RESUMO
Aim: Docetaxel is a microtubule-stabilizing drug used for the treatment of several cancers, including prostate cancer. Resistance to docetaxel can either occur through intrinsic resistance or develop under therapeutic pressure, i.e., acquired resistance. A possible explanation for the occurrence of acquired resistance to docetaxel is increased drug efflux via P-glycoprotein (P-gp) drug transporters. Methods: We have generated docetaxel-resistant cell lines DU-145DOC10 and 22Rv1DOC8 by exposing parental cell lines DU-145DOC and 22Rv1 to increasing levels of docetaxel. Gene expression levels between DU-145DOC10 and 22Rv1DOC8 were compared with those of their respective originator cell lines. Both parental and resistant cell lines were treated with the taxane drugs docetaxel and cabazitaxel in combination with the P-gp/CYP3A4 inhibitor ritonavir and the P-gp inhibitor elacridar. Results: In the docetaxel-resistant cell lines DU-145DOC10 and 22Rv1DOC8, the ABCB1 (P-gp) gene was highly up-regulated. Expression of the P-gp protein was also significantly increased in the docetaxel-resistant cell lines in a Western blotting assay. The addition of ritonavir to docetaxel resulted in a return of the sensitivity to docetaxel in the DU-145DOC10 and 22Rv1DOC8 to a level similar to the sensitivity in the originator cells. We found that these docetaxel-resistant cell lines could also be re-sensitized to cabazitaxel in a similar manner. In a Caco-2 P-gp transporter assay, functional inhibition of P-gp-mediated transport of docetaxel with ritonavir was demonstrated. Conclusion: Our results demonstrate that ritonavir restores sensitivity to both docetaxel and cabazitaxel in docetaxel-resistant cell lines, most likely by inhibiting P-gp-mediated drug efflux.
RESUMO
PURPOSE: ModraDoc006 is a novel oral formulation of docetaxel. The clearance of intravenous docetaxel is higher in medically castrated prostate cancer patients as compared to patients with other types of solid tumours. Oral docetaxel requires co-administration ritonavir (r), which might further impact the pharmacokinetics (PK). We now compare the PK of docetaxel and ritonavir between patients with Hormone Sensitive Prostate Cancer (HSPC), metastatic Castration-Resistant Prostate Cancer (mCRPC) and other metastatic solid tumours, treated on the same dose and weekly schedule of ModraDoc006/r. METHODS: The docetaxel and ritonavir PK were compared between four patient groups from three clinical phase I trials, including eight male and eight female patients with different types of solid tumours (study 1), seven patients with HSPC (study 2) and five patients with mCRPC (study 3). All patients were treated with ModraDoc006 30 mg and ritonavir 100 mg in the morning, followed by ModraDoc006 20 mg and ritonavir 100 mg in the evening (ModraDoc006/r 30-20/100-100). For comparative purposes, the PK of six mCRPC patients that received 30-20/200-100 in study 3 were also evaluated. RESULTS: The maximum plasma concentration (Cmax) was significantly lower for both docetaxel and ritonavir in the prostate cancer patients as compared to the patients with other types of solid tumours treated at ModraDoc006/r 30-20/100-100. The docetaxel area under the plasma concentration versus time curve (AUC) was significantly different at this dose, with a mean AUC0-48 of 1359 ± 374 ng/mL*h (N = 8) in female patients and 894 ± 223 ng/mL*h (N = 8) in male patients with different solid tumours (study 1), 321 ± 81 (N = 7) in HSPC (study 2) and 367 ± 182 ng/mL*h (N = 5) in mCRPC (study 3). A similar pattern was observed for ritonavir. ModraDoc006/r 30-20/200-100 in six mCRPC patients led to a comparable ritonavir exposure as compared to the patients at 30-20/100-100 in study 1 and increased the docetaxel AUC0-48 to 1266 ± 473 ng/mL*h (N = 6). CONCLUSION: The exposure to docetaxel and ritonavir was significantly lower in prostate cancer patients as compared to patients with other types of solid tumours, treated on ModraDoc006/r 30-20/100-100. An increase of the ritonavir dose increased the docetaxel exposure in mCRPC patients. Therefore, a different RP2D of ModraDoc006/r is pursued in castrated prostate cancer patients as compared to patients with other types of solid tumours. TRIAL REGISTRATION: Study 1: ClinicalTrials.gov Identifier NCT01173913, date of registration August 2, 2010. Study 2: ClinicalTrials.gov Identifier NCT03066154, date of registration February 28, 2017. Study 3: ClinicalTrials.gov Identifier NCT03136640, date of registration May 2, 2017.