Use of Pharmacokinetic and Pharmacodynamic Principles To Determine Optimal Administration of Daptomycin in Patients Receiving Standardized Thrice-Weekly Hemodialysis

Abstract

This study identified optimal daptomycin dosing for patients receiving thrice-weekly hemodialysis (HD). Twelve adult patients on HD received daptomycin at 6 mg/kg of body weight intravenously (i.v.) one time; plasma and dialysate samples were collected over 3 days. A 2-compartment model with separate HD and non-HD clearance terms was fit to the data. A series of 9,999-subject Monte Carlo simulations (MCS) was performed to identify HD dosing schemes providing efficacy and toxicity profiles comparable to those obtained for MCS employing the daptomycin population pharmacokinetic (PK) model derived from patients in the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. For efficacy, we selected the HD dosing scheme which generated an area-under-the-curve (AUC) exposure profile comparable to that for the SAB-IE population model. For toxicity, we selected HD dosing schemes that minimized trough concentrations of >24. Daptomycin is a lipopeptide approved for the treatment of Staphylococcus aureus bacteremia and complicated skin and skin structure infections, both of which are common in patients receiving hemodialysis (HD) (1,4,(14)(15)(16)(17)(18). While the pharmacokinetic (PK) properties of daptomycin are well described for the general population, there are scant data for patients on HD (12, 13). An understanding of how PK changes during HD is essential to determining optimal dosing schemes for these patients. Furthermore, such dosage adjustments necessitate cognizance of interactions between antibiotic exposure, efficacy, and toxicity. Given the dearth of treatment options available against methicillin-resistant S. aureus (MRSA), it is imperative that daptomycin regimens be optimized for those on HD.The two objectives of this study were (i) to characterize the PK profile of daptomycin in patients receiving traditional thrice-weekly hemodialysis and (ii) to identify the optimal dosing scheme for daptomycin among patients on HD. With respect to the latter, the intent was to identify HD dosing schemes with efficacy and toxicity profiles comparable to those obtained from Monte Carlo simulations (MCS) employing the daptomycin population PK model derived from patients enrolled in the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) clinical study for doses of 4 mg/kg of body weight given intravenously (i.v.) every 24 h (q24h) and 6 mg/kg given i.v. q24h (2, 7).Separate dosing schemes were developed for both FDAapproved daptomycin dosing regimens (4 mg/kg i.v. q24h and 6 mg/kg i.v. q24h) and for the two interdialytic periods (48 and 72 h). For efficacy, the primary exposure target was the area under the curve (AUC). Animal model data suggest that daptomycin is a concentration-dependent antibiotic, and the AUC/ MIC ratio is the pharmacodynamic (PD) parameter that best describes its activity (3,5,9,11). However, the AUC/MIC ratio associated with maximal effect has varied (3,5,9,11). Given the lack of a definitive AUC/MIC threshold, especially for patients with bloodstream infections, the ...

Pharmacokinetics and Pharmacodynamics of Intravenous Daptomycin during Continuous Ambulatory Peritoneal Dialysis

“…Mean volume in the peritoneal space was 2.6 L, roughly the amount of fluid administered during each exchange. Clearance was approximately 0.3 L/h, close to previous approximations for patients with minimal kidney function (8,(23)(24)(25). Finally, a physiologic amount of residual drug (approximately 0.5 mg) was estimated to remain in the peritoneal cavity after drainage.…”

Daptomycin Pharmacokinetics and Pharmacodynamics in a Pooled Sample of Patients Receiving Thrice-Weekly Hemodialysis

“…This PK/PD systems analysis was performed utilizing concentration-time data from three previous evaluations in patients receiving thrice-weekly HD (reported by Salama et al, Benziger et al, and Patel et al [10][11][12][13]). Details of these studies have been published previously (10)(11)(12)(13) and are provided in Table 1. Briefly, two of the studies were single-dose (6 mg/kg on total body weight post-HD, infused over 30 min) PK studies (10,11,13).…”

“…While the pharmacokinetics (PK) of daptomycin among patients receiving HD have been described by several groups, there are inconsistencies in the HD dosing recommendations offered (10)(11)(12)(13). Regardless of the interdialytic period (48 h versus 72 h) during thrice-weekly HD, one study recommended administering a 50% increase in the parent daptomycin dose (4 or 6 mg/kg of body weight, depending on the indication) intra-HD, while another study advocated post-HD administration.…”

“…In light of the discordant thrice-weekly HD dosing recommendations, the objectives of this study were to (i) combine concentration-time data from these previous HD PK evaluations and (ii) derive uniform pharmacokinetic/pharmacodynamic (PK/PD)-optimized HD dosing recommendations. With respect to the HD dosing recommendations, the goal was to identify total body weight-based HD dosing schemes for each FDA-approved daptomycin dosing regimen with efficacy and toxicity profiles comparable to those obtained from Monte Carlo simulations (MCS) employing the daptomycin population PK model derived from patients enrolled in the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) clinical study (13)(14)(15). Furthermore, optimized dosing schemes were sought for the two interdialytic periods of a typical thrice-weekly HD schedule (48 h and 72 h).…”

Methicillin-Resistant Staphylococcus aureus [Mrsa] Catheter Related Bloodstream Infections in Renal Dialysis: Case Report, Present and Future Directions

“…We have demonstrated a lack of accumulation, whilst maintaining a trough level of >15 mg/L with the regime of high dosing (up to 8mg/kg thrice weekly). Based upon Monte-Carlo simulations [38], a 50% dose increase may be required to reach therapeutic area under the curve (AUC 48-72 ) whilst minimising trough concentrations [24] of >24.3 mg. Many patients who undergo outpatient haemodialysis attend three sessions per week, with the largest gap over the weekend.…”