72 h to facilitate the creation of PK and PK/PD mod- by administering the same total dose of an agent over a multitude els. The observed and model-predicted data generated are shown of dosing intervals. Multiple doses are administered in this manner in Figure 2. These data revealed that killing was most extensive to obtain a range of exposures. and rapid following administration of the single azithromycin Figure 1 shows data obtained from a dose-fraction study con- 1500 mg dose, suggesting that optimal outcomes could be ducted by Andes et al.,19 in which neutropenic mice were infected achieved by administering a single dose of azithromycin, which with Candida glabrata and administered one of 20 anidulafungin maximizes exposures early in therapy and produces sustained

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Single-dose regimen 3 day regimen 5 day regimen 10.0 600 10.0 600 10.0 600 cfu cfu 500 cfu 500 500 10 10 10 % of Baseline Kdo % of Baseline Kdo 7.5 7.5 % of Baseline Kdo 7.5

400 400 400 5.0 5.0 5.0 300 300 300

2.5 2.5 2.5 200 200 200 Concentration (mg/L) / log Concentration (mg/L) / log Concentration (mg/L) / log 0.0 100 0.0 100 0.0 100 0 20406080 0204060 80 0 20 40 60 80 Time (h) Time (h) Time (h) Points = Observed Data | Lines = Model-Predicted Data

Red = Plasma Concentrations | Black = Log10 cfu

Figure 2. Plots of gerbil plasma concentration–time and changes in bacterial density superimposed over observed data and the model-predicted function for the rate of bacterial death.

therapeutic concentrations to maintain antimicrobial activity. Rethinking echinocandin dosing These analyses also served to demonstrate that, for some agents, the shape of the drug exposure is a determinant of efficacy. As previously stated, the dosing of echinocandins has remained largely unchanged since these agents were brought to the clinic, whereas echinocandin-resistant Candida spp. have been increas- When does exposure shape matter? ingly emerging over this period.6–14 The most notable of these The hypothesis that the shape of the drug exposure can impact resistant pathogens has been C. glabrata, owing to this organism’s 29 efficacy was also explored for the lipoglycopeptide oritavancin.21 natural predisposition for expressing resistance mutations. In that evaluation, the authors provided support for the use of an As mentioned above, increases in C. glabrata MIC values have been 15,16 oritavancin 1200 mg single-dose regimen for the treatment of associated with increases in treatment failures and mortality. acute bacterial skin and skin structure infections (ABSSSIs), which Consequently, the consideration of treatment options for patients is now an approved treatment for such patients. This regimen was with these resistant organisms has become a priority. chosen with two considerations in mind, the first being that orita- Clinical studies have been conducted to establish differences in vancin demonstrates concentration-dependent bacterial killing. efficacy between approved caspofungin and micafungin dosing Second, oritavancin exhibits a very long terminal half-life of regimens and regimens with higher doses (70 mg followed by 245 h.22 Azithromycin, for which the PK/PD index associated with 50 mg daily versus 150 mg daily and 100 mg daily versus 150 mg 30–32 efficacy is AUC:MIC ratio23,24 and which has a relatively short ter- daily, respectively). However, none of these studies demon- minal half-life of 68 h, also exhibits these characteristics.25 strated statistically significant differences in clinical outcomes Consequently, without the use of a loading dose, it would take between the standard and high-dose treatment regimens. These weeks for these agents to achieve steady-state concentrations. results are not surprising given that treatment differences are Conversely, when a front-loaded regimen is administered, the more likely to be seen when treating patients with isolates at the maximal rate and extent of bacterial killing can be achieved early upper end of the MIC distribution, a population that is often too in therapy, as previously shown with azithromycin.20 limited in sample size. When the MIC distributions for both agents The applicability of this concept to clinical practice was demon- were reported for these studies, the drug concentrations required strated through the results of a Phase 2 study in which 302 patients to inhibit 90% of isolates (MIC90)were0.03 mg/L across all non- with ABSSSI were randomized to receive one of three oritavancin C. parapsilosis spp.30,31 These data suggest that exposures for both treatment regimens: (i) 200 mg daily for 3–7 days; (ii) 800 mg on treatment regimens should have exceeded non-clinical PK/PD tar- Day 1 plus 400 mg on Day 5 (at the discretion of the treating gets for the majority of isolates. However, the number of patients physician); or (iii) a single 1200 mg dose on Day 1.26 Evaluation of in clinical studies infected with pathogens with higher MIC values is data from patients across multiple analysis populations in this study often too limited to discriminate between dosing regimens. Given revealed that clinical outcomes improved as the magnitude of expo- the limitations of the data described above, results of PK/PD target sures early in therapy increased. Data from two Phase 3 studies attainment analyses can be utilized to forecast the efficacy of dif- served to confirm the efficacy and safety of the single 1200 mg ori- ferent dosing regimen at fixed MIC values, including those that are tavancin dosing regimen in patients with ABSSSI.27,28 higher but less frequently encountered. The above-described data demonstrate that the shape of expo- Recent analyses that we conducted33 served to assess the sure impacts efficacy when an antibacterial agent exhibits a adequacy of approved echinocandin dosing regimens for the concentration-dependent pattern of bacterial killing and has a long treatment of patients with candidaemia in the context of contem- half-life in plasma. Thus, such attributes together provide a basis for porary in vitro surveillance data for C. glabrata.34 In that evalua- assessing candidate anti-infective agents for single or extended- tion, Monte Carlo simulation was used to generate daily AUC interval dosing regimens. We can now enquire as to whether or not values for simulated patients following the administration of these same principles can be applied to antifungal agents. 200 mg of anidulafungin followed by 100 mg daily, 70 mg of

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caspofungin followed by 50 mg daily, or 100 mg of micafungin dependent pattern of fungal killing both in vivo and in vitro.17,38 daily. The simulated AUC values obtained from these analyses Moreover, anidulafungin and caspofungin exhibit relatively long ter- were evaluated relative to AUC:MIC ratio targets associated with minal half-lives in human plasma (40–50 h).39,40 Conversely, mica- net fungal stasis to assess the likelihood of achieving PK/PD targets fungin exhibits a more typical half-life of 13–17 h.41 However, associated with efﬁcacy among highly resistant isolates.35 despite micafungin’s short half-life relative to anidulafungin and Relative to MIC90 values, caspofungin and micafungin were likely caspofungin, murine disseminated candidiasis model studies have to achieve therapeutic drug exposures in the majority of simulated been conducted utilizing humanized single-dose and extended- patients, whereas anidulafungin was unlikely to achieve target interval dosing regimens.42,43 Although these studies showed exposures in the majority of simulated patients (Figure 3). promise for the use of single and extended-interval dosing of mica- However, when evaluating micafungin one dilution above the fungin, clinical data evaluating such regimens are lacking. MIC90 (0.06 mg/L), the percentage probabilities of PK/PD target However, recent work has been conducted to demonstrate the attainment were less favourable, ranging from 10.3% to 49.9% potential for single-dose administration of rezafungin acetate over Days 1–14. These results are in contrast with caspofungin’s (previously CD101), a novel echinocandin in Phase 2 of develop- highly favourable percentage probabilities of PK/PD target attainment for the treatment of candidaemia and invasive candidiasis ment when evaluated relative to one dilution above the C. glabrata that has activity against Aspergillus and Candida spp., including 44 MIC90 of 0.12 mg/L (100% across the entire 14 day treatment azole- and echinocandin-resistant isolates. Lakota et al. eval- period). In response to these ﬁndings, PK/PD-optimized dosing reg- uated rezafungin in a neutropenic murine disseminated candidia- imens were proposed with the goal of providing therapeutic expo- sis model, in which rezafungin 2 mg/kg was administered using sures early in therapy and maintaining these over a 2 week course either a single-dose, twice weekly, or daily regimen. Across these of therapy. Increasing the anidulafungin dosing to 300 mg fol- regimens, reductions in fungal density 168 h post-dose increased lowed by 200 mg resulted in percentage probabilities of PK/PD tar- in parallel with the intensity of early exposures (Figure 4). The get attainment across Days 1–14 improving from 0%–0.95% to 5%–54.3% for approved dosing at the C. glabrata MIC90 of 0.12 mg/L. Similarly, improvements were observed when a micafungin regimen of 200 mg followed by 150 mg daily was evaluated 1 (from 10.3%–49.9% to 85.1%–87.5%) at the C. glabrata MIC97 of 0.06 mg/L. These results suggest that the current dosing regimens 0

for caspofungin and micafungin are able to combat C. glabrata iso- cfu at 168 h 10 lates up to and including the MIC90 values for these agents. –1 However, this was not the case for micafungin if the C. glabrata MIC90 shifts upward even if only by one dilution. This is concerning given that resistance rates among C. glabrata isolates have been –2

reported to be as high as 12% and acquired echinocandin resist- Change in log ance has been observed among various Candida spp.,36,37 all of –3 which support the need for new therapies. Vehicle Single dose Twice weekly Daily One question that remains is whether the approved echinocan- Figure 4. Mean (bar) and range (error bars) change in log10 cfu from dins can achieve greater efﬁcacy when administered in larger baseline at 168 h after administration of 2 mg/kg rezafungin by a fractio- quantities over extended intervals. It is well established that nation schedule. This ﬁgure is reproduced from reference 44 with kind currently approved echinocandin agents exhibit a concentration- permission from the American Society for Microbiology.

Anidulafungin 200 mg followed by Caspofungin 70 mg followed by 100 mg q24h (MIC=0.12) Micafungin 100 mg q24h (MIC=0.03) 50 mg q24h (MIC=0.06) 20 20 400

15 15 300 :MIC ratio :MIC ratio :MIC ratio 0–24 0–24 0–24

10 10 200

5 5 100 Free–drug plasma AUC Free–drug plasma AUC Free–drug plasma AUC

0 0 0 12345678 9 10111213 14 12345678 910111213 14 12345678 910111213 14 Day of therapy Day of therapy Day of therapy

Figure 3. Distributions of free-drug plasma AUC:MIC ratio based on C. glabrata MIC90 values (mg/L) for each respective FDA-approved echinocandin administered. The boxplot whiskers denote the 5th and 95th percentiles among simulated patients. Free-drug plasma AUC:MIC ratio PK/PD targets associated with net fungal stasis for each echinocandin are indicated by dashed lines.

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Rezafungin 400 mg × 1 Rezafungin 400 mg weekly × 3 Rezafungin 400 mg × 1 week followed by 200 mg weekly × 2 1000 1000 1000

100 100 100 AUC:MIC ratio AUC:MIC ratio f f AUC:MIC ratio f

10 10 10 Weekly Weekly Weekly

1 1 1 1234 1234 1234 Week of therapy Week of therapy Week of therapy

Figure 5. Distributions of free-drug AUC0–168:MIC ratios for C. glabrata based on MIC90. The boxplot whiskers denote the 5th and 95th percentiles among simulated patients. The rezafungin free-drug plasma AUC0–168:MIC ratio PK/PD target associated with a 1 log10 cfu reduction in C. glabrata from baseline is indicated by dashed lines.

same exposure was administered to each animal, but the magni- associated with daily administration of these doses are lacking to tudes of fungal killing varied greatly, indicating that the shape date. Regardless, it is evident that these agents, regardless of dos- of rezafungin exposure impacts efficacy. This should come as no ing adjustments, are unlikely to provide therapeutic exposures to surprise considering rezafungin, like other echinocandins, demon- treat isolates with elevated MIC values (e.g. those one dilution 45 strates a concentration-dependent pattern of fungal killing and above the MIC90). Consequently, we evaluated rezafungin, a novel exhibits a very long half-life in humans (133 h).46 echinocandin, and conducted PK/PD target attainment analyses to In order to translate these findings to humans infected with demonstrate the potential to administer a single-dose regimen C. glabrata, we conducted PK/PD target attainment analyses utilizing and provide exposures associated with efficacy for up to 4 weeks. the methodology previously employed in our evaluation This finding is significant in that such a regimen presents the 33 of approved echinocandins. A rezafungin free-drug plasma opportunity to deliver drug exposures in a PK/PD-optimized man- AUC0–168:MIC ratio target associated with net fungal stasis of 0.5 ner, improve patient compliance and reduce the resources 47 was utilized. Three dosing regimens were evaluated over 4 weeks: required for therapeutic drug monitoring over a long treatment (i) 400 mg single dose; (ii) 400 mg weekly for 3 weeks; and period. In summary, existing echinocandin regimens can be PK/PD (iii) 400 mg % 1 for Week 1 followed by 200 mg weekly for 2 weeks. optimized to better balance the competing needs for high efficacy Each of the dosing regimens evaluated performed well at the and low toxicity when treating patients with resistant Candida iso- 48 C. glabrata MIC90 of 0.06 mg/L, including the single-dose 400 mg lates. There may also be an opportunity in the future to utilize reza- regimen. This regimen achieved percentage probabilities of PK/PD fungin and administer it as a single-dose regimen. target attainment of 100% across Weeks 1–4 at this high MIC benchmark. In order to further evaluate these dosing regimens, PK/PD target attainment analyses were conducted utilizing a Funding free-drug plasma AUC:MIC0–168 ratio target associated with a This article is part of a Supplement sponsored by Cidara Therapeutics, 1log10 cfu reduction in C. glabrata of 2.94, and as described above for the net fungal stasis endpoint, all regimens achieved probabilities Inc. Editorial support was provided by T. Chung (Scribant Medical) with funding from Cidara. of PK/PD target attainment of 100% across Weeks 1–4 (Figure 5).

Concluding remarks Transparency declarations Herein, we described PK/PD target attainment analyses as a mech- The Institute for Clinical Pharmacodynamics, Inc. (J. C. B., S. M. B. and P. G. anism to evaluate labelled doses of approved echinocandins in the A.) has received research support from and/or provides consulting for context of contemporary in vitro surveillance data and to ‘pre- Achaogen Inc., Actelion Pharmaceuticals, Actavis Generics, AiCuris GmbH, screen’ revised regimens prior to conducting clinical assessments. Arsanis Inc., Basilea Pharmaceutica, Cellceutix Corporation, Cempra The benefits of evaluating additional regimens were apparent in Pharmaceuticals, Cidara Therapeutics Inc., Contrafect Corporation, extending the utility of micafungin, which has been safely adminis- Debiopharm International SA, Emergent, Entasis Therapeutics, Geom tered up to doses of 900 mg with limited occurrences of serious Therapeutics, Inc., GlaxoSmithKline, Horizon, Insmed Inc., Kalyra Pharmaceuticals, The Medicines Company, Meiji Seika Pharma Co., Ltd., adverse events,49,50,51 against C. glabrata up to the MIC value of 90 Melinta Therapeutics, The Menarini Group, Merck Sharpe & Dohme., 0.03 mg/L. However, the revised anidulafungin dosing regimen Nabriva Therapeutics, Naeja RGM Pharmaceuticals Inc., Nexcida presented was not predicted to result in clinically meaningful Therapeutics, Inc., Northern Antibiotics, Novartis International, NuCana increases in the likelihood of achieving efficacious drug exposures. Biomed, Paratek Pharmaceuticals, Pernix Therapeutics, Polyphor Ltd., Moreover, the doses included in this regimen, 200 and 300 mg, Polypid Ltd., Prothena Corporation, Regeneron Pharmaceuticals, Roche have only been assessed when administered intermittently over Bioscience, Shionogi, Inc., Sofinnova Ventures, Inc., Spero Therapeutics, 48 and 72 h intervals, respectively.52 Thus, the safety data Takeda Pharma, Theravance Biopharma Pharmaceutica, Tetraphase

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