Pharmacology and safety factors affecting use of flat (rather than weight-based) dosing of tesetaxel, an orally administered....

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Author(s): R. P. Warrell,
M. Beeram, E. Spindler, K. Papadopoulos, A. Patnaik, A. W. Tolcher;
Genta Inc, Berkeley Heights, NJ; South Texas Accelerated Research
Therapeutics, LLC, San Antonio, TX
As a class, taxanes have wide interpatient (pt) pharmacokinetic (PK)
variability at their effective dose, which has been associated with
adverse reactions, especially neutropenia. Tesetaxel is an oral taxane
with Phase 2 activity in pretreated pts with colorectal, non-small cell
lung, gastric, and breast cancers. Tesetaxel is not a substrate for
P-glycoprotein; it is associated with lower neurotoxicity at
equi-myelotoxic does, and it displays a long terminal half-life in
plasma (~180 hrs). We explored PK and clinical safety to determine the
feasibility of using flat dosing in future studies.
Methods: PK parameters were evaluated in 21 pts treated at the maximum tolerated dose (27 mg/m2)
either alone or in combination with capecitabine. We then compared
actual dose (total mg) with the weight-based dose and correlated the
incidence and severity of Grade 3-4 neutropenia with weight-based vs.
flat dosing.
Results: A total of 174 pts were treated with tesetaxel in Phase 2 trials at doses of 27 or 35 mg/m2 once every 3 weeks. For pts prescribed with weight-based dosing (27 mg/m2), mean Cmax in 3 separate cohorts was 24.6, 42.5, and 47.9 µg/L, with AUC0-inf of 1363, 1592, and 1663 h*µg/L, respectively. In 103 pts prescribed a dose of 27 mg/m2,
17% and 16% of pts received doses of 40 mg or 60 mg, respectively,
whereas 67% received 50 mg. Correlations between drug exposure AUC0-inf and actual dose (mg and mg/m2) across the entire range of administered doses showed r2 values of 0.455 and 0.492, respectively. Similar correlations after a second repeat dose showed r2 values of 0.731 and 0.653, respectively. The incidence of Grade 3-4 neutropenia at 27 mg/m2 was 33%.
PK and clinical safety suggest that weight-based dosing offers no
substantial advantage compared with flat dosing. Future studies could
incorporate a starting dose of 50 mg administered once every 3 weeks.
Flat dosing should also be tested using different schedules, including
weekly x 3 weeks and "metronomic dosing" (1-2 mg/d).