Omar Elkayal (1), Joseph Standing (2,3), Sophida Boonsathorn (2,4), Sian Bentley (5,6), Athanasios Tragiannidis (7,8), Andreas Groll (7), Jenna Nickless (9), Adam Brothers (9), Romina Valenzuela (10), Jorge Morales (10), Anne Uyttebroeck (11), Isabel Spriet (1,12), Erwin Dreesen (1)
(1) Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. (2) Paediatric Infectious Disease Research Group, St. George’s, University College London, London, UK. (3) Great Ormond Street Hospital for Children, London, UK. (4) Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. (5) Pharmacy Department, Royal Brompton Hospital, London, UK. (6) National Heart and Lung Institute, Imperial College London, London, UK. (7) Infectious Disease Research Program, Centre for Bone Marrow Transplantation and Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, Münster, Germany. (8) Haematology Oncology Unit, and Department of Paediatrics, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece. (9) Department of Pharmacy, Seattle Children's Hospital, Washington, USA. (10) Hospital Dr. Luis Calvo Mackenna, Universidad de Chile, Santiago, Chile. (11) Department of Paediatric Haematology and Oncology, University Hospitals Leuven, Leuven, Belgium. (12) Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.
Introduction: Posaconazole is active against invasive Aspergillus and Candida infections [1]. Based on its use for prophylaxis against and treatment of invasive fungal infections (IFIs) in adults, it has been subject of off-label use in paediatric patients [2]. According to recent guidelines, different posaconazole formulations are recommended in paediatric patients, including oral suspension, tablet and intravenous (IV) infusion [3]. Posaconazole demonstrates vast pharmacokinetic (PK) variability, particularly in terms of absorption of the oral suspension [4]. Standard dosing at 600 mg/day may fail to maintain trough concentrations above the 0.7 mg/L and 1.0 mg/L targets for prophylaxis and treatment of IFIs, respectively [5].
Objectives: The objectives of our work were (i) to investigate the target attainment (TA) of different posaconazole formulations, and (ii) to develop a population PK (popPK) model for the three posaconazole formulations in immunocompromised paediatric patients.
Methods: A patient-level meta-analysis was performed (PROSPERO record CRD42020214570). Clinical centres with data potentially fulfilling the study requirements were identified through a PubMed search until March 2020. Prophylaxis and treatment TA were evaluated. A popPK analysis was performed (NONMEM 7.5) to describe the PK of the three posaconazole formulations. Structural models with one and two compartments, zero and first order absorption (with or without a lag time) for oral formulations and linear and nonlinear elimination (Michaelis–Menten kinetics) processes were explored. Posaconazole tablets are reported to have linear bioavailability [6]. While the oral suspension has been shown to demonstrate nonlinear bioavailability [7]. Therefore, the oral suspension bioavailability (F) relative to the tablet was described as
F= Ftab-(D/D+ ED50)
where Ftab is the apparent tablet bioavailability that was fixed to 1, D is the dose in mg/m2 body surface area (BSA), and ED50 is the estimated dose in mg/m2 that yields a 50% decrease in F. Allometric scaling was tested with exponents of 0.75, 1, and 0.25 on clearance (CL), volume of distribution (Vd), and absorption rate constant (ka), respectively [8,9]. A final model, including covariate effects, was built through two-way stepwise covariate modelling (αforward=0.010, αbackward=0.001). The tested covariates were body weight, BSA (calculated using Mosteller formula [10]), proton pump inhibitor (PPI) comedication, presence of diarrhoea, and age.
Results: Six centres shared data from 218 paediatric patients, contributing 718 posaconazole plasma concentrations. Since most samples collected were pre-dose trough concentrations, the TA were calculated according to the trough concentration targets. TA for prophylaxis and treatment were found to be lower in children treated with the oral suspension (55% [237/432] and 33% [142/432] for prophylaxis and treatment, respectively) compared to the tablet (90% [162/181] and 81% [146/181]) and the IV infusion (88% [30/34] and 71% [24/34]).
The popPK of posaconazole in paediatric patients was described by a one-compartment model with first-order absorption and linear elimination. The lag time was 2.09 h [24.2%] (typical value [relative standard error]) for the oral suspension, and 2.29 h [7.4%] for the tablet. The oral suspension ED50 was 33.3 mg/m2 [13.7%]. Since our data lacked patients with crossover oral/IV dosing, the absolute oral bioavailability couldn’t be estimated. The first-order ka could not be estimated and was fixed to 0.197 h-1 and 0.588 h-1 for the suspension and the tablet, respectively, based on prior knowledge [11, 12]. The apparent volume of distribution (V/F) was 159 L [14%] and the apparent clearance (CL/F) was 6.85 L/h [8.3%] (standardized to a 70-kg individual). The suspension bioavailability decreased in the presence of diarrhoea and PPI comedication. The interindividual variability in CL/F and F was estimated at 35.4% [15%] and 67.7% [10.3], respectively. An additive (±0.0279 mg/L for high performance liquid chromatography [HPLC]- mass spectrometry [MS]) and proportional (11.1 %CV and 46.5 %CV for HPLC-fluorescence and HPLC-MS, respectively) error models described the unexplained residual variability.
Conclusion: A popPK model was developed based on the largest patient cohort to date. The developed model will be the base for a simulations study to identify a posaconazole dosing strategy for children with an optimised probability of TA.
References:
[1] Sun QN et al. Antimicrob Agents Chemother 46:1581–1582.
[2] Cornely OA et al. J Antimicrob Chemother 71:718–726.
[3]www.accessdata.fda.gov/drugsatfda_docs/label/2021/214770s000,205053s012,205596s012lbl.pdf.
[4] Ashbee HR et al. J Antimicrob Chemother 69:1162–1176.
[5] Dolton MJ et al. Antimicrob Agents Chemother 56:5503–5510.
[6] Krishna G et al. J Antimicrob Chemother 67:2725–2730.
[7] Ezzet F et al. Clin Pharmacokinet 44:211–220.
[8] Germovsek E et al. Br J Clin Pharmacol 83:777–790.
[9] Holford N et al. J Pharm Sci 102:2941–2952.
[10] Sigurdsson TS et al. Acta Paediatr 109:1838–1846.
[11] Petitcollin A et al. Antimicrob Agents Chemother 61.
[12] Ezzet F et al. Clin Pharmacokinet 44:211–20.
Reference: PAGE 30 (2022) Abstr 10087 [www.page-meeting.org/?abstract=10087]
Poster: Drug/Disease Modelling - Infection