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Daptomycin Pharmacokinetics and Pharmacodynamics in Patients on Methadone Substitution Therapy

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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 (Ctrough; Cmax) 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 (AUC0–24/MIC) and Cmax/MIC.

Results

Five IDUs hospitalized for IE were enrolled. The mean measured daptomycin Cmax and Ctrough were 54.1 μg/mL (CV: 0.32) and 8.7 μg/mL (CV: 0.59), respectively; the mean calculated AUC0–24 was 742.7 μg × h/mL (CV: 0.31). The estimated average volume of distribution at the steady state (Vd,ss) and the half-life (t1/2) 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 (CLwp) was 17.3 mL/(h × kg) (CV: 0.33). The calculated average Cmax and AUC0–24 (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.

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Authors and Affiliations

  1. Clinical and Experimental Pharmacokinetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Simona De Gregori, Maria Delfina Molinaro & Antonella Bartoli

  2. Servizio di Epidemiologia Clinica e Biometria Direzione Scientifica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Annalisa De Silvestri

  3. U.O.C Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Vincenzina Monzillo

  4. Clinica di Malattie Infettive, IRCCS Policlinico San Matteo, Piazzale Golgi 2, 27100, Pavia, Italy

    Simona Biscarini, Marta Colaneri, Ilaria Gallazzi, Raffaele Bruno & Elena Seminari

  5. University of Pavia, Pavia, Italy

    Simona Biscarini, Marta Colaneri, Ilaria Gallazzi, Raffaele Bruno & Elena Seminari

  6. Department of Clinical, Surgical, Diagnostics and Pediatric Scieces, University of Pavia, Pavia, Italy

    Raffaele Bruno

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  1. Simona De Gregori
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  10. Elena Seminari
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Corresponding author

Correspondence to Elena Seminari.

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Funding

This work was supported by a BlueSky research grant (n. 08072320).

Conflicts of interest

All authors: none to declare.

Ethics approval

All procedures in this study were in accordance with the 1964 Helsinki Declaration (and its amendments). The study was approved by the local ethics committee (protocol number 20200006979).

Consent to participate

A written informed consent was obtained from all participants.

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Not applicable.

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Not applicable.

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Not applicable.

Authors’ contributions

Conceptualization: ES, SDG ADS. Methodology: MDM. Validation: SDG, VM. Formal analysis: ADS. Investigation: AB, IG, MC, SB. Writing—original draft preparation: ES, SDG, RB. Writing—review and editing: RB. Supervision: ES.

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De Gregori, S., De Silvestri, A., Molinaro, M.D. et al. Daptomycin Pharmacokinetics and Pharmacodynamics in Patients on Methadone Substitution Therapy. Eur J Drug Metab Pharmacokinet 46, 547–554 (2021). https://doi.org/10.1007/s13318-021-00690-4

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  • DOI: https://doi.org/10.1007/s13318-021-00690-4

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