Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56+ lymphocytes after oral and intravenous administration.
XR9576 is a novel inhibitor of P-glycoprotein (P-gp) that has been shown to reverse P-gp-dependent multidrug-resistance in tumor cell lines and tumor-bearing animals. Here we report the first i.v. and p.o. administration to healthy volunteers of XR9576 in dose-escalating studies with the aim of investigating its effects on safety, its pharmacokinetics, and a surrogate marker of efficacy. XR9576 was administered as a single dose-upward titration of 0.1, 0.2, 0.5, 1.0, and 2 mg/kg XR9576 i.v. or 50, 100, 200, 500, and 750 mg/volunteer p.o. The surrogate marker for in vivo efficacy examined the accumulation of the P-gp substrate Rhodamine-123 (Rh-123) in P-gp-expressing CD56+ lymphocytes by flow cytometry. Addition of Rh-123 to blood samples from subjects given XR9576 or a placebo demonstrated drug-dependent modulation of P-gp activity. Even at the lowest doses, significant effects were observed on Rh-123 accumulation in CD56+ cells. Maximal effects were seen during the i.v. infusion or 4-6 h after oral administration. As the dose was increased, a concomitant rise in the level and duration of P-gp blockade was observed. A dose of 2.0 mg/kg i.v. and > or = 200 mg/volunteer p.o. gave approximately 100% inhibition of P-gp for in excess of 24 h. All doses of XR9576 were well tolerated. Inhibition increased with XR9576 plasma concentration, and maximal activity was achieved at 150-200 ng/ml XR9576. In conclusion, XR9576 has demonstrated sustained inhibition of P-gp after i.v. and oral administration and, supported by the elimination half-life of about 24 h, XR9576 is being taken into Phase II as a once-daily agent.
Stewart
A
A
Xenova, Ltd., Slough, United Kingdom.
Steiner
J
J
Mellows
G
G
Laguda
B
B
Norris
D
D
Bevan
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019002:CD56 Antigen / Q000032:analysis*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007275:Injections, Intravenous; D008214:Lymphocytes / Q000187:drug effects*; D008875:Middle Aged; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019002:CD56 Antigen; D011804:Quinolines; C402343:tariquidar