The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1-infected individuals

Objective: To investigate and to compare the steady-state plasma pharmacokinetics of nevirapine in a dosing regimen of 400 mg once daily versus 200 mg twice daily in HIV-1-infected individuals. Design: Open-label, randomized, cross-over study. Methods: Twenty HIV-1-infected individuals who already used nevirapine as part of their antiretroviral regimen were randomized to continue their current regimen (200 mg twice daily) or to switch to the alternate regimen (400 mg once daily). The steady-state plasma pharmacokinetics of nevirapine were assessed after 2 weeks during a 24-h period. Subsequently, patients were switched to the alternate regimen and the pharmacokinetics of nevirapine were assessed again after 2 weeks. Noncompartmental methods were used to calculate the area under the plasma concentration versus time curve (AUC([24 h])), and the maximal (C(max)) and minimal plasma concentration (C(min)), the time to C(max) (t(max)), the plasma elimination half-life (t(1/2)), the apparent oral clearance (Cl/F) and the apparent volume of distribution (V/F). Differences in these pharmacokinetic parameters for the two dosing regimens were tested using ANOVA. Results: The exposure to nevirapine, as measured by the AUC([24 h]), was not significantly different between the 400 mg once daily and 200 mg twice daily dosing regimen (P = 0.60). Furthermore, the values for t(max), t(1/2) Cl/F and V/F were not significantly different between the two dosing regimens (P ≥ 0.08). However, C(max) and C(min) were higher and lower, respectively, when nevirapine was used in the once daily regimen as compared with the twice daily regimen. The median values for C(max) and C(min) as measured for the once daily and twice daily regimens were 6.69 and 5.74 μg/ml, respectively (P = 0.03), and 2.88 and 3.73 μg/ml, respectively (P < 0.01). Conclusion: These data show that the daily exposure to nevirapine, as measured by the plasma AUC([24 h]), is not different between a 400 mg once daily and a 200 mg twice daily dosing regimen. However, C(max) and C(min) are higher and lower, respectively, for the once daily regimen as compared with the twice daily regimen. The clinical implications of these differences remain to be established. (C) 2000 Lippincott Williams and Wilkins

Safety and biodistribution of 99mtechnetium-labeled anti-CD44v6 monoclonal antibody BIWA 1 in head and neck cancer patients

The CD44 protein family consists of isoforms, encoded by standard exons and up to nine alternatively spliced variant exons (v2-v10), which are expressed in a tissue-specific way. Expression of v6-containing variants (CD44v6) has been related to aggressive behavior of various tumor types and was shown to be particularly high in squamous cell carcinoma (SCC). Therefore, CD44v6 might be a suitable target for radioimmunoscintigraphy (RIS) and therapy. The present study evaluates the novel high-affinity murine anti-CD44v6 monoclonal antibody (MAb) BIWA 1 for its safety and targeting potential in patients with SCC of the head and neck (HNSCC). Twelve HNSCC patients, who had planned to undergo resection of the primary tumor and neck dissection, were included. Preoperatively, 2, 12, or 52 mg of 99mTc-labeled MAb BIWA 1 was administered. RIS results obtained 21 h after injection were compared with palpation, computed tomography, and magnetic resonance imaging, with histopathology as the gold standard. Moreover, biodistribution of BIWA 1 was evaluated by radioactivity measurement in blood and bone marrow and in biopsies from the surgical specimen obtained 40 h after injection. The distribution of BIWA 1 in tumor biopsies was analyzed by immunohistochemistry. BIWA 1 integrity in the blood was assessed by high-performance liquid chromatography and related to soluble CD44v6 levels in serum samples. No drug-related adverse events were observed. Human antimouse antibody responses were observed in 11 patients. The diagnostic efficacy of RIS appeared to be comparable for the three BIWA 1 dose levels and for the four diagnostic methods. Besides activity uptake in tumor tissue, minimal accumulation of activity was observed in mouth, lungs, spleen, kidney, bone marrow, and scrotal area. Analysis of tissue biopsies revealed high uptake in tumors, with a mean value of 14.2 ± 8.4% of the injected dose/kg tumor tissue and a mean tumor:blood ratio of 2.0 ± 1.4 at 40 h after injection. Differences among the three dose groups were not statistically significant, although a trend toward lower uptake in the highest dose group was noted. Distribution of BIWA 1 throughout the tumor was heterogeneous for all dose groups, which might be related to the high affinity of the MAb. The mean biological half-life in blood (34.5 ± 6.1 h) was not dose dependent. Extensive complex formation of BIWA 1 was observed in the 2-mg group, most probably with soluble CD44v6 present in the blood, and complex formation relatively diminished upon increase of the MAb dose. BIWA 1 is a promising MAb for targeting HNSCC because it can be safely administered to HNSCC patients, while it shows high and selective tumor uptake. However, BIWA 1 is immunogenic, and therefore a chimerized or humanized derivative of BIWA 1 with intermediate affinity will be used in future clinical trials