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

 

Abstract:

Background: 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%.

 

Conclusions: 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).

Comments

Mikael Nordfors's picture

An orally available taxane could be a great step forward for metronomic low-dose chemotherapy!