Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment

Background & Aims: Paritaprevir, ombitasvir, and dasabuvir are direct-acting antivirals for treatment of chronic hepatitis C virus (HCV) infection. The aim of this study was to characterize the effects of mild, moderate, and severe hepatic impairment on the pharmacokinetics of these drugs. Methods: HCV-negative subjects with normal hepatic function (n = 7) or mild (Child-Pugh A, n = 6), moderate (Child-Pugh B, n = 6), or severe (Child-Pugh C, n = 5) hepatic impairment received a single-dose of the combination of paritaprevir plus ritonavir (paritaprevir/r, 200/100 mg), ombitasvir (25 mg), and dasabuvir (400 mg). Plasma samples were collected through 144 hours after administration for pharmacokinetic assessments. Results: Paritaprevir, ombitasvir, dasabuvir, and ritonavir exposures (maximal plasma concentration, C max , and area under the concentration-time curve, AUC) were minimally affected in subjects with mild or moderate hepatic impairment. Differences in exposures between healthy controls and subjects with mild or moderate hepatic impairment were less than 35%, except for 62% higher paritaprevir AUC in subjects with moderate hepatic impairment. Paritaprevir and dasabuvir AUC were significantly higher in subjects with severe hepatic impairment (950% and 325%, respectively). However, ombitasvir AUC was 54% lower and ritonavir AUC was comparable. Adverse events included eye stye, insomnia, and pain from an infiltrated intravenous line. Conclusions: The changes observed in paritaprevir, ritonavir, ombitasvir, and dasabuvir exposures in subjects with mild or moderate hepatic impairment do not necessitate dose adjustment. Subjects with severe hepatic impairment had substantially higher paritaprevir and dasabuvir exposures.

Pharmacokinetics and Tolerability of Anti-Hepatitis C Virus Treatment with Ombitasvir, Paritaprevir, Ritonavir, with or Without Dasabuvir, in Subjects with Renal Impairment

The direct-acting antiviral agent (DAA) combination of ombitasvir and paritaprevir (administered with ritonavir) with (3D regimen) or without (2D regimen) dasabuvir has shown very high efficacy rates in the treatment of chronic hepatitis C virus (HCV) infection. Renal impairment, a common comorbidity in patients with chronic HCV infection, can influence the pharmacokinetics of antiviral agents and hence their efficacy and safety profiles. The aim of this study was to evaluate the influence of renal impairment on the pharmacokinetics and tolerability of the 3D and 2D regimens. Overall, 24 subjects, six in each of four renal function groups (normal, mild, moderate, and severe), received a single dose of the 3D and 2D regimens in separate dosing periods. Plasma and urine were analyzed to assess the effect of renal impairment on drug exposure. DAA exposures changed by up to 21, 37, and 50 % in subjects with mild, moderate, and severe renal impairment, respectively, versus subjects with normal renal function. Ritonavir exposure increased with the degree of renal impairment (maximum 114 %). The half-lives of DAAs and ritonavir in subjects with renal impairment were generally comparable with those in healthy subjects. No safety or tolerability concerns arose in this study. The 3D and 2D regimens do not require dose adjustment for patients with HCV infection and concomitant renal impairment

Pharmacokinetics and Exposure–Efficacy Relationship of Adalimumab in Pediatric Patients with Moderate to Severe Crohnʼs Disease

Background:Adalimumab, a fully human monoclonal antibody (IgG1) to tumor necrosis factor, has shown benefit in the treatment of inflammatory bowel disease. The purpose of this analysis was to evaluate the pharmacokinetics (PK) and the serum concentration-efficacy relationship of adalimumab in pediatric patients with moderate-to-severe Crohn's disease.Methods:The safety, efficacy, and PK of adalimumab was evaluated in a phase-3, randomized, double-blind, 52-week study (IMAgINE-1, N = 192), which had a 4-week open-label induction phase (dose was determined by patient weight) followed by a 48-week double-blind maintenance phase (standard and low-dose arms, drug given every other week). Trough serum adalimumab (baseline, weeks 2, 4, 16, 26, and 52) and anti-adalimumab antibody measurements (baseline, weeks 16, 26, and 52) were collected. Disease activity was assessed using the Pediatric Crohn's Disease Activity Index.Results:At week 52, adalimumab trough concentrations (mean SD) were higher for patients in the standard-dose (9.48 +/- 5.61 g/mL) compared with the low-dose (3.51 +/- 2.21 g/mL) arm. In patients whose doses were increased from every other week to weekly, higher trough concentrations were observed after dose escalation. Higher body weight, baseline C-reactive protein, and lower baseline albumin levels were associated with greater clearance of adalimumab. An exposure (serum concentration)-efficacy relationship was observed, in which higher concentrations of adalimumab were associated with greater rates of remission.Conclusions:This study is the first to describe the PK of adalimumab in pediatric patients with moderate-to-severe Crohn's disease. A positive association between serum adalimumab concentration and remission/response was identified