Methods: A population pharmacokinetic model (Wu and Kiser, AAC, Apr;59(4):2179-88, 2015) was utilized using previous estimates of EC50 to define the concentration effect relationship for ribavirin. A 10,000 patient Monte Carlo Simulation (MCS) evaluated the 24h Steady State Area Under the Concentration Time Curve (AUCss) in relation to probability of target attainment (PTA) of response in achieving an AUC50 which was derived using EC50 value of 11 mcM from the package insert data from a stable HCV replicon model system which inhibited autonomous HCV RNA replication with a 50% effective concentration. In the MCS, the following daily doses were simulated using AUCss =CLT/Dose for ribavirin 1000, 1200, 1400, 1600, 1800, 2000, 2200, and 2400 mg.
Results: The population median (mean) of 14.7 (15.5) L/hr (range of 5.01 to 59.3 L/hr) for apparent total clearance (CLT/F) with an inter-individual variability of 33.2% was recapitulated in the 10,000 patient MCS. The mean of ribavirin AUCSS (mg/L/hr) for the following daily ribavirin dosages were as follows: 1000mg: 71.8, 1200mg: 86.2, 1400mg: 100, 1600mg: 115, 1800mg: 129, 2000mg: 144, 2200 mg: 158, 2400 mg: 172. The (PTA by achieving the AUC50 which inhibits autonomous HCV RNA replication with a 50% exposure for the following daily doses of ribavirin monotherapy was: 1000 mg: 57.5%, 1200mg: 77.7%, 1400mg: 95.1%, 1600mg: 94.6%, 1800mg: 97.4%, 2000mg: 98.8%, 2200mg: 99.5%, and 2400mg: 100.0%.
B. T. Tsuji,
Q. Ma, None
R. Difrancesco, None
C. Bednasz, None
N. Smith, None
G. Morse, None
A. Talal, Merck: Grant Investigator , Research grant
Abbvie: Grant Investigator , Research grant
Gilead: Grant Investigator , Research grant
Abbot: Grant Investigator , Research grant
Abbott: Grant Investigator , Research grant
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