Influence of Morbid Obesity on the Single-Dose Pharmacokinetics of Daptomycin

Self Cite

The effects of several antimicrobial agents are predicted by the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC). Peak (C p ) and trough (C t ) concentrations are often measured clinically as surrogates of AUC because actual computation of AUC from 1 or 2 samples requires sophisticated mathematical methods. Given that the effects of daptomycin are predicted by AUC/MIC, our objective was to compare simple equation calculated AUC based on C p and C t to model integrated AUC. A standard population pharmacokinetic model was used to simulate 5,000 daptomycin concentration-time profiles after 5 doses of 6 mg/kg of body weight/day (0.5-h infusions). The AUC for the 24-h period was computed by integration and by equations with 110 C p -C t combination pairs. The C p time points were in 15-min increments between 0.5 h and 3 h and C t in 15-min increments within an hour of the end of the dosing interval for each dose. The precision and bias of the calculated AUC relative to the integrated AUC were determined to identify C p -C t pairs associated with the lowest bias and highest precision. The equations were further validated using two daptomycin concentration-time data sets from healthy volunteers and critically ill patients. The precision and bias of calculated AUC were based primarily on C p , and use of a daptomycin C p 1.5 h to 3 h from the start of infusion was associated with a bias of <10% and an R 2 of >0.95. Data from the healthy volunteers and critically ill patients also demonstrated declining bias with use of C p >1.5 h from the start of infusion with relatively good precision. Simplified equations using a daptomycin C p approximately 2 h from the start of infusion and a C t within an hour of the end of the dosing interval should yield precise and unbiased estimates of daptomycin AUC.

Section: Tablesupporting

confidence: 55%

Section: Methodsmentioning

confidence: 99%

Simplified Equations Using Two Concentrations To Calculate Area under the Curve for Antimicrobials with Concentration-Dependent Pharmacodynamics: Daptomycin as a Motivating Example

Pai

Russo

Novelli

et al. 2014

Self Cite

“…Exposure to daptomycin (maximum concentration and area under the curve) following a 4-mg/kg dose is increased by approximately 25 to 30%, respectively, in moderately and morbidly obese healthy patients compared to matched, nonobese controls (14). A subsequent study revealed an approximate 60% increase in maximum concentration and area under the curve following a 4-mg/kg dose in morbidly obese healthy patients compared to normal-weight patients (15). A recent study showed an increased rate of CPK elevation in obese patients, but discontinuation rates remained low (16).…”

Section: Discussionmentioning

confidence: 99%

“…In our analysis, one patient (patient 4 from Table 3) with CPK levels of Ͼ1,000 U/liter on combination therapy would have received every-other-day dosing if the CrCl rate was based on their IBW but received daily dosing. The use of actual body weight with the Cockcroft-Gault formula has been demonstrated to overestimate glomerular filtration rate (GFR) in obese patients receiving daptomycin (15). Overestimation of GFR may lead to more frequent dosing of daptomycin than appropriate, increasing drug exposure and subsequent risk of toxicity.…”

Section: Discussionmentioning

confidence: 99%

Musculoskeletal Safety Outcomes of Patients Receiving Daptomycin with HMG-CoA Reductase Inhibitors

Bland

Bookstaver

Zhiqiang

et al. 2014

dDaptomycin, a cyclic lipopeptide antibiotic, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are commonly administered in the inpatient setting and are associated with creatine phosphokinase (CPK) elevations, myalgias, and muscle weakness. Safety data for coadministration of daptomycin with statins are limited. To determine the safety of coadministration of daptomycin with statin therapy, a multicenter, retrospective, observational study was performed at 13 institutions in the Southeastern United States. Forty-nine adult patients receiving statins concurrently with daptomycin were compared with 171 patients receiving daptomycin without statin therapy. Detailed information, including treatment indication and duration, infecting pathogen, baseline and subsequent CPK levels, and presence of myalgias or muscle complaints, was collected. Myalgias were noted in 3/49 (6.1%) patients receiving combination therapy compared with 5/171 (2.9%) of patients receiving daptomycin alone (P ‫؍‬ 0.38). CPK elevations of >1,000 U/liter occurred in 5/49 (10.2%) patients receiving combination therapy compared to 9/171 (5.3%) patients receiving daptomycin alone (P ‫؍‬ 0.32). Two of five patients experiencing CPK elevations of >1,000 U/liter in the combination group had symptoms of myopathy. Three patients (6.1%) discontinued therapy due to CPK elevations with concurrent myalgias in the combination group versus 6 patients (3.5%) in the daptomycin-alone group (P ‫؍‬ 0.42). CPK levels and myalgias reversed upon discontinuation of daptomycin therapy. Overall musculoskeletal toxicity was numerically higher in the combination group but this result was not statistically significant. Further prospective study is warranted in a larger population.

“…In two studies evaluating ABW-dosed daptomycin pharmacokinetics in the morbidly obese (1,4), the AUC increased 30 to 60% compared to in normalweight individuals. Volume of distribution (V) and clearance (CL) were reduced when normalized for weight.…”

mentioning

confidence: 99%

Daptomycin Dosing Based on Ideal Body Weight versus Actual Body Weight: Comparison of Clinical Outcomes

Schulz

Rose

et al. 2014

dDaptomycin use at our institution changed to ideal body weight dosing based on a published analysis of pharmacokinetic-pharmacodynamic efficacy target attainment, bacterial ecology, and a desire to reduce drug toxicity. The current study compared outcomes between actual body weight and ideal body weight dosing of daptomycin before and after this intervention. In the evaluable group, 69 patients received doses based on actual body weight and 48 patients received doses based on ideal body weight. Patients were treated for documented Enterococcus species, Staphylococcus aureus, or coagulase-negative Staphylococcus infections, including bloodstream, intraabdominal, skin and soft tissue, urinary, and bone. There was no statistically significant difference in clinical success between the groups (88.9% for actual body weight compared to 89.1% for ideal body weight, P ‫؍‬ 0.97). After we adjusted for gender, age, body mass index, concomitant 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, infection type, and organism type, clinical success rates remained similar between groups (adjusted odds ratio of 0.68 in favor of actual body weight, 95% confidence interval [CI] of 0.13 to 3.55). Microbiological outcomes, length of stay, mortality, and adverse effects were also similar between groups. Further studies are warranted to confirm that ideal body weight dosing provides similar outcomes to actual body weight dosing for all patients and types of infections and organisms. C onventional daptomycin doses, based on actual body weight (ABW), result in sufficient drug exposure to meet an effective area under the curve (AUC)-to-MIC ratio. Dvorchik and Damphousse demonstrated that a single dose of 4 mg of daptomycin/kg of body weight administered to nonobese patients resulted in an AUC of 418 Ϯ 25 g · h/ml (1). A 6-mg/kg dose resulted in AUC values of 726 Ϯ 79 g · h/ml in healthy, nonobese patients (2). In a mouse thigh infection model, Safdar et al. determined that the 24-h AUC/MIC parameters associated with bacteriostatic effect were 388 to 537 for four ATCC Staphylococcus aureus strains and 0.94 to 1.67 for two clinical isolates of Enterococcus faecium (3).Pharmacokinetic parameters may change in some patient populations, including the obese population. In two studies evaluating ABW-dosed daptomycin pharmacokinetics in the morbidly obese (1, 4), the AUC increased 30 to 60% compared to in normalweight individuals. Volume of distribution (V) and clearance (CL) were reduced when normalized for weight.Daptomycin dosing can be limited by toxicity, especially myositis and creatine phosphokinase (CPK) elevations with exposures exceeding 2 weeks of duration (5). In an examination of data from a randomized trial of daptomycin treatment of bacteremia and endocarditis, a direct relationship between minimum serum concentration (C min ) and incidence of CPK elevation was established. Patients weighing Ն111 kg had a significantly higher probability of elevated C min than patients weighing Ͻ111 kg. Using a Monte Carlo evaluation, d...