David Busse (1,2), Lisa Ehmann (1,2), Niklas Hartung (3), Robin Michelet (1), Philipp Simon (4,5), David Petroff (6), Wilhelm Huisinga (3), Hermann Wrigge (4,5,7), Charlotte Kloft (1)
(1) Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, (2) and Graduate Research Training program PharMetrX, (3) Institute of Mathematics, University of Potsdam, (4) Department of Anaesthesiology and Intensive Care, University of Leipzig Medical Center, (5) Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, (6) Clinical Trial Centre Leipzig, University of Leipzig, (7) Department of Anaesthesiology, Intensive Care and Emergency Medicine, Pain Therapy, Bergmannstrost Hospital Halle
Background: Recommended antibiotic dosing regimens often rely on probability of target-attainment (PTA) analysis, an established pharmacometric concept for informing clinical decision-making[1,2], which relates antibiotic exposure and bacterial minimum inhibitory concentration (MIC) to clinical outcome. Antibiotic exposure in plasma is selected as a proxy for exposure at the site of infection to establish pharmacokinetic/pharmacodynamics (PK/PD) targets. PK/PD targets are typically based on studies in non-obese patients receiving standard dosing regimens; hence the validity in special populations such as obese patients and in alternative dosing regimens is unclear.
This analysis aimed to: (i) evaluate the adequacy of PK/PD targets for obese patients over a range of MIC values/dosing regimens, and if inadequate (ii) suggest alternative PK/PD targets based on target-site exposure in obese patients.
Methods: Previously, NLME PK models of meropenem (MER) and linezolid (LIN) have been developed based on drug concentration-time data in plasma and interstitial space fluid (ISF, the target-site) of subcutaneous fat tissue. ISF concentrations were obtained via microdialysis from 15 obese (BMImean=49 kg/m2) and 15 non-obese surgery patients (BMImean=24 kg/m2), receiving a standard infusion of 1000 mg MER/600 mg LIN[3,4].
Monte-Carlo simulations (n=1000) were performed to predict drug concentration-time profiles in plasma/ISF for body weight ranges in obese and non-obese patients after administration of a thrice-daily (MER) and twice-daily (LIN) standard dose, double standard dose and prolonged infusion over 24 h. PTA was calculated for the PK/PD target “unbound concentrations exceed MIC for >98% of dosing interval” (98%fT>MIC, MER and LIN[5, 6]) and “area under the unbound concentration-time curve divided by MIC≥80” (fAUC/MIC≥80, LIN[6]) in plasma for MIC=0.5-2 mg/L. In non-obese patients, the relationship between PTA in plasma and ISF was established to define ISF PK/PD targets by: (i) computing %fT>MIC and fAUC/MIC for a virtual population of non-obese individuals, and (ii) determining the ISF thresholds ensuring the same PTA as the above-mentioned plasma thresholds. This relationship was then compared to obese patients. Finally, a PTA analysis based on the newly derived ISF PK/PD targets was performed for both populations. A dosing regimen was considered clinically adequate if PTA≥90%.
This analysis was performed in NONMEM 7.4.3 and R 3.6.0, with assistance of PsN 4.6.0 and Pirana 2.9.6.
Results: The derived time dependent MER and LIN ISF PK/PD targets showed little variability across different dosing regimens for the same MIC and decreased with increasing MIC (MER: 80.3–83.3%fT>MIC-ISF for MIC=0.5 mg/L, 74.8–77.0%fT>MIC-ISF for MIC=2.0 mg/L and LIN: 93.1–96.0%fT>MIC-ISF for MIC=0.5 mg/L, 86.2–89.6%fT>MIC-ISF for MIC=2.0 mg/L). %fT>MIC-ISF corresponding to the plasma PK/PD target was 8.50–11.5% (MER) and 6.80–15.5% (LIN) lower in obese compared to non-obese patients reflecting population-dependent differences in the relevant exposure in ISF. When the ISF-based PK/PD targets from non-obese patients were applied to obese patients PTA was ≤41.0% (MER) and ≤74.0% (LIN) lower compared to PTA using conventional plasma-based PK/PD targets.
When the index fAUC/MIC was applied to LIN, ISF PK/PD targets showed overall larger variability (fAUC/MICISF=46.8–50.5 for MIC=0.5 mg/L, fAUC/MICISF=45.7–52.3 for MIC=2.0 mg/L). LIN fAUC/MICISF corresponding to the plasma PK/PD target was 4.9–6.8% lower in obese which translated into ≤72.0% lower PTA compared to PTA based on conventional targets.
These differences led to changes in evaluation of dosing regimens compared to the conventional PTA for obese patients for e.g. the standard dosing regimens and MIC=0.5 mg/L and 1 mg/L.
Conclusion: We critically reviewed the application of conventional PK/PD targets in PTA analysis of obese patients and proposed an approach to derive more appropriate new ISF-based PK/PD targets for obese patients.
Importantly, we revealed the risk of overestimating PTA in obese patients based on conventional PK/PD targets, which can result in misleading evaluation of dosing regimens. In turn this might lead to inadequate dosing decisions in this population. Next, new plasma-based PK/PD targets for obese patients should be derived based on the approach presented here.
References:
[1] M.B. Bauer et al., SWAB guideline: Perioperative antibiotic prophylaxis (2017). Available at: http://www.swab.nl/richtlijnen
[2] European Medicines Agency. Guideline on the use of pharmacokinetics and pharmacodynamics in
the development of antibacterial medicinal products. (2016).
[3] D. Busse et al., 28th Population Approach Group Europe (PAGE), Stockholm, Sweden: 8993 (2019).
[4] L. Ehmann et al., Risk of target non-attainment in obese compared to non- obese patients in calculated linezolid therapy. CMI (in revision).
[5] J.L. Crandon et al., Pharmacodynamics of carbapenems for the treatment of Pseudomonas aeruginosa ventilator-associated pneumonia: associations with clinical outcome and recurrence. JAC 71: 2534–7 (2016).
[6] C.R. Rayner et al., Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme. Clin. Pharmacokinet. 42:1411–23 (2003).
Reference: PAGE () Abstr 9498 [www.page-meeting.org/?abstract=9498]
Poster: Oral: Methodology - New Tools