Pharmacokinetics and pharmacodynamics of thalidomide in HIV patients treated for oral aphthous ulcers: ACTG protocol 251

Thalidomide has increasing clinical benefits, including the healing of apht hous ulcers in patients with HIV. Unfortunately, pharmacological informatio n addressing the pharmacokinetics (PK) of this compound in HIV patients is limited. Concern exists as to whether thalidomide may alter its own metabol ism owing to in vitro data previously reported. Furthermore, no information is available defining the relationship between drug exposure and clinical response. This study evaluated the PK and pharmacodynamics (PD) of thalidom ide in patients enrolled in AIDS Clinical Trials Group Protocol 251. Study patients had HIV infection and oral aphthous ulcers of at least 2 weeks' du ration. Pharmacologic studies were completed in those subjects randomized t o receive active thalidomide at a dose of 200 mg daily for the 4week study period. PK studies involving serial sampling were carried out in 7 subjects following multiple dosing during study weeks 1 and 4. In addition, trough measurements were done in 20 subjects during each of the 4 study weeks to e xplore the relationship between time-averaged trough values and extent of c linical response. All samples were analyzed using a validated HPLC method, and parameters were determined using noncompartmental PK analysis. Thalidom ide oral clearance averaged 0.14 +/- 0.08 and 0.12 +/- 0.05 l/h/kg on weeks 1 and 4 (p = 0.72), while the terminal elimination half-life averaged 5.7 +/- 1.5 and 7.3 +/- 1.7 hours (p = 0.12). The median time-averaged trough v alue for subjects deemed complete responders was 0.60, while the median val ue for noncomplete responders was 0.54. Adjusting for baseline CD4 count an d initial index ulcer area, no significant effects were observed of increas ed thalidomide levels on response. In summary, this study provides steady-s tate PK data in HIV patients managed with thalidomide and suggests negligib le effect of chronic dosing on drug clearance (comparing results from weeks 1 and 4). Furthermore, variable trough measurements between patients do no t directly influence the effectiveness of thalidomide for oral aphthous ulc ers. (C) 2001 the American College of Clinical Pharmacology.