The pharmacokinetic analysis of a therapeutic drug interaction between a type-1 multidrug resistance modulator, valspodar (PSC 833), and an anticancer agent, doxorubicin, in patients.

摘要

It is believed that the inhibition of multidrug resistance type 1 with valspodar (PSC 833, [PSC]) would enhance chemotherapeutic effectiveness of doxorubicin (Dox). The co-administration of Dox with PSC, however, did not improve patient anti-tumor response. We therefore, hypothesized that the pharmacokinetic analysis of Dox and PSC interaction will uncover a mechanistic basis for their chemotherapeutic failure. An in-depth pharmacokinetic analysis was conducted on Dox, doxorubicinol (Doxol), a metabolite of Dox, and PSC plasma concentrations, in the absence and presence of Dox and PSC, within a patient population having a solid-tumor diagnosis. Both non-parametric and compartmental modeling pharmacokinetic analyses were applied. Dox and PSC appeared to affect each other's clearance and apparent distribution. Unexpectedly, both Dox and PSC distribution and efflux rate constants decreased. PSC anticipated effect on Dox distribution is an expansion not a contraction. Our findings furnish evidence that there is a need for a PSC clinical paradigm shift.