Flecainide Plasma Level Modifications during Ledipasvir/Sofosbuvir Coadministration in Two Patients Affected by Chronic Hepatitis C

Currently, the interferon (IFN)-free therapies with direct-acting antivirals (DAAs) strongly enhance the effectiveness of chronic hepatitis C (CHC) treatment. These new drugs are administered in several combinations, based on patient features, viral genotype and previous treatments. Among these, sofosbuvir (SOF) and ledipasvir (LDV) is the most used combination for patients affected by CHC and genotype-1 and 4 [1].

Although this regimen is characterized by a poor potential for drug–drug interactions (DDIs), since both the molecules are not substrates of cytochromes [2] (LDV has a marginal activity as inductor and inhibitor), the investigation of possible DDIs is still useful, particularly when the concomitant drugs have an already known concentration–effect–toxicity relationship. For instance, an unexpected DDI with lethal consequences was recently identified between SOF, daclatasvir and amiodarone [3].

In this work we report for the first time the effect of SOF/LDV on the concentrations of flecainide (FLC) in two patients undergoing anti-arrhythmic therapy due to atrial fibrillation. Orally administrated FLC has a mean 90% bioavailability with protein binding of 40% and it is metabolized through CYP2D6 and CYP1A2 to the active meta-O-dealkylated FLC and its inactive lactam [4]; both FLC and metabolites are mainly excreted by the kidney. These features do not suggest any potential for DDIs with SOF, LDV or ribavirin (RBV).

Previous studies reported that serious adverse effects (pro-arrhythmic events or ventricular tachycardia), can occur in patients with plasma levels outside the well-known therapeutic range (200–1,000 ng/ml) so its therapeutic drug monitoring (TDM) is strongly recommended to prevent adverse events or inefficacy [5].

In this study, plasma sampling was performed at the end of dosing interval (C trough), before starting treatment with SOF/LDV and at the time points reported in Figure 1 during anti-HCV treatment and in follow-up.

Figure 1

Graphical representation of the trend of flecainide concentrations during the 3 months (end of treatment) and 12 weeks of follow-up of anti-HCV treatment with sofosbuvir/ledipasvir

Measurement of FLC concentrations during treatment was developed and validated according to FDA guidelines [6], characterized by a solid phase extraction protocol, and this method resulted in a very high accuracy (98.2%), intra- and inter-day precision (relative standard deviation [RSD] 3.3% and 5.4%), while extraction recovery was high and reproducible for both the internal standard and FLC (94.5%, RSD 9.4% and 99.5%, RSD 2.6%, respectively). SOF, GS-331007 (the main SOF metabolite in plasma) and LDV plasma concentrations were quantified through a published UHPLC-MS/MS method [7], RBV was quantified through HPLC-UV [8].

Treated patients affected by CHC, were naive, with genotype-1b and fibrosis METAVIR score 3 and received SOF/LDV for 12 weeks (Table 1).

Table 1

Demographic and clinical data of patients

Patient	Age, years	Sex, M/F	Body mass index, kg/m2	Serum creatinine, mg/dl	Haemoglobin, g/dl	Albumin, g/dl	HCV genotype	Naive/ experienced	Urinary pH	Dose of flecainide
1	66	M	24.5	0.9	13.8	4.5	1b	Naive	5.5	150 mg/12 h
2	61	M	23.1	0.7	14.5	3.9	1b	Naive	6	50 mg/12 h

The results from pharmacokinetic analysis evidenced an immediate reduction of FLC plasma concentrations after the first week (198 and 742 ng/ml for patient 1 and patient 2, respectively) by about 35% (132 and 498 ng/ml at day 14, respectively) and a stabilization during the following weeks (Figure 1): this resulted in being potentially dangerous for one patient, who had FLC concentrations lower than 200 ng/ml. However, by electrocardiographic analysis this patient did not show any sign of arrhythmia.

By contrast, GS-331007 and LDV resulted adequate and comparable with other patients. Both the patients achieved the SVR at the end of treatment without any significant side effects.

The concentrations of FLC raised up almost to baseline levels after 12 weeks of follow-up.

The observed results suggest that attention should be paid when administering SOF/LDV to patients undergoing therapy with FLC. The nature of this interaction is currently unknown: this could be caused by, for instance, a faster metabolism of FLC due to protein displacement and higher bioavailability. The use of TDM of FLC concentrations can be useful in this cases, in order to prevent possible adverse events due to the FLC concentration reduction by adjusting FLC dose; the concomitant treatment with FLC did not impact the effectiveness of SOF/LDV.