Abstract

Background: Mitochondrially Targeted Tamoxifen (MitoTam), the first mitochondrial inhibitor to disrupt Complex I (CI)-dependent respiration, previously showed antitumor activity against Renal Cell Carcinoma (RCC) with a good safety profile. We investigated the relationships of Pharmacokinetic (PK) parameters, biodistribution and patient baseline diagnosis with the clinical outcome and toxicity of Mitotam.

Methods: In the phase I/Ib MitoTam-01 trial, patients with metastatic solid tumors were treated with Mitotam monotherapy. PK parameters were calculated separately for the doses used in both trial phases. Data were analyzed descriptive analyses and using the generalized linear model framework as stochastic test.

Results: The non-compartmental analysis of PK parameters showed that the extent of exposure was positively correlated with the dose. Most of the PK profiles suggested that MitoTam was redistributed from the tissues or from protein binding back into the blood circulation, with very low accumulation. The exposure efficacy relationship did not show significant differences between responders and non-responders in phase Ib. However, the Area Under the Curve from time zero to time (AUC_0-t) and Maximum Concentration (C_max) values were greater in Renal Cell Carcinoma (RCC) patients than in responders with other diagnoses. These data are consistent with the preclinical findings showing preferential MitoTam accumulation in kidneys and the high clinical benefit rate in RCC patients in the phase Ib part.

Conclusion: These comprehensive analyses demonstrate the impact of MitoTam on the clinical benefit rate that is related to the dose and corresponding PK parameters, as well the underlying diagnosis. The PK data supported the previously recommended dose of 3.0 mg/kg weekly for future trials.

Keywords: Mitotam; Pharmacokinetics; Phase I/Ib; Clinical benefit rate; Safety; Renal cell carcinoma