Continuous infusion prochlorperazine: pharmacokinetics, antiemetic efficacy, and feasibility of high-dose therapy

Purpose: The purpose of these sequential phase 1 studies was to evaluate th e antiemetic efficacy and pharmacokinetics of high-dose continuous infusion prochlorperazine. Methods: A total of 52 patients with advanced cancer wer e treated in two sequential phase 1 studies utilizing high-dose prochlorper azine. In study 1, designed to investigate the antiemetic effects of dose-i ntensive prochlorperazine, Various cisplatin-based multiagent chemotherapeu tic regimens were administered in combination with escalating doses of proc hlorperazine. In study 2, a fixed dose of cisplatin (60 mg/m(2)) was admini stered over 24 h as a continuous intravenous infusion in combination with i nfusional high-dose prochlorperazine. Antiemetic efficacy in the first tria l was assessed in terms of the number of episodes of nausea, retching, and/ or emesis during the 24 h following cisplatin administration. The pharmaco kinetics of high-dose prochlorperazine were evaluated in eight patients tre ated in study 2 at the two dose levels below those at which dose-limiting t oxicity was noted. Results: The maximally tolerated dose of prochlorperazin e in combination with cisplatin (60 mg/m2 administered as a continuous infu sion over 24 h) was 24 mg/h. The dose-limiting toxicity was grade 4 agitati on and confusion noted in one patient treated at 26 mg/h. This patient died 3 days following cessation of chemotherapy due to the toxicity of the regi men in combination with the debilitating pulmonary effects of the disease. The mean end of infusion prochlorperazine level at the 24 mg/h dose level w as 1.1 muM, a concentration previously reported to be consistent with the r eversal of the multidrug resistance phenotype. Two partial responses were o bserved in study 2. Conclusions: We conclude that the antiemetic efficacy o f high-dose infusional prochlorperazine does not appear to be improved over more convenient bolus administration. However, prochlorperazine levels con sistent with those required in vitro for drug resistance reversal are attai nable within the dose range having a tolerable toxicity profile.