613. Novel use of Ritonavir boosting to achieve therapeutic itraconazole levels in disseminated Histoplasmosis
Authors: Patel Hasinaa , O'Hara Geraldine , Brown Aisling 
Published: December 2022

Abstract

Background
Itraconazole is a poorly soluble antifungal drug with variable pharmacokinetics. Serum levels vary between patients and over time, due to absorption issues and drug-drug interactions. Itraconazole suspension has more predictable absorption than capsules, but is poorly tolerated. Newer formulations dispersing drug in polymer aim to improve bioavailability, but are costly and not widely available. Standard therapy for histoplasmosis is induction with liposomal amphotericin B (LAmB) followed by 12+ months of itraconazole therapy with target pre-dose levels of 1-4 mg/L.

Methods
A 33yo M presented with weight loss, fever and dyspnoea, having returned to the UK from Nicaragua. He had been taking adalimumab for Crohn’s disease, quiescent for years following a prior small bowel resection. Empiric antifungal therapy with LAmB was commmenced, prior to confirmation of disseminated histoplasmosis by urinary antigen and blood culture. His course was complicated by significant bowel inflammation, requiring subtotal colectomy and end-ileostomy. Since surgery, he has had a high output stoma, with rapid transit time and reduced absorption.

Results
Despite itraconazole dose titration to 300mg TDS, levels were generally &lt; 0.5 mg/L and maximum serum itraconazole level achieved was 0.64 mg/L. The patient was trained with a view to self-OPAT LAmB.
On day 117 of antifungal therapy, ritonavir 100mg once daily was added. Four days after this, itraconazole level was 1.39 mg/L (from 0.34 mg/L) and maintained target concentration even after a switch from itraconazole suspension to capsules (Fig.1) with significant fungal marker response (Fig. 2). Figure 1.Itraconazole dosing and levels pre- and post-ritonavir
Total daily itraconazole dose (suspension followed by capsules) was mapped over time. There is a period where LAmB alone was used surrounding the colorectal surgery. Serum itraconazole levels dramatically increased 2 days after the introduction of ritonavir 100mg once daily and remained above target trough even after switching to itraconazole capsules. Figure 2.Fungal marker (B-D-glucan and Histoplasma urinary Ag) response to antifungal therapy
The response of serum beta-D-glucan and quantitative urinary Histoplasma antigen EIA (Miravista Labs) is represented alongside concurrent antifungal therapy. Of note, the first four urinary Histoplasma Ag levels were reporte as above the limit of detection (&gt; 20 ng/mL) and are represented here as an arbitrary value of 25 ng/mL.

Conclusion
Use of ritonavir alone to boost itraconazole has not previously been described. It avoids the longer-term complications of intravenous access and adverse renal and other effects of LAmB. Itraconazole is both a substrate and inhibitor of cytochrome P450 3A4 (CYP3A4) and inhibits P-glycoprotein, resulting in considerable drug:drug interactions. Ritonavir is a more potent inhibitor of CYP3A4. Use of ritonavir-boosted itraconazole amounted to a 99% reduction in cost vs LAmB over 6 months. It may offer a reliable and cost-effective method of boosting itraconazole where other drug:drug interactions do not preclude its use.

Disclosures
All Authors: No reported disclosures.