A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer

Abstract

Purpose: P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex pharmacokinetic interactions and a failure to show meaningful results. Here we report the results of a pharmacokinetic and pharmacodynamic trial using a third-generation, potent, noncompetitive inhibitor of Pgp, tariquidar (XR9576), in combination with docetaxel.

Experimental design: In the first treatment cycle, the pharmacokinetics of docetaxel (40 mg/m(2)) were evaluated after day 1 and day 8 doses, which were administered with or without tariquidar (150 mg). (99m)Tc-sestamibi scanning and CD56(+) mononuclear cell rhodamine efflux assays were conducted to assess Pgp inhibition. In subsequent cycles, 75 mg/m(2) docetaxel was administered with 150 mg tariquidar every 3 weeks.

Results: Forty-eight patients were enrolled onto the trial. Nonhematologic grade 3/4 toxicities in 235 cycles were minimal. Tariquidar inhibited Pgp-mediated rhodamine efflux from CD56(+) cells and reduced (99m)Tc-sestamibi clearance from the liver. There was striking variability in basal sestamibi uptake; a 12% to 24% increase in visible lesions was noted in 8 of 10 patients with lung cancer. No significant difference in docetaxel disposition was observed in pairwise comparison with and without tariquidar. Four partial responses (PR) were seen (4/48); 3 in the non-small cell lung cancer (NSCLC) cohort, measuring 40%, 57%, and 67% by RECIST, and 1 PR in a patient with ovarian cancer.

Conclusions: Tariquidar is well tolerated, with less observed systemic pharmacokinetic interaction than previous Pgp antagonists. Variable effects of tariquidar on retention of sestamibi in imageable lung cancers suggest that follow-up studies assessing tumor drug uptake in this patient population would be worthwhile.

Figure 1

Rhodamine efflux from CD56+ cells showing the extent and duration of Pgp inhibition. A) Whole blood was obtained from patients before tariquidar treatment (Pre) and at 24 and 48 h post treatment. Rhodamine fluorescence was measured in the CD56+ population. The blood was incubated with rhodamine 123 in the presence (Control histogram, solid line) or absence (PSC histogram, dashed line) of the Pgp inhibitor valspodar for 30 min (upper left panel). These samples were divided and a portion incubated in rhodamine-free medium for an additional hour, continuing with (PSC/Efflux histogram, dashed line) or without (Efflux histogram, solid line) valspodar. Representative histograms following this efflux period in Pre, 24, and 48 h samples are shown for an individual patient. For all patients, the difference in mean channel number between the PSC and Control histograms (B) or between the PSC/Efflux and Efflux histograms (C) was calculated and compared by boxplot at each timepoint. The top and bottom of the boxes represent the 25th to 75th percentile, respectively, of the data, while the whiskers represent the minimum and maximum of all data.

Figure 2

Comparison of ^99mTc-Sestamibi areas under the concentration curve (AUC) before and after tariquidar administration. Boxplots of AUC before tariquidar and up to three hours after (AUC_0-3) for (A) liver, (B) heart (C) R lung, (D) L lung or (E) any lesion are shown. The box plots represent the calculated AUC_0-3h mean not normalized to heart, with the top and bottom of the boxes representing the 25th to 75th percentile, respectively, of sestamibi counts obtained in radionuclide imaging. The whiskers represent the minimum and maximum of all data. A statistically significant difference in AUC after tariquidar was found in both liver and visualized tumor tissue (P<0.001).

Figure 3

^99mTc-Sestamibi scans performed in two patients with NSCLC. A: CT scan (left image) shows a large supraclavicular mass (denoted by arrow) that also exhibits ^99mTc-Sestamibi uptake (arrow, left image). B: Chest X-ray (left image) and CT scan (center image) clearly show a peripheral right lung lesion (denoted by arrow) that does not uptake ^99mTc-Sestamibi (right image).

Figure 4

Changes in docetaxel pharmacokinetics when administered with or without tariquidar. A) Pairwise comparison of maximal docetaxel plasma concentration (Cmax) when administered with and without tariquidar. Each dot represents a single patient and cycle and lines connect the two cycles per patient. B) Pairwise comparison of docetaxel exposure (AUC_0-24) with and without tariquidar. C) Docetaxel exposure ratios of Cmax and AUC_0-24 calculated as (with tariquidar/without tariquidar). Each dot represents an individual patient. Horizontal lines represent the geometric mean and 95% CI. D) Docetaxel AUC_0-24 after single agent treatment did not differ based on sequence, based on comparison of docetaxel alone cycle on either Day 1 or Day 8. Each dot represents an individual patient. Horizontal lines represent the geometric mean and 95% CI.