Phase I study of docosahexaenoic acid-paclitaxel: a taxane-fatty acid conjugate with a unique pharmacology and toxicity profile.
OBJECTIVE
Docosahexaenoic acid (DHA)-paclitaxel, a novel conjugate formed by covalently linking the natural fatty acid DHA to paclitaxel, was designed as a prodrug targeting intratumoral activation. This Phase I trial examined its toxicity and pharmacokinetics (PKs).


METHODS
Patients with advanced refractory solid tumors received a 2-h i.v. infusion of DHA-paclitaxel every 3 weeks. Plasma and urine samples were obtained to characterize the pharmacological profile of DHA-paclitaxel and paclitaxel.


RESULTS
Twenty-four patients received 78 cycles of DHA-paclitaxel over five dose levels (200-1100 mg/m(2)). Median number of cycles was 2 (range, 1-8). Myelosuppression was the principal toxicity observed (grade 3/4 neutropenia in 21%/53% of courses at 1100 mg/m(2)); during cycle 1, febrile neutropenia occurred in 1 of 9 patients treated at 1100 mg/m(2). Other grade 3 toxicities were infrequent. No patients developed alopecia, peripheral neuropathy > grade 1, or musculoskeletal toxicity > grade 1. At 1100 mg/m(2), DHA-paclitaxel had a mean (CV%) volume of distribution of 7.5 (64) liters, beta half-life of 112 (56) h, and clearance of 0.11 (30) liters/h. Paclitaxel PK parameters at 1100 mg/m(2) were: C(max), 282 (46) ng/ml; AUC, 10,705 (60) ng/ml x h; and terminal half-life, 85 (101) h. Paclitaxel plasma exposure represented < or =0.06% of DHA-paclitaxel exposure. Paclitaxel AUC was correlated with neutropenia. One partial response was observed.


CONCLUSIONS
The starting dose recommended for subsequent studies is 1100 mg/m(2). DHA-paclitaxel dramatically alters the PK profile of derived paclitaxel compared with values observed after a 3-h infusion of paclitaxel (175 mg/m(2)). In addition, its favorable toxicity profile offers potential advantages over existing taxanes.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D004281:Docosahexaenoic Acids / Q000008:administration & dosage*; D005227:Fatty Acids / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage*; D043823:Taxoids / Q000627:therapeutic use; D013997:Time Factors
D005227:Fatty Acids; D043823:Taxoids; D004281:Docosahexaenoic Acids; D017239:Paclitaxel