D. P de Alwis1, S. Callies2, J G Wright1, I Pouliquen1 and L Aarons2
1Eli Lilly & Company, Global Pharmacokinetics Department, Erl Wood Manor, Surrey, UK, 2University of Manchester, Manchester, UK
PURPOSE. Previous clinical investigations indicated that P-glycoprotein modulators dramatically decrease the systemic clearance of co-administered oncolytics. Potential impact of LY335979, a potent modulator of the P-gp efflux transporter on the pharmacokinetics of doxorubicin and doxorubucinol was examined in a phase I dose escalating trial using a population approach.
METHODS. The pharmacokinetics of doxorubicin, doxorubucinol and LY335979 was studied during two cycles. In cycle 1, day 1, patients received LY335979 by intravenous infusion over 48 hours; on Day 15, patients received doxorubicin IV over 30 minutes. In cycle 2, LY335979 was infused over 48 hours with doxorubicin administered 24 hours after commencing LY335979. A total of 41 patients with advanced malignancies were enrolled into 9 cohorts. Doxorubicin dose was escalated from 45 – 75 mg/m2 and of LY335979 from 20mg/m2/day – 640mg/m2/day.
RESULTS. A three-compartmental pharmacokinetic model best described the doxorubicin pharmacokinetics. The population model also characterised, inter, intra-subject and inter-occasion variability. Doxorubicin plasma clearance (CL) and volume of distribution at steady state (Vss) were reduced (25 % and 26 % respectively) in the presence of an LY335979 dose greater than or equal to 160mg/m2/day. Similarly doxorubicinol pharmacokinetics was also examined and the tmax of doxorubicinol was delayed in was delayed in the presence of LY335979 (doses greater than or equal to 160mg/m2/day).
CONCLUSIONS. The decrease in doxorubicin CL in the presence of LY335979 is most likely to represent inhibition of P-gp by LY335979 in the bile canaliculi impeding biliary excretion of doxorubicin. The observed change in doxorubicin pharmacokinetics in the presence of LY335979 is likely to be of insufficient magnitude to be clinical significant. Infusions of the MDR modulator was well tolerated and no toxicity due to LY335979 were observed.
Reference: PAGE 10 () Abstr 205 [www.page-meeting.org/?abstract=205]
Poster: poster