Rilpivirine Pharmacokinetics in 3 HIV-Positive Patients With Liver Cirrhosis Concomitantly Receiving Pantoprazole.

To the Editor: Rilpivirine, a HIV-1 nonnucleoside reverse transcriptase inhibitor, has shown a favourable tolerability profile with minimal central nervous system and metabolic side effects. Rilpivirine pharmacokinetics is characterized by a higher bioavailability when administered with food, by high plasma protein binding (99.7%), and by hepatic metabolism (mostly through cytochrome P450, isoenzyme 3A4); omeprazole coadministration is associated with a significant reduction in rilpivirine plasma exposure [40% reduction in 24-hour area under the curve (AUC) and Cmax], thus contraindicating its concomitant use. Several antiretrovirals have been shown to reach higher plasma concentrations in patients with chronic liver disease; nevertheless, the impact of hepatic impairment on rilpivirine exposure has been investigated in few HIV-negative subjects. Rilpivirine plasma exposure was marginally affected in subjects with mild and moderate hepatic impairment despite a longer elimination half-life (81 and 91 hours, respectively) than in healthy volunteers (60 hours). Data in HIV-positive cirrhotic patients are currently unavailable; furthermore, the net effect of concomitantly administered proton pump inhibitors (frequently included in the treatment of patients with severe liver impairment) is also unknown. Three HIV-positive patients with compensated liver cirrhosis, multiple intolerances to other antiretrovirals, and receiving rilpivirine-containing antiretroviral combinations (25 mg daily, with food) were included; they were already on once-daily pantoprazole (40 mg daily) either for chronic gastritis or for preventing oesophageal variceal bleeding. Written informed consents for sample collection and data publication were obtained. Intensive sampling throughout the dosing interval (before and 1, 2, 4, 6, 8, 12, and 24 hours after the morning dose) was performed. Plasma concentrations were measured through a validated HPLC-PDA method (modified from D’Avolio et al). Steadystate pharmacokinetic parameters were derived by noncompartmental analysis using Kinetica software. Estimated creatinine clearance (eCRCL) was calculated using the Cockroft–Gault equation. Patient A was a 52-year-old man with hepatitis C virus (HCV)-related liver cirrhosis (child A5, plasma albumin: 2.8 g/dL, and eCRCL: 87.08 mL/ min), with a body weight and body mass index (BMI) of 57 kg and 18.4 kg/m2. He had been on abacavir/lamivudine for 9 months with excellent results (CD4+ T lymphocytes: 1083 cell/mm3, HIV RNA: ,20 copies/mL). On the finding of very low rilpivirine plasma concentrations, pantoprazole was withdrawn and AUC repeated after 14 days. Patient B was a 49-year-old man (weight: 50 kg, BMI: 17.93 kg/m2, and eCRCL: 52.23 mL/min) on coformulated tenofovir/ emtricitabine/rilpivirine (269 CD4/mm3, HIV RNA: 1819 copies/mL after a selfimposed treatment interruption). He was admitted for a decompensated HCVrelated liver cirrhosis (child C12, plasma albumin: 2.2 g/dL); 2 weeks after being discharged, plasma concentrations were measured. Patient C was a 56-year-old man with HCV/HBV–related cirrhosis (child B8, plasma albumin: 2.7 g/dL, eCRCL: 84.58 mL/min) with body weight and BMI of 58 kg and 18.1 kg/m2. He had been on coadministered tenofovir/emtricitabine/rilpivirine for 1 year with excellent results (CD4: 706/mm3, HIV RNA: ,20 copies/mL). Pantoprazole was administered 4 hours after rilpivirine administration (range 3–5). The rilpivirine pharmacokinetic profile is shown in Figure 1 and Table 1; despite a wide interpatient variability, no subject had rilpivirine plasma concentrations below the wild-type protein-free 90% effective concentration (EC90, 0.66 ng/mL) and only patient A’s Cmin was below the proteincorrected EC90 (25.8 ng/mL). 8 Abacavir, emtricitabine, lamivudine, and tenofovir plasma concentrations were similar to published data (not shown). In patient A, on pantoprazole withdrawal, rilpivirine AUC, Cmax, and Cmin increased 7.5, 5.9, and 18 fold. Over an average follow-up of 12 months, no significant hepatic worsening (excluding patient B