III-23 Anouk Jansen

Population pharmacokinetics of itraconazole and hydroxy-itraconazole following administration of an intravenous nanocrystal formulation

Anouk M.E. Jansen (1,2), Rob ter Heine (1), Eva Molendijk (3), J. Peter Donnelly (4), Nicole Blijlevens (3), Roger J.M. Brüggemann (1,2)

(1) Department of Pharmacy, Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands, (2) Center of expertise in Mycology Radboud university medical center/Canisius Wilhelmina Ziekenhuis, Nijmegen, The Netherlands, (3) Department of Haematology, Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands, (4) Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Introduction: Itraconazole is a broad-spectrum antifungal agent used to treat various fungal infections, including aspergillosis, and for prophylaxis of invasive fungal disease (IFD) in immunocompromised patients [1-3]. Itraconazole pharmacokinetics (PK) following oral administration are poor, highly variable and influenced by food intake while intravenous (IV) itraconazole formulations are not widely available [4, 5]. To overcome these shortcomings, new pharmaceutical formulations have been developed, such as the oral Super BioAvailability (SUBA)-itraconazole formulation and an IV nanocrystal formulation (NCF). For the current IV itraconazole formulation, interindividual variability (IIV) on itraconazole clearance (CL) was reported to be 66% in patients with neutropenic fever [6]. Variability in itraconazole exposure following administration of the SUBA-itraconazole formulation was estimated to be 22% [7]. Pharmaceutical development of a novel formulation of a drug warrants information on its PK. 

Objectives: To assess the PK of itraconazole and its metabolite hydroxy-itraconazole after administration of itraconazole NCF in subjects receiving an allogeneic hematopoietic cell transplant (HCT).

Methods: In a prospective PK study, 10 HCT recipients received itraconazole NCF as prophylaxis for IFD following standardized conditioning with idarubicin, cyclophosphamide and total body irradiation. Itraconazole was administered in 2-hour infusions of 200 mg two times daily for two days, followed by 200 mg once daily until day 14. On day 7 and 14, full PK curves were obtained. In addition, samples were collected pre- and post-infusion for all administrations until day 6 and pre-dose on day 10 and 12. Additional samples were collected on days 16, 17, 18, 19, and 28 during the washout period to determine terminal elimination. Itraconazole and hydroxy-itraconazole plasma concentrations were measured by a validated high-performance liquid chromatography (HPLC) assay. Itraconazole and hydroxy-itraconazole PK were analysed by non-linear mixed effects population PK modelling. Model development was conducted in a stepwise manner where itraconazole data were used to develop a base model which was extended with hydroxy-itraconazole data to develop an integral model for parent and metabolite. Allometric scaling based on total body weight was applied a priori on the volume and flow parameters to account for the impact of body weight on the PK.

Results: A total of 471 itraconazole and 471 paired hydroxy-itraconazole concentrations from 10 patients were included for analysis. The PK data were described by an integral model with two parent compartments and one metabolite compartment with first-order distribution and elimination. Final population parameter estimates for itraconazole CL and intercompartmental clearance (Q) were 3.63 (RSE 0.3%) and 18.5 L/h (RSE 0.4%), respectively. Hydroxy-itraconazole CL was estimated to be 2.74 L/h (RSE 0.1%). The final model included 11.1% (RSE 72%) and 24.1% (RSE 98%) IIV on CL of itraconazole and its metabolite, respectively, and 28.0% (RSE 8%) intraindividual variability on the fraction administered. The residual variability was best described by an additive residual error model on the log scale, corresponding with proportional error models for both the parent and metabolite compound separately.

Conclusions: The developed population PK model described the PK of itraconazole and hydroxy-itraconazole following administration of itraconazole NCF well. This study thereby provides useful information for pharmaceutical development of this formulation. PK variability on itraconazole CL appeared to be reduced compared to the conventional IV itraconazole formulation and the available oral formulations, including SUBA-itraconazole. Our results may give rise to the renewal of the IV itraconazole formulation in the setting of drug repurposing, although large-scale production may be challenging. Findings on the PK of the NCF in this study may be useful for reformulation of other highly lipophilic compounds as well.

References:

  1. Glasmacher, A., et al., An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia. J Antimicrob Chemother, 2006. 57(2): p. 317-25.
  2. Maertens, J.A., et al., European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia. J Antimicrob Chemother, 2018. 73(12): p. 3221-3230.
  3. Lestner, J. and W.W. Hope, Itraconazole: an update on pharmacology and clinical use for treatment of invasive and allergic fungal infections. Expert Opin Drug Metab Toxicol, 2013. 9(7): p. 911-26.
  4. Glasmacher, A., et al., Breakthrough invasive fungal infections in neutropenic patients after prophylaxis with itraconazole. Mycoses, 1999. 42(7-8): p. 443-51.
  5. Zimmermann, T., et al., Influence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole. Eur J Clin Pharmacol, 1994. 46(2): p. 147-50.
  6. Lee, D.G., et al., Population pharmacokinetics of intravenous itraconazole in patients with persistent neutropenic fever. J Clin Pharm Ther, 2009. 34(3): p. 337-44.
  7. Abuhelwa, A.Y., et al., Population pharmacokinetic modeling of itraconazole and hydroxyitraconazole for oral SUBA-itraconazole and sporanox capsule formulations in healthy subjects in fed and fasted states. Antimicrob Agents Chemother, 2015. 59(9): p. 5681-96.

Reference: PAGE 30 (2022) Abstr 10069 [www.page-meeting.org/?abstract=10069]

Poster: Drug/Disease Modelling - Infection