ABSTRACT
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.
Subject(s)
Anilides/pharmacokinetics , Carbamates/pharmacokinetics , Hepatic Insufficiency/blood , Hepatitis C, Chronic/drug therapy , Macrocyclic Compounds/pharmacokinetics , Ribavirin/pharmacokinetics , Ritonavir/pharmacokinetics , Sulfonamides/pharmacokinetics , Uracil/analogs & derivatives , 2-Naphthylamine , Anilides/administration & dosage , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Carbamates/administration & dosage , Cyclopropanes , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Hepatic Insufficiency/etiology , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/complications , Humans , Lactams, Macrocyclic , Liver Function Tests , Macrocyclic Compounds/administration & dosage , Male , Middle Aged , Proline/analogs & derivatives , Ribavirin/administration & dosage , Ritonavir/administration & dosage , Sulfonamides/administration & dosage , Treatment Outcome , Uracil/administration & dosage , Uracil/pharmacokinetics , ValineABSTRACT
Respiratory syncytial virus (RSV) is a significant cause of morbidity in high-risk infants. Palivizumab is proven to prevent serious RSV disease, but compliance with prophylaxis (monthly doses during the RSV season) is essential to ensure protection. We invited 453 pediatricians to participate in a survey to identify their perspectives of barriers to compliance and interventions to improve compliance with palivizumab prophylaxis schedules. One hundred physicians from five continents completed the survey, identifying caregiver inconvenience, distance to clinic, cost of prophylaxis, and lack of understanding of the severity of RSV as the most common reasons for noncompliance. They recommended provision of educational materials about RSV, reminders from hospital or clinic, and administration of prophylaxis at home to increase compliance. Globally, physicians recognize several obstacles to prophylaxis compliance. This survey suggests that focused proactive interventions such as empowering caregivers with educational materials and reducing caregiver inconvenience may be instrumental to increase compliance.