Terbinafine in Combination with Other Antifungal Agents for Treatment of Resistant or Refractory Mycoses: Investigating Optimal Dosing Regimens Using a Physiologically Based Pharmacokinetic Model

Abstract

dTerbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of highdose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (C max ), and minimum concentration (C min ) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.T he allylamine antifungal terbinafine is a well-established agent in the treatment of onychomycosis (1). Due to its broad antifungal spectrum, interest in terbinafine has expanded to include its use in a range of cutaneous and subcutaneous mycoses, such as sporotrichosis, eumycetoma, and chromoblastomycosis (2-4), as well as in combination with other antifungal agents to treat resistant or refractory invasive fungal infections (IFIs), as described in numerous case reports (1, 5). In support of the latter indication, synergistic in vitro antifungal activity has been demonstrated with terbinafine in combination with azole antifungals for many important fungal pathogens, including Aspergillus spp., zygomycetes, Fusarium spp., Paecilomyces spp., Candida albicans, dematiaceous molds, and the highly resistant Scedosporium prolificans (6-11).High dose is a consistent feature of terbinafine use in these indications, with daily doses of up to 1,000 mg daily (1) used to boost the plasma concentrations of terbinafine, which are known to be low following standard dosing, such as the standard dosing regimen of 250 mg daily in onychomycosis, due to extensive accumulation in skin and adipose tissue (12). However, no studies have assessed the systemic exposure of higher-dose terbinafine treatment (Ͼ250 mg daily) or divided daily doses (every 12 h [q12h] or q8h), factors that are likely to be crucial to the utility of terbinafine in effectively treating systemic mycoses in combination with other antifungals. This pauci...

Clinical characteristics and outcomes of invasive Lomentospora prolificans infections: Analysis of patients in the FungiScope® registry

“…In vitro synergism has been demonstrated for combination antifungal therapy with terbinafine + itraconazole against Mucorales, terbinafine + voriconazole against Fusarium spp and terbinafine + voriconazole against L prolificans , and it was suggested almost 20 years ago that combination therapy with an azole plus terbinafine may be a treatment option for these infections . However, the benefit of terbinafine‐based regimens was not significant in the recent review of 56 published cases of invasive lomentosporiosis (including 5 more recent cases that were also included in this study), where voriconazole‐based regimens were superior but significance was not reached in the subgroups of combination treatment .…”

In Vitro Antifungal Activity of Cysteine Derivatives and their Combinations with Antifungal Agents Against Clinically Relevant Scedosporium species

“…In combination with LCME, the MIC ranges of AMB, CSP, TRB, and VRC were decreased to 0.25 -4 µg/ml, 0.125 -16 µg/ml, 4 -8 µg/ml, and 0.125 -4 µg/ml, respectively (Table 3). Compared to the single use, the MIC values of antifungal drugs in the combination tests could be decreased to their achievable therapeutic plasma concentrations in several cases [18][19][20][21].…”

Rational for drug dosimetry and duration of terbinafine in the context of recalcitrant dermatophytosis: Is 500 mg better than 250 mg OD or BD?

“…Hence, findings from the article may not be relevant to manage recalcitrant dermatophytic superficial skin infections where the target skin concentration plays an important role rather than plasma concentration. [ 15 ]…”