When dosing daptomycin, is adjusted body weight preferred over actual body weight in obese patients?

Comment by InpharmD Researcher

Per prescribing information, daptomycin has a specified dosing regimen based on total body weight, and no adjustment of daptomycin dosage is warranted in obese patients. Available literature shows there is no statistical difference in clinical or safety outcomes between daptomycin dosed actual body weight- and adjusted body weight-based dosing, even in obese patients.

Background

A critical review of the literature discussed the available evidence of antibiotic use in obese adult patients and provided a list of recommended doses and comments. For daptomycin, obese patients dosed by total body weight seem to observe higher exposure rates. However, daptomycin has a wide therapeutic index and is generally well-tolerated, which led to the authors recommending a higher dose range (up to 10 to 12 mg/kg) with ABW/adjABW to ensure treatment efficacy while balancing the risk of muscle toxicity. Monitoring of creatine phosphokinase (CPK) elevations and toxicities is still highly recommended. [1]

A 2014 review article discusses 15 weight-based antimicrobials dose strategies in obese patients including daptomycin. From six clinical trials and one case report, daptomycin dosing in obese patients appears to have similar efficacy, cost, and safety profile regardless of dosing based on ideal body weight (IBW) or adjusted body weight (AdjBW). The studies including daptomycin dosing are summarized in Table 4. Since several prospective pharmacokinetic studies advocate the use of actual body weight (ABW), a retrospective analysis recommends IBW dosing, and a case report suggests AdjBW dosing in obese patients, more studies are warranted to determine the definite dosing strategy. [2]

A 2016 review article assessed the potential pharmacokinetic (PK) changes of antimicrobials in obese critically ill patients and its impact on dosing. A total of 116 articles were included in the review. Hydrophilic antimicrobials (e.g. β-lactams, vancomycin, daptomycin) were more likely to have altered PK in critically ill obese patients. For daptomycin, an increased volume of distribution (Vd) is not considered to be clinically relevant. For lipophilic antimicrobials, total body weight was the most relevant size descriptor for the volume of distribution. However, the authors added that to date, no single size descriptor had been shown to accurately correlate with Vd and/or clearance in obese patients. Even though pharmacodynamic targets could be achieved with most of the standard dosage of antimicrobials, larger doses would likely be required for pathogens with higher minimum inhibitory concentrations. [3]

A 2019 poster presented the results of a retrospective study (N= 47; pre-protocol n= 25; post-protocol n= 22) that evaluated the use of adjusted body weight (ABW) for daptomycin dosing at a community hospital. The new dosing protocol required pharmacists to use ABW for daptomycin dosing in patients with a body mass index (BMI) > 30 kg/m^2 and/or total body weight (TBW) above 20% of their ideal body weight (IBW). No significant change in the average length of stay was noted pre- and post-protocol revision (10.4 days vs. 13.6 days) and average days on daptomycin were similar between the two groups (4.04 days vs. 3.77 days). The average creatinine phosphokinase (CPK) level was higher after implementing the revised protocol compared to the original protocol (154.32 U/L vs. 117.95 U/L); however, the higher level might be potentially due to an outlier with a CPK level of 1,620 U/L not directly associated with daptomycin use. Overall, the estimated cost of therapy was lower in the post-protocol revision group at $14,469.85 compared to $19,584.41 prior to the protocol revision, leading to an estimated cost savings of $5,115.56 during the study period. Information from this poster might be incomplete, even though results demonstrated cost savings for the institution and less unnecessary exposure to high-dose daptomycin for patients. [4]

References:

[1] Meng L, Mui E, Holubar MK, et al. Comprehensive guidance for antibiotic dosing in obese adults. Pharmacotherapy. 2017;37(11):1415-1431.doi:10.1111/jcpt.12200
[2] Polso AK, Lassiter JL, Nagel JL. Impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and comprehensive literature review. J Clin Pharm Ther. 2014;39(6):584-608. doi:10.1111/jcpt.12200
[3] Alobaid AS, Hites M, Lipman J, et al. Effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients: A structured review. Int J Antimicrob Agents. 2016;47(4):259-268. doi:10.1016/j.ijantimicag.2016.01.009
[4] Porras Jr. LM, Andre M, and Hasib S. Evaluation of a Daptomycin Dosing Protocol Based on Adjusted Body Weight at a Community Hospital. Poster presented at: 2019 Baptist Health Scholarly Showcase: Miami, FL. August 26, 2019.
Relevant Prescribing Information

The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m2) and 6 extremely obese (BMI ≥40 kg/m2) adult subjects and controls matched for age, gender, and renal function. Following administration of daptomycin for injection by IV infusion over a 30-minute period as a single 4 mg/kg dose based on total body weight, the total plasma clearance of daptomycin normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects than in nonobese controls. The AUC0-∞ of daptomycin was approximately 30% higher in moderately obese subjects and 31% higher in extremely obese subjects than in nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No adjustment of daptomycin for injection dosage is warranted in obese patients. [5]

References:

[5] Daptomycin. Prescribing information Fresenius Kabi; 2022.
Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

When dosing daptomycin, is adjusted body weight preferred over actual body weight in obese patients?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→


Please see Tables 1-7 for your response.

 

Recommended Daptomycin Dosing Regimens from Guidance Statements and Clinical Trials

Reference

Weight used for dosing

Suggested dosing/author conclusion statements

Janson [1]

Total body weight

Exposure increased by 25–30% when dose based on TBW, but still safe and tolerated in individuals ranging from 56–147 kg.

Meng [2]

Same weight-based dose but use adjusted body weight (correction factor 0.4)

Caution in renal insufficiency, dialysis. Monitor creatinine phosphokinase and signs of myopathy

Dvorchik [3]

 Total body weight

Exposure to daptomycin in obese subjects (Cmax, AUC) was increased by 25% and 30%, respectively, compared to nonobese matched controls. Daptomycin may be dosed based on total body weight, and no adjustment in daptomycin dose or dose regimen should be required based solely on obesity.

Fox [4]

 Total or adjusted body weight

The two daptomycin dosing cohorts were statistically equivalent for both clinical failure and 90-day mortality. Adjusted body weight dosing is a reasonable option for dosing obese patients with similar infection distribution given these findings of statistical equivalence for clinical failure and combined safety endpoints.

Ng [5]

 Actual or ideal body weight

ABW and IBW daptomycin dosing may provide similar clinical and microbiological outcomes, and there was no difference in clinical or microbiologic outcomes when adjusted for body mass index.

 

References:

[1] Janson B, Thursky K. Dosing of antibiotics in obesity. Curr Opin Infect Dis. 2012;25(6):634-649. doi:10.1097/QCO.0b013e328359a4c1
[2] Meng L, Mui E, Holubar MK, et al. Comprehensive guidance for antibiotic dosing in obese adults. Pharmacotherapy. 2017;37(11):1415-1431.doi:10.1111/jcpt.12200
[3] Dvorchik BH, Damphousse D. The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects. J Clin Pharmacol. 2005;45(1):48-56
[4] Fox AN, Smith WJ, Kupiec KE, et al. Daptomycin dosing in obese patients: analysis of the use of adjusted body weight actual body weight. Ther Adv Infect Dis. 2019;6:2049936118820230
[5] Ng JK, Schulz LT, Rose WE, et al. Daptomycin dosing based on ideal body weight versus actual body weight: comparison of clinical outcomes. Antimicrob Agents Chemother. 2014;58(1):88-93.

 

Daptomycin summary of studies

Citation, design

Population

Results

Safety

 Conclusions

Pai (2007)

Single-dose pharmacokinetics study

N= 14

Adult (18–50 years old), morbidly obese (BMI ≥ 40 kg/m2) matched with normal (BMI 18–25 kg/m2) female patients

Daptomycin dosed at 4 mg/kg of ABW

Cmax of 67.3 and 42.3 mg/L
(p = 0.029) and AUC0–24 of 494 and 307 mg/h/L (p= 0.002) in the morbidly obese and normal-weight patients, respectively


The relationship of Vd and total body clearance to weight was best predicted by ABW and BMI

No serious adverse events reported

 

Dosing based on ABW resulted in increased plasma Cmax and AUC0–24 values in morbidly obese subjects.

Increases were not due to differences in Vd or clearance.

Dvorchik (2005)

Open-label, single-dose, parallel-group study of pharmacokinetics

N= 25

Morbidly obese (BMI ≥ 40 kg/m2), moderately obese (BMI 25–39.9 kg/m2), and non-obese (BMI 18.5-24.9 kg/m2) patients matched by age, sex, and renal function

Daptomycin dosed at 4 mg/kg of ABW

 

Cmax of 67.0 and 53.2 μg/mL
(p= 0.030) and AUC0–∞ of 548 and 419 μg/h/mL (p= 0.004) in moderately obese and non-obese patients, respectively

Cmax of 58 and 46μg/mL (p= 0.030) and AUC0–∞ of 421 and 322 μg/h/mL (p= 0.012) in moderately obese and non-obese patients, respectively

Absolute Vd of 11.3 and 7.4 (p< 0.001) in morbidly obese and non-obese subjects, respectively

Weight-normalized (ABW) CL of 7.8 and 10.2 mL/h/kg (p= 0.045) in morbidly obese and non-obese subjects, respectively

One of seven morbidly obese patients’ adverse events determined to be unrelated to daptomycin treatment.

Six moderately obese subjects and 12 controls did not experience any adverse events.

Dosing based on ABW resulted in increased plasma Cmax, AUC0–24, and Vd values in morbidly obese subjects relative to normal-weight subjects.

Weight-normalized pharmacokinetics indicate that these differences are not just a result of increased dosing in obese patients.

Increased drug exposure does not pose a safety issue.

Bhavnani (2010)

Subset analysis of phase 3 trial

N= 108

Patients with Staphylococcus aureus bacteremia

daptomycin dosed at 6 mg/kg every day for 10–42 days

 

Elevated CPK was observed in 5.56% of patients, independent of Cmax.

Cmin ≥ 24.3 mg/L, was significantly associated with elevations in CPK (p= 0.002)

Statistically significant association with obesity (weight ≥ 111 kg) and CPK elevations (p= 0.001)

Discontinued in 3 patients with musculoskeletal effects

CPK levels returned to normal during treatment within the post-treatment follow-up period for six patients with elevated CPK

Daptomycin
Cmin ≥ 24.3 mg/L is associated with an increase in CPK.

Obese patients
(ABW ≥ 111 kg) were significantly associated with an increase in CPK.

 

Bubalo (2009)

Single-dose pharmacokinetic study

N= 29

Pharmacokinetics of daptomycin determined in oncology patients (BMI 18.8–45.9 kg/m2) with neutropenic fever

Daptomycin dosed at 6 mg/kg x ABW Q24h

Clearance of 18.9, 14.6, 11.9, and 4.3 mL/h/kg in normal-weight, overweight, obese, and morbidly
obese subjects

Drug concentrations >MIC of 0.12–0.25 μg/mL for 50–100% of the dosing interval

Drug concentrations >MIC of 0.5 for 50–100% of dosing interval in
90% of patients

All patients achieved pharmaco- dynamic target ratio of Cmax/MIC and AUC/MIC ratio for Staphylococcus pneumoniae and majority for S. aureus

  

All patients with elevated CPK levels were asymptomatic.

No patients experienced myopathy or had daptomycin discontinued due to CPK elevations.

One patient experienced rash and one had mental status change.

Daptomycin dosed at 6 mg/ kg is effective and well-tolerated.

Pea (2011)

Case report

63-year-old male, BMI 81.6 kg/m2 with severe cellulitis

Therapeutic dosing monitoring

Estimated Vd used for dose

Dose progressively varied from 1,200 mg Q48h to q36h

Serum CPK increased from baseline of 657 to a peak of 2241 units/L on day 3; normalized on day 7

Dosed based on estimated Vd, which is lower in obese patients. This supports dosing based on an AdjBW

 

Ng (2014)

Retrospective cohort study

N= 107

Compared clinical and microbiological outcomes between ABW and IBW dosing

40% of ABW and 52% of IBW patients had BMI >30 kg/m2

No difference in clinical success  (88.9% ABW, 89.1% IBW), even
after adjusting for several factors

 

No difference in number of adverse events between groups

Over 33% of patients lacked any CPK documentation during therapy

Study suggests IBW provides similar outcomes to ABW for patients with various infections and organisms.

No obese subjects included.

 

Bookstaver (2013)

Multicenter retrospective cohort study

N= 126

Hospitalized adult obese patients (BMI ≥ 30 kg/m2) who received daptomycin dose on ABW for any indication for ≥7 days

Clinical effectiveness documented in 71% of patients.

Average daptomycin dose of 6.49, 6.51, and 5.83 mg/kg in class I, class II and class III obese patients (p= 0.007)

 

CPK elevations
>1000 units/L in 8.4% of patients, and elevations >500 units/L in 13.7% of patients

Myalgias reported in 3.2% of patients

Discontinuation of therapy due to adverse drug events occurred in 6.3% of patients

One patient developed rhabdomyolysis

Elevations in CPK are increased in high-risk obese patients, but discontinuation rates remained low

Vd, volume of distribution; IBW, ideal body weight; ABW, actual body weight; AdjBW, adjusted body weight; LBW, lean body weight; BMI, body mass index; CPK, creatine phosphokinase

 

References:

Adapted from:
Polso AK, Lassiter JL, Nagel JL. Impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and comprehensive literature review. J Clin Pharm Ther. 2014 Dec;39(6):584-608. doi: 10.1111/jcpt.12200. Epub 2014 Sep 9. PMID: 25203631.

 

Daptomycin dosing in obese patients: analysis of the use of adjusted body weight actual body weight

Design

Retrospective, single-center study

N= 101

Objective

To evaluate the equivalency of clinical and safety outcomes in obese patients with daptomycin dosed on adjusted body weight versus a historical cohort using actual body weight

Study Groups

Actual body weight (ABW) (n= 50)

Adjusted body weight (AdjBW) (n= 51)

Methods

Inclusion criteria: aged ≥18 years, BMI ≥30 kg/m2, daptomycin treatment for ≥72 hours

Exclusion criteria: infections with documented retained surgical hardware or lead infections with pacemakers that were not removed, CrCl ≤ 30 mL/min at any point during the course of therapy, continuous renal replacement therapy, hemodialysis, peritoneal dialysis, microbiologic isolates non-susceptible to daptomycin

This was a single-institution retrospective review of obese patients who received daptomycin dosed on AdjBW based on a newly implemented hospital protocol (April 2014–December 2015) versus a historical cohort receiving daptomycin dosed on ABW (December 2012–2013).

Duration

AdjBW dosing data was collected between April 2014 - December 2015 

ABW dosing data was collected between December 2012 - 2013

Outcome Measures

Primary: clinical failure (development of resistance noted on subsequent culture results, recurrent signs or symptoms of infection as documented on the electronic medical record) 

Secondary: microbiologic success (one documented culture showing microbiologic eradication and no subsequent clinical failure); readmission at 90 days; mortality at 90 days

Baseline Characteristics

  

ABW (n= 50)

AdjBW (n= 51)

    

Age, years (IQR)

 51 (38 to 57) 51 (44 to 59)    

Male

 23 (46%) 26 (51%)    

White

 34 (68%) 32 (63%)    

BMI category

Class I: (30-34.9 kg/m2)

Class II: (35-39.9 kg/m2)

Class III: (≥40 kg/m2)

 

24 (48%)

11 (22%)

15 (30%)

 

14 (27%)

18 (35%)

19 (37%)

    

BMI, kg/m2 (IQR)

 35 (32 to 43) 37 (34 to 43)    

Indication

UTI

SSTI

Abscess

Osteomyelitis

Bacteremia

 

5 (10%)

8 (16%)

6 (12%)

20 (40%)

3 (6%)

 

3 (5.8%)

4 (7.8%)

6 (11.8%)

11 (21.6%)

12 (23.5%)

    

Dose category prescribed, mg/kg

Low: ≤6 mg/kg/day

Medium: 6.1-8.0 mg/kg/day

High: >8 mg/kg/day

 

41 (82%)

7 (14%)

2 (4%)

 

11 (22%)

23 (45%)

17 (33%)

    
IQR=interquartile range; UTI=urinary tract infection; SSTI=skin and soft-tissue infection

Results

 

ABW (n= 50)

AdjBW (n= 51)

Risk difference (90% CI)

Upper margin p-value

Clinical failure

 1 (2%) 3 (6.1%) 3.9 (-2.4 to 10.6) < 0.0001

Developed resistance

1 (2%)

2 (3.9%)

 1.9 (-4.6 to 7.5) < 0.0001

Antibiotic therapy modification

0 (0%)

2 (3.9%)

 4.0 (0.6 to 8.6) < 0.0001

90-day mortality

3 (6%)

2 (3.9%)

 -2.1 (-9.2 to 5.0) < 0.0001

90-day readmission

10 (20%)

5 (9.8%)

 -10.2 (-21.8 to 1.4) 0.0002

Safety Endpoint

CPK elevation

Myopathy

Rhabdomyolysis

 

2 (8%)

1 (2%)

3 (6%)

 

7 (17.5%)

3 (5.9%)

2 (3.9%)

 

9.5 (-0.1 to 22.8)

3.9 (-2.4 to 10.2)

-2.1 (-9.2 to 5.0)

 

0.2484

0.0019

< 0.0001
CI=confidence interval; CPK=creatine phosphokinase

Adverse Events

N/A

Study Author Conclusions

The two daptomycin dosing cohorts were statistically equivalent for both clinical failure and 90-day mortality. Adjusted body weight dosing is a reasonable option for dosing obese patients with similar infection distribution given these findings of statistical equivalence for clinical failure and combined safety endpoints.

InpharmD Researcher Critique

Limitations of this study include the retrospective design and single study site with a small failure rate. Additionally, there was an increased number of patients with osteomyelitis in the ABW group and bacteremia in the AdjBW group and the baseline characteristics were not matched. Overall, the results indicate that ABW or AdjBW are potential options for dosing obese patients with the caveat that those in the AdjBW category received higher doses than those in the ABW category. The AdjBW category also experienced a greater incidence of CPK elevation. 

 

References:

Fox AN, Smith WJ, Kupiec KE, et al. Daptomycin dosing in obese patients: analysis of the use of adjusted body weight versus actual body weight. Ther Adv Infect Dis. 2019;6:2049936118820230. Published 2019 Jan 30. doi:10.1177/2049936118820230

 

 Daptomycin dosing based on ideal body weight versus actual body weight: comparison of clinical outcomes

Design

Retrospective, single-center study

N= 308

Objective

To describe and compare clinical and microbiological outcomes between the actual body weight (ABW) and ideal body weight (IBW) dosing of daptomycin before and after this intervention

Study Groups

ABW (n= 63)

IBW (n= 46)

Methods

Inclusion criteria: aged ≥17 years, positive culture, received daptomycin for ≥72 hours

Exclusion criteria: endocarditis, prosthetic-device-related infections without device removal, ABW<IBW, receipt of daptomycin at an outside institution ≤24 hours of admission, causative isolates unsusceptible to daptomycin, CrCl <30 mL/min

This was a retrospective study of a single institution that adopted ideal body weight daptomycin dosing in 2010. Prior to 2010, daptomycin was dosed based on actual body weight.

Duration

2009 to 2011

Outcome Measures

Clinical success (clinical cure or improvement), clinical cure (clinical signs and symptoms resolved and/or no additional antibiotics with Gram-positive coverage), clinical improvement (required additional antibiotic therapy after daptomycin was stopped but conditions allowed for de-escalation of therapy), microbiologic success (number of patients ≥1 documented or presumed eradication)

Baseline Characteristics

  

ABW (n= 69)

IBW (n= 48)

  

Age, years

 56.9 ± 13.6 57.6 ± 12.4  

Weight, kg

 91.0 ± 24.8 91.4 ± 21.9  

BMI, kg/m2

BMI >30 kg/m2

30.9 ± 8.7

28 (40.6%)

31.0 ± 6.2

25 (52.1%)

  

Male

 37 (53.6%) 28 (58.3%)  

Infection type

Bacteremia

Skin and soft tissue

Osteomyelitis

Intraabdominal

Urinary tract

 

21 (30.4%)

26 (37.7%)

7 (10.1%)

17 (24.6%)

7 (10.1%)

 

18 (37.5%)

14 (29.2%)

1 (2.1%)

15 (31.2%)

12 (25%) 

  

Daily daptomycin dosing rates

4 mg/kg

6 mg/kg

 

39 (56.5%)

30 (43.5%)

 

27 (56.2%)

21 (43.8%)

  

Results

 

ABW (n= 69)

IBW (n= 48)

p-value

Clinical success

 56 (88.9%) 41 (89.1%) 0.97

Clinical cure

36 (57.1%)

32 (69.6%)

 0.19

Microbiological success

59 (90.8%)

43 (91.5%)

 0.48

Adverse Events

Common Adverse Events (ABW vs IBW): eosinophilia (8.7% vs 8.3%)

Study Author Conclusions

These results suggest that ABW and IBW daptomycin dosing may provide similar clinical and microbiological outcomes, and there was no difference in clinical or microbiologic outcomes when adjusted for body mass index.

InpharmD Researcher Critique

Despite the retrospective, single-center design, data was limited to what was available in the electronic medical records, and follow-up cultures and CPK monitoring were not completed for all patients. This study also lacked the power to detect significant differences or superiority in outcomes or adverse events between ABW and IBW groups.

 

References:

Ng JK, Schulz LT, Rose WE, et al. Daptomycin dosing based on ideal body weight versus actual body weight: comparison of clinical outcomes. Antimicrob Agents Chemother. 2014;58(1):88-93.

 

A Fixed versus Weight-Based Dosing Strategy of Daptomycin may Improve Safety in Obese Adults

Design

Nonparametric population pharmacokinetic analysis

N= 14

Objective

To compare daptomycin exposures and predicted safety outcomes with a simulated weight-based and fixed-dose in morbidly-obese and non-obese subjects

Study Groups

Morbidly obese (n= 7)

Normal weight (n= 7)

Methods

Inclusion criteria: adults aged 18 to 50 years; nonsmokers; body mass index (BMI) of >40 kg/m2, with a BMI between 18 and 25 kg/m2 in matched normal-weight volunteers; total body weight >200 lbs (obese subjects only); serum creatinine of <1.4 mg/dL

Exclusion criteria: hypersensitivity or intolerance to daptomycin or iodine; history of significant cardiac, neurological, thyroid, muscular, or immune disorder; absolute neutrophil count of <1×109/L; estimated CLCR of <50 ml/min/1.73 m2

Participants received a single dose of daptomycin 4 mg/kg. Plasma and urine samples were collected for pharmacokinetic analysis.

Based on the initial analysis, Monte Carlo simulations were performed to predict 6 mg/kg/day versus a fixed 500 mg daily dose in these patients.

Outcome Measures

 Pharmacokinetic parameters

Baseline Characteristics

  

Morbidly obese (n= 7)

Normal weight (n= 7)

Age, years

 36.8 ± 11 29.1 ± 12

Women

7 (100%) 7 (100%)

Race

White

Hispanic

Black

 

3 (43%)

3 (43%)

1 (14%)

 

3 (43%)

3 (43%)

1 (14%)

BMI, kg/m2

 46.2 ± 5.5  21.8 ± 1.9

Total body weight (TBW), kg

 114.3 ± 15.8 58.8 ± 6.2

Results

  

Morbidly obese (n= 7)

 Normal weight (n= 7)

Total daptomycin dose, mg

 461 ± 61 236 ± 26

Maximum concentration (Cmax), mg/L

Cmax, mg/L/kgTBW

67.3 ± 12.3

0.61 ± 0.16

42.3 ± 11.9

0.72 ± 0.18

Volume of distribution (Vd), L

 10.04 ± 2.04 7.69 ± 1.05

Clearance (CL), L/h

 0.82 ± 0.21 0.73 ± 0.14

Half-life (t1/2), h

 8.68 ± 1.67 7.72 ± 0.76

No significant differences were found in clearance, volume of distribution at steady state (Vss), or terminal half-life (t1/2) between the morbidly obese and nonobese pharmacokinetic models.

Daptomycin 6 mg/kg/day resulted in AUC, Cmax, and Cmin values that were ~2-fold higher in morbidly obese subjects relative to nonobese individuals. In contrast, fixed dosing (500 mg/day) resulted in relatively isometric exposures. The fraction of simulated morbidly obese subjects with a Cmin target associated with CPK elevations was 10.8% with 6 mg/kg/day and 2.0% at the 500 mg/day dosage.

Adverse Events

No serious adverse events were reported during the study, and all subjects tolerated the daptomycin infusion.

Study Author Conclusions

Dosing of daptomycin based on TBW resulted in higher Cmax and AUC values in the morbidly obese group than in the normal-weight group, and both sets of values were associated with higher total doses received in the morbidly obese group.

Weight-based maintenance dosing of daptomycin is less likely to yield bioequivalent exposures in morbidly obese subjects and provides credence for the evaluation of fixed maintenance doses across adult body size to improve safety.

InpharmD Researcher Critique

Although well-matched, this study only includes female, healthy patients. The subsequent Monte Carlo simulations were conducted based upon the analysis in only female patients. Additionally, the study did not evaluate the impact of renal insufficiency on the pharmacokinetic profile of daptomycin in morbidly obese subjects. 



References:

Pai MP, Norenberg JP, Anderson T, et al. Influence of morbid obesity on the single-dose pharmacokinetics of daptomycin. Antimicrob Agents Chemother. 2007;51(8):2741-2747. doi:10.1128/AAC.00059-07

Butterfield-Cowper JM, Lodise TP Jr, Pai MP. A Fixed versus Weight-Based Dosing Strategy of Daptomycin May Improve Safety in Obese Adults. Pharmacotherapy. 2018;38(9):981-985. doi:10.1002/phar.2157

 

The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects

Design

Pharmacokinetic study

N= 25

Objective

To assess the single-dose pharmacokinetics and safety of daptomycin in moderately to morbidly obese subjects as compared with nonobese subjects

Study Groups

Moderately obese (n= 6)

Morbidly obese (n= 7)

Nonobese control (n= 12)

Methods

Inclusion criteria: healthy subjects, CrCl >70 mL/min

Exclusion criteria: out of range CPK, absence of matched control, anemia with hematocrit <27%, use of investigational drug or experimental procedure in prior 30 days of study entry, use of statin within 7 days or warfarin within 15 days of daptomycin administration, donated blood in past 30 days, history of muscular disease or neurological disease, received intramuscular injections or weight training within 7 days of daptomycin administration

Participants were stratified as moderately obese (body mass index [BMI] =25-39.9 kg/m2 ) or morbidly obese (BMI ≥40 kg/m2 ) and were matched (gender, age, renal function) with nonobese (BMI =18.5-24.9 kg/m2 ) controls. All participants received a single dose of daptomycin 4 mg/kg over 30 minutes and were evaluated over 24 hours. One of the morbidly obese patients did not have a matched control and was not included in the pharmacokinetic analysis, but was included in the safety assessment.

Duration

24 hours

Outcome Measures

 Area under the curve (AUC), maximum concentration (Cmax), clearance (CL)

Baseline Characteristics

  

Moderately obese (n= 6)

Morbidly obese (n= 6)

Nonobese control (n= 12)

Age, years

 40.7 41.7 36.6

Female

 6 (100%) 3 (43%) 8 (67%)

Hispanic

 6 (100%) 5 (71%) 10 (83%)

Weight, kg

Actual body weight

Ideal body weight

 

85.7 ± 9

52.8 ± 4

 

125.8 ± 17

60.2 ± 11

 

64.3 ± 9

56.0 ± 7

BMI, kg/m2

 33.2 ± 4 46.2 ± 6 24.3 ± 1

Results

Ratios of obese/controls (95% CI)

 Moderately obese (n= 6) Morbidly obese (n= 6)  

AUC, µg*h/mL

 1.30 (1.13 to 1.49) 1.31 (1.18 to 1.46)  

Cmax, µg/mL

 1.25 (1.08 to 1.45) 1.26 (1.08 to 1.47)  

CL, mL/h

 1.18 (1.10 to 1.27) 1.46 (1.29 to 1.63)  
CI=confidence interval

Adverse Events

One patient (14%) in the morbidly obese group experienced three treatment-emergent adverse events, all of which were mild.

The 6 moderately obese subjects and the 12 matched control subjects did not experience any adverse events during the study.

Study Author Conclusions

Exposure to daptomycin in obese subjects (Cmax, AUC) was increased by 25% and 30%, respectively, compared to nonobese matched controls. Daptomycin may be dosed based on total body weight, and no adjustment in daptomycin dose or dose regimen should be required based solely on obesity.

InpharmD Researcher Critique

This was a single-dose pharmacokinetic study that did not assess efficacy. The sample size was small and consisted primarily of females of Hispanic ethnicity, reducing generalizability to other populations. A comparison of total versus adjusted body weight dosing strategies was not performed to determine if it would result in a statistical difference in measures as compared to nonobese patients. Single-dose pharmacokinetic studies may not provide an accurate depiction of the accumulation and clearance of drugs compared to repeated-dose studies.

Although exposure to daptomycin was 30% higher in the obese groups compared to nonobese, it did not result in an increased risk of adverse events. Use of total body weight in obese patients may be appropriate as it was well tolerated.

 

References:

Dvorchik BH, Damphousse D. The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects. J Clin Pharmacol. 2005;45(1):48-56.

 

Safety and Effectiveness of Daptomycin Across a Hospitalized Obese Population: Results of a Multicenter Investigation in the Southeastern United States

Design

Multicenter, retrospective cohort study

N= 126

Objective

To evaluate the safety and efficacy of daptomycin dosed by actual body weight in a hospitalized obese population in the southeastern United States with varying degrees of renal function

Study Groups

BMI ≥ 30 kg/m² (n= 39)

BMI ≥ 35 kg/m² (n= 39)

BMI ≥ 40 kg/m² (n= 48)

Methods

Inclusion criteria: aged ≥18 years, body mass index (BMI) ≥30 kg/m², any patient who received daptomycin for any indication for a minimum of seven days

Exclusion criteria: duplicate patients

This was a retrospective study from 13 institutions in the Southeastern United States. Normal dosing was daptomycin 4 mg/kg/day for skin and skin structure infections or daptomycin 6 mg/kg/day for bloodstream infections. The highest dose given was 10.31 mg/kg.

Duration

January 2005 to May 2010

Outcome Measures

Primary: incidence of creatine phosphokinase (CPK) elevations more than 500 units/L, CPK elevations more than 1000 units/L, incidence of documented myalgias, and discontinuation of therapy due to an adverse drug event (ADE)

Secondary: efficacy (clinical failure defined as positive blood culture of responsible pathogen obtained ≥ 7 days post daptomycin initiation, recurrent bacteremia of responsible pathogen within 60 days of discontinuation of therapy, recurrent osteomyelitis at same site as evidenced by reinitiation of antibiotics or amputation of infected site, or change of therapy to an alternative agent for any reason other than de-escalation of therapy); other documented ADEs attributed to daptomycin therapy such as arthralgias and hypokalemia

Baseline Characteristics

  

BMI ≥ 30 kg/m² (n= 39)

BMI ≥ 35 kg/m² (n= 39)

BMI ≥ 40 kg/m² (n= 48)

  

Age, years

 54.38 58.15 58   

Women

8 (20.51%)  12 (30.77%)  24 (50%)  

White

 24 (61.54%) 24 (61.54%) 33 (68.75%)   

Weight, kg

 103.52 ± 9.31 113.94 ± 10.05   140.39 ± 29.86  
Daptomycin dose, mg/kg  6.49 ± 1.11  6.51 ± 1.19  5.83 ± 1.14  
Treatment duration, days 18 ± 12 20 ± 14 21 ± 13  

Results

 

 BMI ≥ 30 kg/m² (n=39)

BMI ≥ 35 kg/m² (n=39)

BMI ≥ 40 kg/m² (n=48)

P-value 
CPK elevations more than 500 units/mL 3 (10.71%)  5 (17.24%) 5 (13.15%) 0.773
CPK elevations more than 1000 units/mL 1 (3.57%) 3 (10.34%) 4 (10.53%) 0.554
Incidence of documented myalgias 2 (5.13%) 1 (2.56%) 1 (2.08%) 0.699
Discontinuation of therapy due to an ADE 2 (5.13%)  3 (7.69%) 3 (6.25%) 0.897
Treatment Success 26 (66.7%) 26.7 (68.4%) 37 (77.1%) Not significant

Adverse Events

Serious Adverse Events: Rhabdomyolysis 1 (2.56%), Arthralgia 1 (2.56%), C. diff 1 (2.56%)

Study Author Conclusions

This study suggests that complicated obese patients who receive daptomycin dosed on actual body weight have increased rates of CPK elevations and discontinuation compared with published data for primarily normal-weight patients. However, discontinuation rates due to ADEs remain low, considering this high-risk population.

InpharmD Researcher Critique

Limitations of this study include the small sample size and patients from a limited geographical area. The results of the study may not be applicable to medications that are more lipophilic in nature than daptomycin. 



References:

Bookstaver PB, Bland CM, Qureshi ZP, Faulkner-Fennell CM, Sheldon MA, Caulder CR, Hartis C; SERGE-45 Investigators. Safety and effectiveness of daptomycin across a hospitalized obese population: results of a multicenter investigation in the southeastern United States. Pharmacotherapy. 2013 Dec;33(12):1322-30.