Abstract
The effectiveness of Filgrastim SD/01 (SD/01) has been demonstrated in the relief of neutropenia associated with cancer chemotherapy. The studies reported to date administered SD/01 primarily on the day after chemotherapy in a similar manner to the injection of conventional Filgrastim. It was not clear whether the same dosing paradigm would be optimum for an engineered form of Filgrastim with substantially altered pharmacokinetics. In order to examine the optimum timing of SD/01 relative to chemotherapy, mice were treated with 325 mg/kg cyclophosphamide (CY) on study day 0. They were also treated with a bolus dose of 1000 g/kg SD/01 on days −5, −4, −3, −2, −1, 1, 2, 3, 4 or 5. Blood was collected for complete blood counts on study days −1, +1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12. Normal untreated mice have an ANC of 0.75 to 1.25 × 103/μL. Following CY treatment ANC fell to a nadir of .01 × 103/μL on day 4 then quickly rebounded to a high of 3.5 × 103/μL on day 8, returning to normal by day 10. Post-CY treatment with SD/01 on days 1, 2 or 3 improved the ANC nadir and brought counts back to baseline between days 4 and 5 (one day earlier). Delaying the SD/01 to days 4 and 5 after CY did not accelerate the return to baseline ANC. Pretreatment with SD/01 did not impact the depth or timing of the nadir or the day ANC passed the baseline count during recovery. Pre-treatment with SD/01 raised the ANC depending on the interval between treatment and CY exposure. Thus, 5 days pretreatment yielded an ANC of 14 × 103/μL, 4 days 11 × 103/μL, 3 days 8 × 103/μL, 2 days 3 × 103/μL, and 0.53 × 103/μL with 1 day pre-treatment. Pre-treatment with SD/01 (ie before chemo) is relatively ineffective compared to post-chemo treatment. Day 1 post-chemotherapy treatment appears to be the most effective timing for decreasing the severity and duration of neutropenia—delaying administration makes it less effective, and pre-treating does not appear to improve or worsen ANC recovery.
Published Version
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