Echinocandin Dosing Considerations in Obese Patients: A Review
Obesity significantly impacts the pharmacokinetics (PK) of antifungal drugs like echinocandins, including volume of distribution (Vd) and clearance. However, despite these PK differences, current clinical evidence generally does not support the need for universal dose adjustments in obese patients. Clinicians should consider personalized dosing based on patient characteristics, infection severity, and specific drug properties due to echinocandins' favorable safety profiles.
Obesity is a worldwide epidemic and widespread in the US, affecting over one third of the population. According to the Centers for Disease Control and Prevention (CDC), all US states have an obesity prevalence that exceeds 20% and obesity disproportionately affects certain geographic, socioeconomic, ethnic, and racial groups.1 Obesity is an independent risk factor for various types of infections as well as poorer infection-associated clinical outcomes.2
Obesity has significant effects on the pharmacokinetics (PK) of various anti-infective drugs, including antifungals, with two of the most important being volume of distribution (Vd) and clearance. Vd generally increases with obesity as a result of increased adipose and lean tissue mass, particularly for lipophilic and highly protein bound drugs. This increased Vd may necessitate higher individual doses and, in particular, loading doses. Additionally, wider variability may be seen in overall exposure in obese patients for drugs dosed by weight, increasing risk of both over- and underdosing. Clearance may be increased in obese patients due to increased renal mass and renal blood flow. However, clearance can also be affected by comorbid conditions associated with obesity like chronic kidney or liver disease. Variations in the clearance of obese patients may affect maintenance dosing requirements.3
Echinocandins are fungicidal against Candida species and exhibit free-drug 24-hour area under the curve relative to the organism mean inhibitory concentration (fAUC/MIC)-dependent activity. fAUC/MIC targets were originally established in murine models then subsequently validated in retrospective human studies. Species-specific targets for echinocandins are fAUC/MIC>20 for C. albicans and fAUC/MIC>7 for C glabrata and C parapsilosis.4
This review aims to provide echinocandin dosing considerations in obese patients from the available literature.
Anidulafungin
Anidulafungin demonstrates linear PK with typical doses and protein binding approximating 99%.5 Anidulafungin is generally given intravenously (IV) as a loading dose of 200 mg followed by a maintenance dose of 100 mg daily for most indications and 200 mg daily for endocarditis or cardiac device infections.6 Anidulafungin clearance is unique amongst the echinocandins in that it undergoes non-hepatic spontaneous biodegradation.
Liu et al studied pooled patients from phase 2 and 3 clinical trials to assess the impact of obesity on clinical outcomes and anidulafungin PK parameters. Included for analysis were 262 patients. Weight was found to be modestly negatively associated with decreased AUC but not to a clinically significant degree. When comparing patients at the extremes of weight (40 kg vs. 150 kg), similar clinical efficacy and safety outcomes were observed.7 Hutton et al, in a retrospective study of 173 critically ill patients with candidemia treated with anidulafungin, found no difference in mortality between obese and non-obese patients.8
Other PK analyses have shown variable results. Wasmann et al, in a single-dose PK study of 20 healthy obese and non-obese volunteers found that obese patients had a lower AUC due to increased clearance and Vd, though these patients did not have clinical disease.9 Similarly, Luque et al in 23 critically ill patients with invasive fungal infections and Dowell et al in 225 patients with serious fungal infections found weight was positively associated with clearance.10,11 Conversely, Liu et al in a population PK study of 454 patients with invasive aspergillosis and Bruggemann et al in a PK study of 36 critically ill patients with invasive fungal infections found no effect between weight on anidulafungin PK.12,13
In summary, multiple clinical studies have found no difference in clinical outcomes between obese and non-obese patients treated with anidulafungin. Additionally, PK studies have had mixed findings and even those with detectable signals have acknowledged unclear clinical significance. Thus, the data does not appear to support dose adjustments of anidulafungin for obese patients.
Caspofungin
Caspofungin generally displays linear PK with conventional doses and protein binding is high, exceeding 90%.5 Caspofungin is traditionally given as a loading dose of 70 mg IV once followed by a 50 mg IV daily maintenance dose thereafter. A higher dosing regimen of 150 mg daily is used for endocarditis or cardiac device infections.6 Caspofungin, similar to other echinocandins, is generally well tolerated even at higher doses (ie, 150 mg daily).5
Ryan et al performed a post hoc pooled analysis of patients from phase 3 and 3 clinical trials of caspofungin to assess comparative efficacy and safety between obese and non-obese patients. In total, 1,134 patients across nine trials were evaluated, 163 (14%) were obese and 312 (28%) were overweight. The authors found no difference in clinical success and adverse drug reactions between obese and non-obese patients. This effect held true for studies of esophageal candidiasis, invasive candidiasis, and empirical therapy. There was a signal towards poorer outcomes in studies of invasive aspergillosis, though this is not a condition for which echinocandins are generally used as monotherapy.14
Findings from PK studies of caspofungin in obese patients have been inconsistent. Two dose ranging studies conducted by Wurthwein et al and Muilwjik et al demonstrated either no impact or a detectable but clinically insignificant impact of weight on caspofungin clearance for doses between 50 to 200 mg daily. Of note, Wurthwein et al did find a 20% lower caspofungin AUC in patients weighing 80 kg vs those weighing 60 kg but this was not assessed to be sufficiently clinically meaningful given pharmacodynamic targets were still met. Both studies concluded that standard caspofungin dosing may be adequate for obese patients.5,15
However, 2 subsequently published PK studies had opposing findings. van der Elst et al in an analysis of 20 critically ill patients found a positive association between weight (defined overweight as ≥80 kg) and caspofungin clearance as well as Vd. Based on these findings, the authors recommended a weight-based dosing regimen of 1 mg/kg/day.16 Martson et al in a study of 15 critically ill patients found a similar association (defined overweight as ≥120 kg) and recommended a loading dose of 2 mg/kg followed by a maintenance dose of 1.25 mg/kg/day to optimize AUC.17
Taken together, there does not appear to be strong clinical evidence to support universally increasing dosing of caspofungin in obese patients. Obesity does not appear to impact clinical outcomes for patients with invasive and non-invasive candidiasis treated with caspofungin. That said, findings from PK analyses suggest risk of inadequate exposure, particularly in critically ill obese patients. Given the reliable safety profile of caspofungin and lack of dose-dependent toxicity in doses up to 150 mg daily, clinicians may consider a modest dose increase (eg, 70 mg daily) on a case-by-case basis in critically ill patients with severe candida infections receiving 50 mg daily dosing. A referenceable weight cutoff is used by the European Medicines Agency, which recommends using a maintenance dose of 70 mg daily (instead of 50 mg daily) in patients weighing 80 kg or greater.18
Micafungin
Micafungin, the most commonly used echinocandin in clinical practice, exhibits linear PK and has high protein binding at >99%.19,20 PK/pharmacodynamic (PD) targets have been defined in patients with invasive candidiasis or candidemia based on AUC/MIC ratio.19 Micafungin is generally dosed at 100 – 150 mg IV every 24 hours with 150 mg designated for esophageal candidiasis. Data from two randomized, controlled phase 3 clinical trials found an AUC/MIC ratio breakpoint between 5,000 and 12,000 to have a 98% success rate for all Candida species tested, excluding Candida parapsilosis.21
Only one study has assessed the impact of obesity on micafungin clinical effectiveness.22 In this retrospective cohort study of 132 adult patients, no significant difference in clinical improvement or all-cause mortality was observed between obese and non-obese patients who received micafungin or caspofungin. The authors concluded further research in prospective, multicenter, larger study populations is needed.
While only one study assessed clinical outcomes, six PK studies have been completed that will be briefly summarized.20,23-27 Of these studies, four recommend micafungin dose increases with variations on the use criteria. Gumbo et al evaluated 62 hematopoietic cell transplant patients and concluded that patients with weight > 66.3 kg had increased clearance and decreased AUC, thus recommending 150 mg/day if above this weight cutoff.23 Interestingly, while providing a cutoff based on weight, the findings were lower than obesity definitions. This could be augmented renal clearance due to the population or other factors that impact PK discussed later in the review. Hall et al utilized PK data from 36 healthy volunteers and recommend, similarly to Gumbo et al, dose increases in patients with weight > 66 kg. Interestingly, they found a poor correlation between BMI and clearance of micafungin.24 Maseda et al performed a PK/PD study to evaluate probability of micafungin AUC/MIC target attainment in obese and morbidly obese ICU patients. BMI for all patients was > 45 kg/m2. Upon Monte Carlo simulation, the authors showed that the standard 100 mg micafungin dosing provided inadequate coverage for Candida species. They recommend specific dosing based on Candida species and weight. For Candida albicans, they recommend 150 mg/day for obese patients up to 115 kg and 200 mg/day in patients over 115 kg. For C glabrata, the recommendation is 200 mg/day for obese patients up to 115 kg, but no recommendation for patients > 115 kg.26 Lastly, Wasmann et al investigated 24 healthy volunteers with BMI > 40 kg/m2 and found increased clearance, Vd, and low AUC. The following recommendations were provided in order to reach micafungin’s PD target: for patients > 125 kg and infected Candida species with a micafungin MIC of 0.016 µg/mL provide a dose of 200 mg/day; while if the MIC is 0.032 µg/mL, increase the micafungin dose to 300 mg/day.20
Controversially, Tabata et al and Lempers et al both performed PK studies and concluded micafungin dose increases were not necessary.25,27 Tabata et al evaluated 179 patients and healthy volunteers and found that increasing weight was not associated with a reduction in micafungin exposure.27 Similarly, Lempers et al conducted a small PK study of 20 ICU patients and found micafungin PK values including clearance, Vd, and AUC, were not impacted by weight or BMI. 25
In summary, the majority of the studies have shown lower exposures of micafungin in obese patients, but the one available clinical study found no impact on clinical outcomes reported. Clinicians can utilize these studies to tailor micafungin dosing to their patients' characteristics such as weight and infecting Candida species, however, further research on patient outcomes is needed.
Rezafungin
Rezafungin is a novel echinocandin with a prolonged half-life of ~133 hours allowing for extended-interval dosing; the approved dosing scheme includes a 400 mg loading dose IV followed by 200 mg IV weekly infusions. Few studies are currently available, however a poster abstract presented at IDWeek 2020 by Vazquez et al utilized STRIVE Phase 2 study data to evaluate outcomes stratified by BMI (< 30 or >30 kg/m2).28 Overall response, mycological response, and investigator assessment of clinical cure was similar between the two groups with no concerning safety trends observed. However, following one dose of rezafungin 400 mg, the ranges of AUCs by BMI category observed a minor mean difference of ~20%, lower for those with BMI > 30 kg/m2. Regardless, the authorship concluded from these results that dose adjustments in obese patients are not necessary. Initial findings follow similarly to other echinocandins with no signal of decreased clinical efficacy, but PK evaluation suggests lower exposure with elevated BMIs. More data is needed as rezafungin is incorporated further into clinical practice.
Additional Considerations
Could TDM optimize targeted dosing rather than “a one dose fits all” approach for obese patients? Overall, TDM data is sparse. Evaluation of AUC/MIC has been suggested by models, however utilization in patients is lacking.29 Vena et al evaluated troughs via high performance liquid chromatography for micafungin, anidulafungin, and caspofungin.30 Target therapeutic trough goal was set to > 1µg/mL based on findings from Stone et al.31 They demonstrated that levels were variable between patients, however, patients with troughs at their designated target were associated with favorable clinical outcomes.30 As of yet, there is insufficient evidence to recommend when to utilize TDM and further studies are needed.
Additional considerations for increasing echinocandin doses aside from obesity do exist. Critical illness, continuous renal replacement therapy (CRRT), and extracorporeal membrane oxygenation (ECMO) have been identified in literature.32-36 For example, sequestration by membrane adsorption within the ECMO circuit causes increased Vd and thus lowers exposure. Increased dosing of micafungin has been suggested at 200 mg/day in these situations.34 In such cases, TDM may be of added value, but this has not been studied. Also of note, high doses of echinocandins have been shown to be well-tolerated at increased doses.37 Consideration of the patient in entirety is crucial for optimal care and dosing considerations and although conflicting data, the cons (safety and tolerability) are little to none.
Notably for this review, while controversial findings have previously been described regarding patient outcomes, obesity has been associated with worse outcomes in patients with invasive candidiasis. In a retrospective cohort study of patients with candidemia conducted by Barber et al, obese patients had longer durations of treatment, infection-related length of stay, and duration of candidemia though no differences in mortality of readmissions were found.38 Thus, the astute clinician should appreciate that other factors beyond PK/PD may influence outcomes in obese patients with invasive candidiasis treated with echinocandins.
Conclusion
In this review we have found that while there is robust PK evidence of decreased echinocandin exposure in obese patients, clinical outcomes have not been shown to be significantly affected. However, many of the studies had small sample sizes or various limitations. Due to echinocandins favorable safety profile and tolerability, clinicians should evaluate their patients' on a case-by-case basis on whether to utilize higher dosing. This review provides suggestions from available literature to accompany clinical judgement in providing personalized dosing of echinocandins in obese patients.
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