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Model Predicts Long-Acting IM Rilpivirine Safe With Liver Impairment
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International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020
By Mark Mascolini for NATAP and Virology Education
Long-acting intramuscular (IM) rilpivirine at a dose of 1200/900 mg should be safe in people with Child-Pugh A, B, or C liver impairment, according to physiologically based pharmacokinetic (PBPK) modeling conducted at the University of Liverpool [1]. The findings also have implications for the design of future trials evaluating candidates for long-acting IM therapy in people with cirrhosis.
Long-acting IM nanoformulations of two antiretrovirals-the nonnucleoside rilpivirine and the integrase inhibitor cabotegravir-have been developed for HIV infection [2]. Because liver impairment is common in people with HIV infection, the University of Liverpool team used PBPK modeling to predict the pharmacokinetics of long-acting rilpivirine in such patients.
The researchers qualified their model with clinical data from people with liver impairment (oral dose) or without liver impairment (oral and long-acting IM dose). They assumed the model was qualified if simulated values lay within 2-fold of average reported values using the absolute average fold error (AAFE) approach. The Liverpool investigators validated the model against clinical data for an oral dose of 25 mg daily and for an IM dose of 1200 mg followed by a maintenance dose of 900 mg 28 days later. Pharmacokinetic predictions involved virtual patients with liver damage ranked as Child-Pugh score A, B, or C with 1-year survival chances of 100%, 80%, and 45%.
In the validation analysis, simulated oral and IM pharmacokinetic rilpivirine values for people without liver impairment agreed with published clinical data for oral and IM rilpivirine:
Observed vs simulated rilpivirine values without liver impairment:
Oral mean area under the concentration-time curve (AUC): 2708 vs 2875 ng*h/mL (AAFE* 1.05)
Oral mean maximum concentration (Cmax): 111.7 vs 111.2 ng/mL (AAFE 1.00)
IM mean AUC: 209,494 vs 256,975 ng*h/mL (AAFE 1.23)
IM mean Cmax: 154.4 vs 175.4 ng/mL (AAFE 1.14)
IM mean Ctrough: 74.4 vs 87.7 ng/mL (AAFE 1.17)
Simulated oral rilpivirine values also agreed with published clinical data for people with liver impairment:
Observed vs simulated rilpivirine values with liver impairment:
Oral mean AUC with Child-Pugh A: 2844 vs 4003 ng*h/mL (AAFE 1.40)
Oral mean AUC with Child-Pugh B: 3981 vs 5275 ng*h/mL (AAFE 1.32)
Oral mean Cmax with Child-Pugh A: 106.1 vs 141.4 ng/mL (AAFE 1.33)
Oral mean Cmax with Child-Pugh B: 141.8 vs 177.7 ng/mL (AAFE 1.25)
Simulated 1200/900-mg IM rilpivirine dosing at 4 weeks increased predicted AUC, Cmax, and Ctrough with liver impairment compared with healthy conditions:
Mean percent change with simulated IM rilpivirine values with vs without liver impairment:
AUC increase with Child-Pugh A, B, and C: +42.0%, +72.1%, +136.0%
Cmax increase with Child-Pugh A, B, and C: +37.2%, +61.8%, +121.2%
Ctrough increase with Child-Pugh A, B, and C: +45.1%, +81.7%, +149.1%
The Liverpool researchers believe their findings indicate that the 1200/900-mg IM dose of long-acting rilpivirine IM "may be suitable for treatment of HIV regardless of Child-Pugh classification." They proposed that the modeling approach used in this analysis can inform trial design and help identify candidates for long-acting IM therapy in people at different cirrhosis stages.
*AAFE, absolute average fold error.
References
1. Cottura N, Rajoli R, Kinvig H, Bunglawala F. In-silico prediction of intramuscular long-acting rilpivirine in liver impairment with PBPK models. International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020. Abstract 5.
2. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med 2020;382:1124-1135. doi 10.1056/NEJMoa1909512. https://www.nejm.org/doi/full/10.1056/NEJMoa1909512
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