Development of an optimal pharmacokinetic sampling schedule for rubitecan administered orally in a daily times five schedule

Abstract

An optimal sampling schedule was derived which allowed assessment of the pharmacokinetic parameters of both the parent compound and its metabolite 9-AC after oral administration of rubitecan.

Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes

“…In our previous studies of 9NC, most of the drug remained in the 9NC form, with a mean 9NC to 9AC ratio of 4 to 1, which is consistent with other previous studies [6][7][8].…”

“…Several studies have evaluated the relationship between ABC genotypes and disposition of camptothecin analogues [5,22,23,[36][37][38][39][40]. 9NC is an orally administered camptothecin analogue with significant interpatient variability in drug disposition [6][7][8][9][10]. This is the first study that compares the disposition of 9NC and its 9AC metabolite to the ABCB1, ABCC2, and ABCG2 genotypes in patients.…”

“…In the Phase I and II studies, the resulting plasma sample was then processed immediately using solid phase extraction in order to separate the lactone and hydroxy acid forms of 9NC and 9AC as previously described [8]. In the singledose pharmacokinetic study, the plasma was processed via methanolic extraction to measure 9NC and 9AC total as previously described [6][7][8]13].…”

“…Several studies have reported significant interpatient variability in the pharmacokinetics of some orally administered drugs, including camptothecin analogues [1][2][3][4][5][6][7]. In our previous pharmacokinetic studies of 9-nitrocamptothecin (9NC, rubitecan, RFS2000) and its 9-aminocamptothecin (9AC) metabolite, we found that at any given dose of 9NC there was 4 to 16-fold variability in 9NC and 9AC exposure, and that no relationship between dose and AUC was detectable [8].…”

Optimal modeling for phase I design of a two drug combination—results of a phase I study of cisplatin with 9-nitrocamptothecin

“…Pharmacokinetics performed on days 1 and 15 suggested induction of 9-NC metabolism, since clearance was higher on day 15 relative to day 1 at each dose level (although significant only at 2.25 mg/day). The increase in 9-NC clearance was possibly due to reduction of the nitro group of 9-NC, yielding 9-AC [10][11][12]. Additional in vitro studies indicated that 9-NC metabolism to 9-AC may be mediated through Table 5 Grade One patient (breast cancer with peritoneal carcinomatosis) with grade 3 nausea, vomiting, and dehydration were aggravated by partial bowel obstruction c One patient (breast cancer) with grade 3 nausea and vomiting.…”