Imran Chaudhary

Alterations of chemotherapeutic pharmacokinetic profiles by drug-drug interactions.

Background: Drug interactions in oncology are common place and largely ignored as we tolerate high thresholds of ‘toxic’ drug responses in these patients. However, in the era of ‘targeted’ or seemingly ‘less toxic’ therapy, these interactions are more commonly flagged and contribute significantly towards poor ‘quality of life’ and medical fatalities. Objective: This review and opinion article focuses on alteration of chemotherapeutic pharmacokinetic profiles by drug interactions in the setting of polypharmacy. The assumption is that the drugs, with changes in their pharmacokinetics, will contribute towards changes in their pharmacodynamics. Methods: The examples cited for such drug–drug interactions are culled from published literature with an emphasis on those interactions that have been well characterized at the molecular level. Results: Although very few drug interaction studies have been performed on approved oncology based drugs, it is clear that drugs whose pharmacokinetics profiles are closely related to their pharmacodynamics will indeed result in clinically important drug interactions. Some newer mechanisms are described that involve interactions at the level of gene transcription, whereby, drug metabolism is significantly altered. However, for any given drug interaction, there does not seem to be a comprehensive model describing interactions. Conclusions: Mechanisms based drug interactions are plentiful in oncology; however, there is an absolute lack of a comprehensive model that would predict drug–drug interactions.

Abstract A89: A phase I study of the novel DNA topoisomerase-1 inhibitor, TLC388 (Lipotecan®), administered intravenously to patients with advanced solid tumors.

Introduction: TLC388 (Lipotecan) is a potent Topoisomerase-1 inhibitor and it can disrupt both Sonic Hedgehog and HIF1-α pathways to overcome cancer drug resistance and inhibit angiogenesis induced by tumor hypoxia. This phase I first-in-human study of Lipotecan examined the MTD, safety, anti-tumor activity and pharmacokinetic profiles of TLC388 in patients with advanced incurable solid tumors. Methods: Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle. Patients underwent safety assessments regularly and tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8 and 15 of cycles 1 and 2 for all treated patients. Results: The enrollment for this study has been concluded and 54 previously-treated patients with advanced or metastatic solid tumors received Lipotecan. The dose was escalated from 1.5 mg/m2 to 60 mg/m2 over 12 patient cohorts (11 dose levels). MTD was reached at 50 mg/m2, following the emergence of two DLTs at 60 mg/m2: one grade 3 febrile neutropenia and one toxicity that precluded treatment within the 14 days specified by the protocol. Other DLTs occurred in other dose levels include hyponatremia (grade 3 and 4; 40 mg/m2) and thrombocytopenia (grade 4; 40 mg/m2). To date, all the subjects except one have completed the study. Lipotecan given at this dosing schedule was well-tolerated and no cumulative toxicity was observed. Non-hematological toxicity was generally mild, including fatigue (41%), nausea (37%), diarrhea (28%), vomiting (14%) and constipation (14%). Anemia was the most frequently reported hematological toxicity (67.0%). Neutropenia (30%), thrombocytopenia (28%), and leukopenia (26%) were also reported. Grade 3 or grade 4 hematological toxicity included neutropenia (28%), anemia (22%), leucopenia (17%), and thrombocytopenia (13%). Other G3/4 non-hematological side effects included hyponatremia (11%), abdominal pain (7%), fatigue (6%), and hypokalaemia (6%). Twenty one of 35 evaluable patients (60%) continued therapy beyond cycle 2, received a median of 5 cycles (range of 2–18 cycles), and experienced stable disease or minor tumor regression. Prolonged (≥ 6 months) stable disease was noted in 9 patients (26%), including renal (chromophobe and clear cell types), docetaxel refractory prostate, salivary gland, sorafenib refractory hepatic, and vaginal cancers. One minor response occurred in a heavily pretreated 70-year-old male with stage II B thymoma cancer metastatic to lung, liver and lymph nodes who was treated for 18 courses and remains on the study. PET-CT scan revealed reduction in his tumor size by 27% at the end of cycle 16. His disease had progressed through prior treatment with cyclophosphamide, cisplatin and doxorubicin. Pharmacokinetics of TLC388 were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m2 for S,R-TLC388 and 996 (1333) L/m2 for S,S-TLC388, and 7420 (8151) L/h-m2 for S,R-TLC388 and 4949 (5678) L/h-m2 for S,S-TLC388, respectively. The half-life values averaged 0.76 (1.15) hours for S,R-TLC388 and 0.75 (1.13) hours for S,S-TLC388. Conclusions: Lipotecan administered doses up to 50 mg/m2 on current treatment schedule is safe, well tolerated, and demonstrates broad antitumor activity to support Phase 2 disease-specific investigations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A89.