Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (atra) and orally administered atra in healthy volunteers

Bulent Ozpolat, Gabriel Lopez-Berestein, Peter Adamson, Chau Hwei J. Fu, Anthony H. Williams

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82 Scopus citations

Abstract

Purpose: To determine single-and multiple-dose pharmacokinetics of liposomal-all-trans-retinoic acid (Atragen) following intravenous and oral ATRA (Vesanoid) administration in healthy volunteers. Methods: This was a randomized, prospective, open-label, parallel pharmacokinetic study in which 29 subjects were given 90 mg/m2 i.v. liposomal (L)-ATRA (16 subjects) every other day or 45 mg/m2 oral ATRA (13 subjects) daily over 15 days. Pharmacokinetic parameters were assessed on days 1, 9, and 15. Results: Twenty-two subjects (11 in each group) completed the study and were evaluated. Area under the plasma concentration-time curve [AUC(0,∞)] and maximum plasma concentration (Cmax) of ATRA did not decrease during the 15 days of L-ATRA treatment. However, the oral ATRA regimen resulted in a significant decrease in the AUC(0,∞) and Cmax of 45.3% and 31.8%, respectively, on day 9 as compared with that to day 1 (p<0.05). In addition, the mean AUC(0,∞) was 13- and 22-fold greater for L-ATRA than for oral ATRA on days 1 and 9, respectively. Despite the significantly higher plasma concentrations after L-ATRA treatment, the side effects of each formulation were similar, except for dermal exfoliation, which was seen in 31% of the subjects after L-ATRA dosing, and abnormal liver function tests that were seen in 23% of the subjects after oral ATRA administration. Conclusions: These findings suggest that i.v. administration of L-ATRA maintains higher and stable plasma ATRA concentrations than oral ATRA in healthy subjects after repetitive administration. L-ATRA with a favorable pharmacokinetic profile may have potential advantages over oral ATRA and may be more efficacious in the treatment of acute promyelocytic leukemia or other retinoid-responsive cancers.

Original languageEnglish (US)
Pages (from-to)292-301
Number of pages10
JournalJournal of Pharmacy and Pharmaceutical Sciences
Volume6
Issue number2
StatePublished - May 2003

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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