Pharmacokinetics (PK) of oxaliplatin (OX) after intraperitoneal (IP) and intravenous (IV) administration in patients with gynecological malignancies.

Abstract

2584 Background: Combined IV/IP chemotherapy has been associated with improved survival in ovarian cancer patients. Cisplatin is the most common drug used IP but is associated with significant toxicity. OX is a significantly larger molecule and may therefore have improved IP PK as compared to cisplatin IP. We evaluated the PK disposition of IP and IV OX as part of a phase I study. Methods: A phase I study with 2 arms was performed using modified Fibonacci dose escalation in patients (pts) with intraperitoneal ovarian cancer. In arm 1, pts received docetaxel (Doc) 75 mg/m2 IV on day 1 and OX 50 mg/m2 IP (dose level [DL] 1; n = 3) or OX 75 mg/m2 IP (DL2; n = 6) on day 2. In arm 2, pts received OX 75 mg/m2 IV on day 1 and Doc 50 mg/m2 IP (DL1; n = 3) or Doc 75 mg/m2 IP (DL2; n = 1) on day 2. IP fluid and plasma was collected at 0-24 h, 48 h, and 72 h after OX IP. Plasma was collected at 0-24 h after OX IV. Total and ultrafiltrate (UF) platinum (Pt) were measured in plasma and IP fluid via inductively coupled plasma mass spectrometry (ICP-MS). Area under the concentration versus time curve (AUC) and maximum concentration (Cmax) were estimated. Results: The PK of OX IP at 50 mg/m2 and 75 mg/m2 were similar and thus combined in the Table. Conclusions: Total and UF Pt were approximately 1.9- and 10.8-fold higher, respectively, in IP fluid compared with plasma after OX IP. The plasma exposure of UF Pt was approximately 1.5- to 2-fold lower after OX IP as compared with OX IV. The intraperitoneal tumor site has a higher exposure of the active unbound Pt with less systemic exposure following OX IP compared with OX IV. The PK properties of OX IP appear to be superior to OX IV and potentially cisplatin IP. Units IP Plasma Ratio IP:Plasma Arm 1 OX IP (n=9) Total Pt (mean ± SD) UF Pt (mean ± SD) Total Pt (mean ± SD) UF Pt (mean ± SD) Total Pt (mean ± SD) UF Pt (mean ± SD) AUC0–72h μg/mL·h 88.5 ± 58.5 50.9 ± 35.8 46.3 ± 10.6 4.7 ± 1.5 1.9 10.8 AUC0–24h μg/mL·h 60.5 ± 39.4 47.6 ± 34.4 21.1 ± 7.3 3.1 ± 1.0 2.9 15.4 Cmax μg/mL 11.1 ± 5.9 11.8 ± 7.6 1.2 ± 0.6 0.2 ± 0.05 9.4 65.9 Arm 2 OX IV (n=4) AUC0–24h μ g/mL·h — — 32.4 ± 12.3 5.7 ± 3.1 — — Cmax μ g/mL — — 7.0 ± 9.2 1.7 ± 2.6 — — Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis