Dosing Recommendations for Concomitant Medications During 3D Anti-HCV Therapy

The development of direct-acting antiviral agents (DAAs) has revolutionized the treatment of chronic hepatitis C virus (HCV) infection. In head-to-head comparisons, combination therapy with DAAs has proven to be more effective and better tolerated than interferon-based therapies in both treatment-naïve and treatment-experienced patients [1‐4]. One such investigational combination includes ombitasvir, paritaprevir (identified as a lead compound by AbbVie, Inc., North Chicago, IL, USA, and Enanta Pharmaceuticals, Inc., Watertown, MA, USA), ritonavir, and dasabuvir, together known as the 3D regimen. Ombitasvir, paritaprevir, and dasabuvir combine unique antiviral mechanisms of action (nonstructural protein 5A inhibition, nonstructural protein 3/4A protease inhibition, and non-nucleoside nonstructural protein 5B polymerase inhibition, respectively). This potent three-class combination approach has achieved high rates of sustained virologic response in a broad range of patients, including those with cirrhosis or those who have undergone liver transplant [5, 6]. The antiviral activity of paritaprevir is boosted by its co-formulation with a low dose of ritonavir (i.e., 100 mg), facilitating the use of a lower dose of paritaprevir and once-daily dosing. Ritonavir is a strong inhibitor of cytochrome P450 (CYP) 3A4, a major enzyme involved in the metabolism of paritaprevir [7].

In pivotal clinical trials, the 3D regimen with ribavirin achieved sustained virologic response rates at 12 weeks (SVR12) of 94–100 % in treatment-naïve and treatment-experienced non-cirrhotic patients with genotype-1 HCV and 93–100 % after 24 weeks of treatment in patients with genotype-1 HCV and cirrhosis, including prior null responders [5, 8‐11]. Additionally, in liver transplant recipients with recurrent HCV genotype-1 infection and no cirrhosis (Metavir ≤F2) at least 12 months after transplantation, 33 of 34 patients (97 %; 95 % confidence interval [CI] 85–100 %) who were treated with the 3D regimen plus ribavirin for 24 weeks achieved SVR12 [6]. No graft rejection events occurred during the study. The 3D regimen was well tolerated when administered with or without ribavirin; treatment discontinuation rates were low and adverse events (AEs) were generally mild [5, 6, 8‐12]. In subjects receiving 3D with ribavirin, the most commonly reported AEs (occurring in >10 % of subjects) were fatigue, nausea, pruritus, other skin reactions, insomnia, and asthenia. In subjects receiving 3D regimen without ribavirin, the most commonly reported AEs (occurring in ≥5 % of subjects) were nausea, pruritus, and insomnia. The safety profile of the 3D regimen was similar in patients with cirrhosis [5] or who were post-transplant [6] to that of the overall population and no significant associations were found between ombitasvir, dasabuvir, and ritonavir exposures and AEs or laboratory abnormalities [13]. Exposure-safety analyses showed that increases in paritaprevir exposure of up to 2-fold are not predicted to meaningfully increase AEs or laboratory abnormalities of Grade 3 or greater [13].

Comparisons of 3D pharmacokinetics in subjects with hepatic impairment vs normal hepatic function demonstrated that DAA exposures were not significantly affected (<35 % change) in subjects with mild hepatic impairment (Child-Pugh A) and, hence, no dosage adjustment of 3D therapy is required for such patients [12]. In patients with moderate hepatic impairment (Child-Pugh B), ombitasvir, ritonavir, and dasabuvir area under the plasma concentration-time curves (AUCs) decreased by 30 % or less, whereas paritaprevir AUC increased by 62 % [12]. Because of these exposure changes, 3D therapy is not recommended in patients with moderate hepatic impairment. A more substantial effect on DAA exposures (54 % decrease in ombitasvir and 325 and 945 % increase in dasabuvir and paritaprevir, respectively) was observed in patients with severe hepatic impairment (Child-Pugh C) [12]. Therefore, 3D therapy is contraindicated in patients with severe hepatic impairment.

Pharmacokinetic study data indicate that the presence of mild, moderate, or severe renal impairment does not increase DAA exposures to a clinically significant degree (<50 % change); therefore, no dose adjustment is indicated for 3D therapy when given to patients with renal impairment [14].

Food has been shown to significantly increase exposures for 3D components, by as much as 82, 211, 49, and 30 % for ombitasvir, paritaprevir, ritonavir, and dasabuvir, respectively [12]. Fat and/or calorie content do not appear to influence the magnitude of interaction. In all phase I–III studies, 3D regimen components were administered with food. Given the magnitude of the effect of food, 3D therapy should be administered with food to maximize absorption.

As new therapeutic options for treating HCV become available, it will be important to assess their abilities to interact with established medications, particularly those drugs or drug classes that are commonplace among patients with HCV infection. Adverse drug reactions resulting from concomitantly administered medications are an ongoing concern for patients undergoing HCV treatment because of the heavy burden of polypharmacy that coincides with a high prevalence of comorbidities in this patient population [15‐17]. The interplay of therapies influences not only the safety profile (via the potential for increasing drug exposures) but also may reduce therapeutic efficacy in cases where metabolic enzyme induction decreases circulating drug concentrations. Mechanistic data have shown a propensity for all DAAs to act as substrates, inhibitors and/or inducers of metabolic enzymes, and transporters, which is the foundation for the observed drug–drug interactions (DDIs) [18, 19].

In clinical practice, non-HCV medications that have the potential for interactions with HCV treatments are frequently prescribed to patients with chronic HCV infection [20, 21]. In a recent study, more than half of the medications that were commonly prescribed to a large representative sample of patients with chronic HCV infection (N = 53,461) were found to have interaction potential with telapravir and boceprevir.[21] However, later-generation DAAs represent an improvement in DDI propensity compared with the first-generation protease inhibitors.

Pharmacokinetic studies are the ideal method by which to evaluate the DDI potential of the 3D regimen; however, such an undertaking is not feasible given the number of prescription and over-the-counter medications available and their various permutations. In recognition of these limitations, regulatory agencies have created recommendations regarding which drugs should be studied to interrogate potential enzymatic and transporter pathways that may lead to significant DDIs [22, 23]. With results from key DDI studies, data can then be extrapolated to other medications based on what is known about drug metabolism.

To provide clear guidance regarding the clinical use of the 3D regimen and facilitate prescription decisions, in this report, we have gathered information on the metabolism and disposition of more than 200 commonly used drugs. These data, together with DDI studies involving the 3D regimen, were used to develop recommendations for DDI evaluation and management. In addition, these recommendations were successfully implemented for co-medication management in the pivotal phase III clinical trials of the 3D regimen and are also being implemented in the ongoing phase IIIb studies.