Lack of effect of cisplatin on i. v. L-PAM plasma pharmacokinetics in ovarian cancer patients

Abstract

Melphalan (L-PAM) pharmacokinetics were investigated in nine ovarian cancer patients before and after cisplatin (DDP) treatment. When L-PAM was given 24 h before DDP, the elimination half-life (t 1/2 beta), plasma clearance (Clp), and volume of distribution (Vd beta) of L-PAM were, respectively: 46.4 +/- 6.7 min, 20.5 +/- 3.7 l/m2, and 306.8 +/- 34.4 ml/min per square meter. When L-PAM was inoculated 24 h after DDP, t 1/2 beta, Clp, and Vd beta were 47.5 +/- 6.3 min, 20.4 +/- 2.8 l/m2, and 322.0 +/- 54.1 ml/min per square meter. Thus, DDP pretreatment does not significantly affect L-PAM pharmacokinetics. Regression analysis showed a significant correlation between the L-PAM elimination rate constant (beta) and renal function assessed by creatinine clearance. One patient who received this sequence of treatment for six courses showed a threefold decrease of L-PAM Clp after the last treatment. The reported high myelotoxicity of the combination of DDP and L-PAM when DDP was given 24 h before L-PAM cannot be attributed to DDP-induced changes in L-PAM kinetics but might to some extent be related to a loss of renal function consequent to many courses of treatment.

Estimation of the haematological toxicity of minor groove alkylators using tests on human cord blood cells

“…The drug concentrations defined in our experiments are in agreement with those achieved in humans: the ID70 range found for tallimustine against myeloid progenitors (90-235 ng ml-') is in the range (104-189 ng ml') of those reported in four patients 1 h after administration of doses near the MTD (Sessa et al, 1994). A similar trend was also seen for carzelesin (in vitro 1.7-6.3 ng ml-', in humans 1-2 ng ml-') (Wolff et al, 1996) and L-PAM (in vitro 590-2100 ng ml-', in humans 100-800 ng ml-' at a dose below the MTD) (Zucchetti et al, 1988). A similar in vivo-in vitro correlation for myelotoxicity between concentrations active on clonogenic tests and plasma concentrations achieved in phase I studies was found with other compounds such as pyrazolacridine (Parchment et al, 1994;Rowinsky et al, 1995).…”