Daptomycin Pharmacokinetics and Pharmacodynamics in Patients on Methadone Substitution Therapy

Abstract

Background and objective: When administered for severe infections in intravenous drug users (IDUs) at a daily dose of 6 mg/kg, daptomycin displayed abnormal pharmacokinetic parameters compared with those seen in healthy volunteers; specifically, decreased trough and maximum concentrations (C_trough; C_max) and increased clearance (CL). The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of daptomycin administered at a daily dosage of 12 mg/kg for Staphylococcus aureus infective endocarditis (IE) in patients concomitantly treated with methadone, and to compare the results with those published in the literature for healthy controls treated with the same daily dose.

Methods: Antibiotic treatment included daptomycin (12 mg/kg daily) in combination with an antistaphylococcal β-lactam (cefazolin 2 g three times a day). The minimum inhibitory concentration (MIC) of Staphylococcus aureus isolated through blood cultures was used to calculate pharmacokinetic and pharmacodynamic parameters such as the ratio of the area under the concentration-time curve over 24 h to the MIC (AUC_0-24/MIC) and C_max/MIC.

Results: Five IDUs hospitalized for IE were enrolled. The mean measured daptomycin C_max and C_trough were 54.1 μg/mL (CV: 0.32) and 8.7 μg/mL (CV: 0.59), respectively; the mean calculated AUC_0-24 was 742.7 μg × h/mL (CV: 0.31). The estimated average volume of distribution at the steady state (V_d,ss) and the half-life (t_1/2) were 316.5 mL/kg (CV: 0.53) and 14.4 h (CV: 0.30), respectively. The mean daptomycin clearance from plasma normalized for body weight (CL_wp) was 17.3 mL/(h × kg) (CV: 0.33). The calculated average C_max and AUC_0-24 (183.7 µg/mL and 1277.4 µg × h/mL, respectively) were lower than and statistically significantly different from (p < 0.001 and p = 0.001, respectively) those expected for healthy volunteers.

Conclusions: Treatment of Staphylococcus aureus IE in IDUs on methadone treatment requires the use of high daptomycin daily doses in order to achieve satisfactory pharmacodynamic parameters. Close monitoring of the daptomycin plasma concentration is suggested.