Pharmacokinetic analysis of an all intraperitoneal carboplatin and paclitaxel regimen in ovarian cancer patients demonstrates favorable systemic bioavailability of both agents

5008 Background: A phase III trial (GOG172) demonstrated improved survival for patients with newly diagnosed and optimally debulked ovarian cancer treated with intraperitoneal (ip) cisplatin and paclitaxel (P), given both as a 24 h iv infusion and ip, as compared with standard iv dosing. Studies to further enhance efficacy and minimize toxicity of ip taxane/platinum regimens are needed. Because adequate systemic drug exposure is thought to be essential for maximum therapeutic benefit of ip chemotherapy, the pharmacokinetics (PK) and bioavailability of ip P and carboplatin (C) were determined in this pt population in a phase II trial to evaluate dosing by the ip route alone. Methods: P 60 mg/m2 once a week and C at an AUC 6 every weeks were infused over 1 h, iv in cycle 1 and ip in the 5 subsequent 21-day cycles. Plasma samples were collected during week 1 of cycles 1, 2 and 6. P was measured by LC/MS and free platinum (fPt) was determined by flameless atomic absorption. Results: PK data is available for 14 pts receiving at least 1 cycle of ip therapy and for 7 pts who received all 5 cycles. When given ip, P achieved a peak conc. in plasma (Cmax) of 0.086 ± 0.034 μM (mean ± SD) at 6.4 ± 2.2 h, 22-times lower than Cmax for iv infusion (1.92 ± 0.80 μM). Thereafter, P plasma levels were comparable for both routes and decayed at similar rates with a half-life of 13.9 ± 4.1 h for iv and 13.7 ± 2.2 h for ip dosing. The systemic bioavailability of ip P was 53 ± 19% for the initial dose and 46 ± 10% in cycle 6. P plasma levels exceeded 0.05 μM, the pharmacologic threshold conc., for >20 h upon ip dosing in 67% (10/15) and 71% (5/7) of pts in cycles 2 and 6, respectively. C was rapidly absorbed into systemic circulation when given ip with a Cmax of 83 ± 11 μM for fPt at 1.6 ± 0.2 h in cycle 2. Consistent with prior reports, systemic availability of fPt exceeded 100% (133 ± 22% in cycle 2; 142 ± 47% in cycle 6). Conclusions: Weekly ip P 60 mg/m2 with ip C (AUC 6) every 3 weeks achieved a potentially effective pattern of systemic exposure to both agents in a majority of pts. The cumulative time that P plasma levels are >0.05 μM per cycle of therapy is likely to be longer than provided by the iv/ip dosing regimen for P (135 mg/m2 24 h iv infusion day 1; 60 mg/m2 ip day 8) used in GOG172. No significant financial relationships to disclose.