Model-based dose optimisation of intravenous posaconazole for treatment of patients with invasive aspergillosis in the intensive care unit
Omar Elkayal (1), Beatrijs Mertens (1,2), Joost Wauters (3), Bart Rijnders (4), Paul E. Verweij (5), Roger J. Brüggemann (6), Isabel Spriet (1,2), Erwin Dreesen (1)
(1) Department of Pharmaceutical and Pharmacological Sciences, KU Leuven – Leuven, Belgium. (2) Pharmacy Department, UZ Leuven – Leuven, Belgium. (3) Medical Intensive Care Unit, UZ Leuven – Leuven, Belgium. (4) Department of Internal Medicine, Section of Infectious Diseases and Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center – Rotterdam, The Netherlands. (5) Department of Medical Microbiology and Radboudumc – CWZ Center of Expertise for Mycology, Radboud University Medical Center – Nijmegen, The Netherlands. (6) Department of Pharmacy and Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen and Center of Expertise in Mycology Radboudumc/CWZ, Radboud University Medical Center – Nijmegen, The Netherlands.
Introduction: Posaconazole is a broad-spectrum triazole antifungal drug used for prophylaxis and treatment of invasive fungal infections in critically ill patients [1]. Owing to its favourable safety profile, the availability as intravenous (IV) infusion, and a good residual activity against azole-resistant A. fumigatus, posaconazole is a go-to drug for patients with invasive pulmonary aspergillosis (IPA) admitted to the intensive care unit (ICU) [2]. Standard dosing was shown to result in adequate attainment of the prophylaxis trough concentration (Cmin) target (0.7 mg/L) but not of the treatment Cmin target (1.0 mg/L) [3].
Objectives: The objectives of our work were
- to develop a population pharmacokinetics (popPK) model for IV posaconazole in critically ill patients admitted to the ICU,
- to identify covariates with a clinically relevant impact on posaconazole Cmin target attainment under standard dosing, and
- to provide a posaconazole dosing recommendation for IV treatment of patients with IPA in the ICU that ensures adequate Cmin target attainment as fast as day 2 and during two weeks of treatment.
Methods: A popPK model was developed using the POSA-FLU dataset (NCT03378479) [4]. Eighty-eight patients enrolled in this prospective multi-centre study were admitted to the ICU and treated with posaconazole 300 mg IV every 12 hours (q12h), followed by 300 mg IV q24h from day 2 onwards. Different model structures were explored. Interindividual variability (IIV), inter-occasion variability (IOV; ≤day 3 or >day 3), and residual unexplained variability (RUV) were quantified. A final model including covariate effects was built through two-way stepwise covariate modelling (SCM; αforward=0.010, αbackward=0.001). The tested covariates were sex, bodyweight, albumin, serum creatinine, the estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration equation, aspartate aminotransferase and alanine transaminase. A prediction-corrected visual predictive check (pcVPC; 1,000 replicates) was used to evaluate the final model. A bootstrap (2,000 replicates) was performed to obtain nonparametric estimates of uncertainty in parameter estimates.
Results: Thirty-one patients participated in the PK sub-study (bodyweight range 56 kg to 140 kg), contributing a total of 532 posaconazole plasma samples. Seven PK samples were taken over a 24-hour dosing interval on an early day (day 2 or 3) and a late day (after day 3).
The popPK of IV posaconazole was best described by a two-compartment model with linear elimination. For a typical 75-kg patient, the clearance (CL) was 4.7 L/h [10%] (typical value [relative standard error]), the intercompartmental clearance (Q) was 41.4 L/h [5.6%], the volume of distribution in the central compartment (Vc) was 130.0 L [12.2%], and the volume of distribution in the peripheral compartment (Vp) was 230.0 L [14.5%]. The IIV in CL, Vc, Vp was estimated at 50.4%CV, 62.3%CV and 23.2%CV, resp. The IOV in CL and Vc was estimated at 20.8%CV and 40.1%CV, resp. The RUV was described by a proportional error model (11.7%CV). Bodyweight was identified as a statistically significant covariate on Vp. Posaconazole Vp increased from 144.1 L (56 kg) to 624.4 L (140 kg), with an increase in elimination half-life from 41.7 h to 120 h.
A standard loading regimen of 300 mg q12h on the first treatment day resulted in inacceptable PTA at day 2 across the entire 56 kg to 140 kg bodyweight range. A loading regimen of 300 mg q12h and 300 mg q8h in the first two treatment days resulted in acceptable PTA at day 2 in patients <100 kg and ≥100 kg, resp. A maintenance dose of 400 mg was needed to maintain PTA ≥90% throughout 14 days, irrespective of bodyweight.
Conclusion: We have identified a bodyweight-stratified loading regimen and a flat maintenance dose for posaconazole that guarantees attainment of the Cmin treatment target as fast as day 2, without the need for therapeutic drug monitoring. This dosing regimen can be helpful for treating IPA in critically ill patients with severe COVID-19, who are often hospitalized in the ICU and typically have higher bodyweight.
References:
[1] Sun QN et al. Antimicrob Agents Chemother 46:1581–1582.
[2] Chen L et al. Drugs 80:671–695.
[3] Daele RV et al. Mycoses 65:656–660.
[4] Vanderbeke L et al. Intensive Care Med 47:674–686.