Phase I study and pharmacokinetics of weekly high-dose 13-cis-retinoic acid

In an attempt to increase the peak plasma levels of 13-cis-retinoic acid (13-cis-RA) and its efficacy in vivo, a Phase I study and pharmacokinetics of weekly high-dose, oral 13-cis-RA was conducted in 23 cancer patients who were refractory to conventional treatments. At 200 mg/sq m, the mean peak pl...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1985-04, Vol.45 (4), p.1874-1878
Main Authors: CLAMON, G, CHABOT, G. G, VALERIOTE, F, DAVILLA, E, VOGEL, C, GOROWSKI, E, BIRCH, R
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic agents
Biological and medical sciences
Chemotherapy
Drug Evaluation
Female
Humans
Kinetics
Male
Medical sciences
Middle Aged
Neoplasms - drug therapy
Pharmacology. Drug treatments
Tretinoin - adverse effects
Tretinoin - metabolism
Tretinoin - therapeutic use
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Summary:In an attempt to increase the peak plasma levels of 13-cis-retinoic acid (13-cis-RA) and its efficacy in vivo, a Phase I study and pharmacokinetics of weekly high-dose, oral 13-cis-RA was conducted in 23 cancer patients who were refractory to conventional treatments. At 200 mg/sq m, the mean peak plasma level of 13-cis-RA was 1.5 +/- 0.1 (SE) micrograms/ml; at 400 mg/sq m, the mean peak plasma level increased to 3.8 +/- 0.7 micrograms/ml. Further increases of the 13-cis-RA dose up to 1800 mg/sq m did not lead to proportional increases in either the mean peak plasma levels or area under the curve, indicating a saturable absorption phenomenon. The terminal half-life was highly variable (range, 2.8 to 101.3 h) and was not related to the dose given. A secondary peak plasma concentration was seen in five patients, suggesting enterohepatic circulation. The toxicities such as headache, cheilitis, dry skin, and dry eyes were frequent on the weekly schedule but were not dose-limiting. One patient had an elevation of the triglycerides of 2 to 5 times the upper limit of normal; five patients had an elevation of 1.1 to 2 times normal. No objective responses were observed to treatment with 13-cis-RA. Of 20 patients receiving an adequate trial of the drug, 18 showed progression of their cancer, and two had stable disease.
ISSN:0008-5472
1538-7445