352   Thalidomide Pharmacokinetics (PK), Safety and Effect on HIV Viral Load and Immune Parameters.

D. Wohl*¹, R. Pomerantz², J. Schmitz¹, F. Aweeka³, L. Fox⁴, D. Weng⁵, J. Spritzler⁵, W. Robinson⁶, M. Holohan⁷, H. Teppler⁸, and the ACTG 267 Team.
¹Univ. of North Carolina at Chapel Hill;²Thomas Jefferson Med. Coll., Philadelphia, PA;³San Francisco Gen. Hosp., CA;⁴NIH, Bethesda, MD;⁵Harvard Sch. of Publ. Hlth.., Boston, MA;⁶Celgene Corp., Warren, NJ;⁷ACTG Operations Ctr., Rockville, MD; and⁸Merck & Co. Inc., West Point, PA.

Background:Thalidomide (TLMD), a selective inhibitor of monocyte TNF-α;production, is used to treat HIV- associated aphthae and wasting. As an immunomodulator TLMD may augment HIV therapies.

Methods:Multicenter, randomized, controlled, dose-escalating study of TLMD. Pts with CD4 counts 200—500/ mm³enrolled to 3 dose cohorts (50 mg QD, 100 mg QD, 150 mg QD) and randomized 3:1 to TLMD or placebo (Pb) for 8 wks. Evaluations were at BL, wks 2, 4, 8 & 10 with 24 h PK at 1st dose, wks 2 & 8.

Results:36 pts enrolled, 12/cohort. Median BL CD4 and plasma HIV RNA = 338/mm³& 3.64 log₁₀c/ml, respectively. MTD was not achieved. Dose-limiting toxicity occurred in 4 pts, 2 on 150 mg TLMD, and 1 Pb pt had >grade (gr) 2 somnolence. 1 Pb pt had gr 2 neuropathy. Adverse effects were rare and not significantly different between TLMD and Pb pts. TLMD concentration in the blood increased with dose, but T_maxand clearance didn't differ across cohorts. LMD did not have a significant effect on HIV RNA or inducible PBMC TNF-α;or plasma TNF-α;levels. There was no dose-related change in CD4 count. A significant decline from BL inb2 microglobulin during treatment was seen in the TLMD 50 mg and 100 mg cohorts but was also observed in Pb arm. Neopterin levels increased significantly from BL in the TLMD 50 mg pts at wks 2, 8, & 10 but only at wk 4 in the TLMD 100 mg arm and at no point in the TLMD 150 mg or Pb arms.

Conclusions:TLMD was generally well tolerated at doses up to 150 mg QD for 8 wks. Somnolence was the major dose-limiting toxicity but occurred at similar frequency in Pb arm. Plasma TLMD levels increased with dose without saturation or evidence of auto-induction of clearance. TLMD had no significant effect on inducible PBMC TNF-α;production or plasma TNF-α;levels. There was no dose effect with respect to CD4 counts, neopterin orb2 microglobulin. TLMD did not have a significant effect on HIV RNA in this cohort of pts without AIDS. This may be due to the relatively better health and immune function of this cohort compared to other trials.