Effect of valspodar on the pharmacokinetics of unbound paclitaxel

Abstract

The aim of this multicenter study was to determine whether valspodar (Amdray; code designation, SDZ PSC 833), a potent P-glycoprotein (P-gp) inhibitor, affects the pharmacokinetics of unbound paclitaxel (Cu). Data were obtained from 31 patients with advanced breast cancer. Thirteen patients were treated with paclitaxel alone (3-h infusion at 175 mg/m2) and another 18 received paclitaxel (3-h infusion at 70 mg/m2) in combination with a 21-day cycle of oral valspodar (5 mg/kg given four times a day) starting 1 day before administration of paclitaxel. Serial blood samples were taken in the first course and Cu in plasma determined using equilibrium dialysis with a [G-3H]paclitaxel tracer. The apparent clearance of Cu was not significantly different between the two groups, with mean +/- standard deviation (+/- SD) values of 230 +/- 56.0 and 202 +/- 49.9 L/h/m2 in the absence and presence of valspodar, respectively (P = 0.17). The volume of Cu distribution was slightly larger in the presence of valspodar (1160 +/- 474 vs. 1620 +/- 552 L/m2; P = 0.025), which contributed to a minor difference in the terminal disposition half-life (6.12 +/- 3.42 vs. 8.50 +/- 2.06 h; P = 0.028). These data indicate that (i) valspodar lacks the significant interaction with paclitaxel observed previously with other P-gp modulators, (ii) the majority of the increased toxicity of the combination does not appear to be attributable to increased levels of Cu, and (iii) provide further evidence of the conjecture that the plasma concentration of paclitaxel may not be an appropriate measure to monitor the impact of P-gp inhibition.

The influence of P-glycoprotein expression and its inhibitors on the distribution of doxorubicin in breast tumors

“…Repopulation of tumor cells has been shown to occur in regions far from blood vessels [29], and it is important to consider factors that affect the distribution of chemotherapeutic agents in solid tumors. Numerous clinical trials evaluating the effects of verapamil or valspodar in combination with chemotherapeutic agents such as doxorubicin, vincristine, dexamethasone, cyclophosphamide, paclitaxel have shown that patients given concurrent administration of PgP inhibitors with chemotherapeutic agents have an increased toxicity and show modest or no increase in survival [45-49]. These results provide insight into an important limitation of PgP inhibitors and this principle is likely to be applicable to other membrane-based drug efflux proteins such as multiple drug resistance protein-1 (MRP-1) and suggest the importance of considering drug distribution in the design and development of novel treatment strategies.…”

Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance

“…TKIs can possibly be exploited to improve pharmacokinetics or overcome resistance to chemotherapeutics that are substrates of ABC drug transporters in cells, tissues or tumors that express high levels of these transporters. As discussed above, a number of studies have already demonstrated that modulation of ABC transporters by inhibitors of these transporters in cancer chemotherapy may also significantly modify the pharmacokinetic and toxic profiles of anticancer drugs (Darvari and Boroujerdi, 2005; Sparreboom et al, 1999; ten Tije et al, 2003). This suggests that a combination of TKIs with cytotoxic anticancer drugs that are substrates of ABC transporters, especially P-gp and ABCG2, may offer an advantage for treating the drug-resistant cancers.…”

The controversial role of ABC transporters in clinical oncology

“…In order to accommodate this pharmacokinetic interaction in valspodar trials, anticancer drug doses were reduced by 25–50% [44,45]. However, because of interpatient variation in CYP3A4 metabolism, some patients were underdosed and others overdosed [46,47]. A Phase III CALGB (Cancer and Leukemia Group B) trial using valspodar in previously untreated AML patients over age 60 was closed early due to excessive mortality in the experimental arm during induction [45].…”