The Body Covers: The 6th Conference on Retroviruses and Opportunistic Infections
Abstract No. 604: BMS-232632: Single and Multiple Oral Dose Safety and Pharmacokinetic Study in Healthy Volunteers
February 3, 1999
This study is one of several posters on new protease inhibitors that are under development. In particular, BMS-232632 shows an EC50 value ranging from 25 nM. This is a report of a single dose study and some preliminary results from ongoing multiple dose studies in healthy volunteers. Both studies were randomized double-blind with eight subjects per dose level. Single oral doses of 100, 300, 600, 900, and 1200 mg were evaluated. Multiple daily oral doses of 200, 400, 500 and 600 mg were given for 14-days (the 600 mg dose was given for 8-days). The authors report that single and multiple oral doses of BMS-232632 were well-tolerated: treatment related adverse events were mild and reversible. The 600 mg multiple dose was discontinued after eight doses by a protocol-specified stopping rule involving elevation of bilirubin. Clinically, however, all the patients were well. The isolated bilirubin elevations reverted to baseline within four days of discontinuation. A subsequent 500 mg cohort completed 14-days of dosing.Abstract: BMS-232632: Single and Multiple Oral Dose Safety and Pharmacokinetic Study in Healthy Volunteers
By way of background, the authors explain that this is a selective inhibitor of HIV aspartyl protease. This particular compound has potent in vitro activity against HIV-1 strains in a variety of host cells that were used in the evaluation. The selectivity index, 50% cytotoxicity concentration over 50% effective concentration [CC50/EC50] ranged from 6,500 to 23,800 for all strains of host type cells that were tested. Comparative studies using the same viral systems have revealed that BMS-232632 is significantly more potent (3 to 19-fold) than other protease inhibitors including indinavir, nelfinavir, ritonavir, saquinavir and amprenavir.
The study design used single and multiple dose designs as mentioned previously. The single dose study included two-way crossover featuring a capsule, then an oral solution, or a prototype formulation. All volunteers were healthy males, 18 to 45 of age. Samples were collected for clinical and biochemical safety management, and plasma pharmacokinetic evaluations. A review of the pharmacokinetic values revealed half-life data at all but the lowest dose: at 100 mg the T one-half had a mean value of 2.81 hours; at 300 mg the mean was 2.82 hours; and, at 600 mg, the mean was 6.14 hours. Indeed, at all but the lowest doses, the area under the curve remained significant for up to 24-hours. After multiple doses, the steady state values were certainly interesting as the dosage ranged from 200 to 600. The T one-half was 4.9 hours for the 200 mg dose, 5.42 hours for 400 mg, 5.7 hours for the 500 mg, and 9.77 hours for the 600 mg.
The adverse events were stratified by single dose and multi-dose as follows. In the single dose study there were headaches in two of eight patients at the 300 mg level and one of eight at the 600 mg level. No headaches were reported at the higher levels. Nausea was seen in only two out of eight of patients at the 300 mg level. Cough was reported in one patient at the same level, as was ear irritation at the 300 mg level as well as in one patient at the 600 mg level. In the multi-dose study ... were as follows. At 200 mg there painful extremities in two of nine; gastrointestinal discomfort occurred in one of nine; and, diarrhea in one of nine. There was no icterus. At 400 mg q.d., there was diarrhea in one of eight and icterus in one of eight. The author's note that this patient had Gilbert's syndrome. There were no reported adverse events a the 500 mg q.d. level in eight patients. At the 600 mg q.d. level, there was gastrointestinal discomfort in one patient, diarrhea in two patients, and icterus in one (this patient did not have Gilbert's syndrome).
The authors concluded that the drug is well-tolerated given as a single oral dose, up to 1200 mg, or as a 14-day multiple dose at 500 mg once daily. Reversible elevations of isolated unconjugated bilirubin were observed in several individuals in the multiple dose studies. This individuals remained clinically well, and the bilirubin elevations reverted to baseline within four days of dosing cessation. Pharmacokinetic data revealed there was good absorption after oral administration with relative bio-availability of about 68%. All multiple dose concentration values exceeded the IC90 at 24-hrs, post-dosing, supporting once daily dosing.
This is an interesting potent protease inhibitor. Current protease inhibitors require multiple daily doses, some with food restrictions and some without, certainly always part of very complicated regimens. The design of a once-daily protease inhibitor, I think, will prove to be invaluable. What will be interesting is the sensitivity data. This is not necessarily well reflected by the potency information, although the information looks promising. We will need to see if the resistance patterns and mutations that have accumulated to the existing protease inhibitors prove to be different from those that may accumulate with exposure to this drug. Indeed, it would be of tremendous value if unique mutation points prove to be necessary. While this data is not available at the moment, the safety profile looks so good in this preliminary data that we look forward to seeing this in vivo genetic information.
Authored by: E.M. O'Mara, et al.
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