A two-year crossover therapeutic trial with halofenate and clofibrate.

Twelve patients with Type IV hyperlipoproteinemia were treated with clofibrate and halofenate in a double blind, crossover trial for two years. Drug intake was monitored by determination of the level of the drugs in serum. Halofenate and clofibrate were equally effective in lowering plasma triglycerides and cholesterol levels. Patients who were secretors of ABO blood group antigens in saliva had a greater hypocholesterolemic response to both drugs than those who were nonsecretors. Clofibrate treatment resulted in a significant rise of low density lipoprotein cholesterol. Both drugs lowered serum bilirubin levels and this effect had a significant positive correlation with that on uric acid levels. Halofenate had a greater hypouricemic effect than clofibrate and may be a useful drug for treatment of patients with Type IV hyperlipoproteinemia who have concomitant hyperuricemia.

Changes in serum thyrotropin (TSH) in man during halofenate administration.

Halofenate, a serum lipid-lowering agent which inhibits binding of thyroid hormone to thyroxine-binding globulin (TBG), was administered daily for 14 days to 8 hypothyroid subjects with elevated TSH concentrations as a result of incomplete thyroxine (T4) therapy. Drug administration resulted in mean increases in serum dialyzable fraction T4 (DFT4) of 52% over pretreatment levels (P less than 0.01) and in dialyzable fraction triiodothyronine (DFT3) of 26% in 7 subjects, (P less than 0.01). During halofenate treatment in these 7 subjects, serum TSH concentrations decreased significantly (mean = 39%, P less than 0.01) when DFT4 and DFT3 were increased by halofenate. In only two subjects was there a convincing temporal relationship between increased serum absolute free T4 (AFT4) and decreased serum TSH concentrations. Contrary to what would be predicted from the "free hormone hypothesis", changes in serum TSH concentration in these hypothyroid patients appeared to relate primarily to changes in the free fraction of circulating T4 and T3 (DFT4, DFT3), rather than to alterations in AFT4 or AFT3. Halofenate did not alter serum TBG binding capacity. An eighth subject did not show increased DFT4 and DFT3 during halofenate treatment despite achievement of therapeutic serum levels of the agent; in this patient, serum TSH levels rose progressively throughout the period of inadequate T4 replacement and halofenate administration. In hypothyroid patients, short-term halofenate use suggests that the pituitary-thyroid hormone feedback circuit can respond to increases in serum DFT4 and DFT3 in the absence of detactable increases in absolute free hormone concentrations.

The interaction between halofenate and propranolol.

The effect of halofenate on beta adrenergic blockade by propranolol was studied in 4 subjects during chronic drug administration in a randomized, double-blind study. The plasma propranolol concentration was significantly lower during treatment with halofenate than with placebo. The reduction in propranolol levels correlated with a decrease in beta adrenergic blockade. The mechanism for the decrease in plasma concentration has not been determined.

The distribution of halofenate in plasma: a comparative analysis using Scatchard vs. stepwise association constants.

The distribution of Halofenate between the free and albumin bound forms was calculated by the use of two computer programs using both Scatchard association constants for a 3,3,7 model, and six stepwise equilbrium constants over a range of drug concentrations reported in man. The calculations, using either set of constants, showed that only 0.3 to 0.5% of the drug would be free. Using Scatchard association constants, it was estimated that 92 to 95% of the drug would be bound by the high affinity set of sites, and lesser amounts by sites of lesser affinity. A more complex pattern of distribution was obtained with the stepwise equilibrium constants. At low concentrations of Halofenate the complex with one mole of drug/mole of protein was most abundant and at the highest concentration studied the complex with two moles of drug/mole of protein was most abundant.