Population pharmacokinetic-pharmacodynamic modeling and simulation of platelet decrease induced by peg-interferon-alpha 2a.

Peg-interferon-alpha-2a (PEG-IFN) has been used all over the world including Japan as the standard of care for chronic hepatitis C (CHC). PEG-IFN causes platelet count decrease, while CHC patients with compensated liver cirrhosis have a low baseline of platelets. To use PEG-IFN more safely in these patients, we analyzed the effect of PEG-IFN on the longitudinal platelet profile with a pharmacokinetic-pharmacodynamic model. Platelet count and serum PEG-IFN concentration obtained from a Japanese clinical study on 40 patients were analyzed. The serum PEG-IFN concentration profile was fitted with an open 1-compartment model and the platelet profile was fitted with a turnover model. After the final model was fixed, the platelet profiles were simulated with various platelet baselines. The simulation revealed that according to PEG-IFN administration platelets decreased gradually and reached steady state within 12 weeks, and almost subjects would not have a lower platelet count than the criteria for discontinuation of the treatment. Once administration was discontinued, platelets recovered up to the baseline within several weeks. In conclusion, platelet count was predicted to be about a 30% (5th-95th percentiles in 1,000 simulation: 11-66%) decrease and to return to the baseline value in 4 to 8 weeks after the last administration of PEG-IFN.