Supplementary Table 4 from Comparison of Human and Rat Uterine Leiomyomata: Identification of a Dysregulated Mammalian Target of Rapamycin Pathway

The targeted silencing of protein expression by interfering with the degradation of specific coding mRNA sequences is an emerging mechanism of action for therapeutics. The two most common “classes” of mRNA silencing agents are the antisense oligonucleotides (ASOs) and short-interfering RNA (siRNA) therapeutics. Although these therapeutic strategies have slightly different mechanisms, each can achieve the same outcome of decreasing target protein expression. Research in the late 70s by Zamecnik and Stephenson1 studying respiratory syncytial virus, suggested that ASOs could be utilized as an antiviral treatment. This research was the basis for the evaluation of these agents as a potential new class of drugs. ASOs developed for clinical use are generally composed of up to ∼ 30 nucleotides of DNA and/or RNA in a single-strand and are chemically modified (eg. phosphorothioates) to prevent degradation from endogenous nucleases. The standard route of non-local administration for an ASO is by subcutaneous (SC) injection. Absorption into the intracellular compartment of target cells is thought to occur by endocytosis. Intracellularly, ASOs can silence target protein expression via various mechanisms that are structurally dependent. One common intracellular mechanism for the marketing approved generation of ASOs is via the enzyme RNase H. Once inside the cell, therapeutic ASOs bind their complementary mRNA within the nucleus. This double-stranded DNA-mRNA or RNA-mRNA hybridization renders the RNA strand(s) within the duplex amenable to degradation by RNase H. Target protein expression is then decreased due to lack of translation from mRNA. Current FDA approved ASO therapeutics include fomivirsen (Vitravene) for cytomegalovirus retinitis, and mipomersen (Kynamro) for homozygous familial hypercholesterolemia. In addition to these agents, there are a number of ASOs in development for ocular, cardiovascular, metabolic, inflammatory, oncologic and rare disease indications. In contrast to the single-stranded ASOs, siRNAs are composed of double-stranded (ds) RNA of up to ∼25 nucleotides per sense and antisense, including a 2 nucleotide overhang on one of the strands to facilitate activity. In some cases, a few DNA nucleotides may be added, but the primary makeup of the duplex is typically RNA. The site of action of siRNAs is within the cytoplasm and does not include a nuclear mechanistic component as utilized by ASOs. The seminal work that led to identification of the process underlying the mechanism of siRNA agents, and ultimately the awarding of a Nobel Prize, was published in 1998 by Andrew Fire and Craig Mello. Fire and Mello's work described the injection of dsRNA into Caenorhabditis elegans leading to a degradation of sequence-specific mRNA that was located in the cytoplasm2. This work in nematodes was then followed by similar findings in a mammalian system3. Delivery of the siRNAs is most commonly via two general mechanisms, lipid-based formulations that are administered intravenously (IV) or via conjugation to a molecule that targets the siRNA to the specific cell type expressing the protein of interest. Conjugated siRNAs can be administered SC, an advantage for certain indications. Local administration can also be achieved such as for ocular indications. Once available systemically, siRNA gains access to cells via fusing with the cell membrane or via endocytosis, depending on the delivery mechanism. Intracellularly siRNA is loaded into the RNAi-induced silencing complex (RISC) and the sense strand is cleaved by a protein, Argonaute 2 (AGO2), within the complex, leaving the antisense strand available for hybridization to the complimentary target mRNA. Once the target mRNA binds the antisense strand within RISC, the target mRNA is then cleaved by AGO2 thereby preventing the translation of the target protein. As of the preparation of this article, no siRNAs have been approved by the FDA or EMA. Several biopharmaceutical companies have siRNAs in late stage development covering various therapeutic areas such as cardiovascular/metabolic, infectious disease, oncology and rare diseases. In the development of small molecule and large molecule biologics such as antibodies, it is the role of the Clinical Pharmacologist to characterize the human ADME properties. Current FDA guidance documents exist in the small molecule and the biologics space, clarifying the types of in vitro and in vivo ADME assessments necessary to understand the human disposition of these classes of agents. Within the nucleic acid therapeutics field, the path is not as clear at this point in time. Scientific reasoning to guide the path forward is paramount; unfortunately with lack of regulatory guidances, this approach on its own could be associated with high risk if it is in contrast to the opinion of health authorities. When considering biotransformation, ASOs and siRNAs are metabolized via endogenous nuclease digestion; CYP and UGT mediated pathways have not been found to be relevant for their metabolism4. Standard pharmacokinetic drug-drug interactions (DDIs) whereby the metabolism of ASOs and siRNAs could be influenced by CYPs or UGTs, is not of concern based on current data5. In terms of perpetrating a DDI via inhibition or induction of these metabolic routes, there is similar low likelihood of an interaction and no currently published data suggests such liability. In addition to in vitro metabolism studies, evaluation of clinical DDIs involving healthy volunteers has also been completed for mipomersen4; there were no clinically meaningful findings from these DDI studies. Although DDIs at the pharmacokinetic level involving standard drug metabolizing enzymes are unlikely, pharmacodynamic interactions must still be considered if the ASO or siRNA mechanistically may directly or indirectly impact the activity of drug metabolizing enzymes. Another area of consideration are QT studies and their applicability to nucleic acid therapies. A review of mipomersen prescribing information and published literature indicate a QT study was conducted in 60 healthy volunteers and showed no exposure related impact of mipomersen on the QTc interval6. Historically, the E14 guidance7 was developed primarily for small molecule therapeutics following the identification of drugs such as terfenadine that prolonged the QT interval triggering torsades de pointes and possible sudden death. The E14 guidance was a mechanism to help rule out drug-induced QT prolongation. While efforts are underway by various working groups to evaluate the appropriate battery of assessments needed to characterize the cardiac safety of drugs, a key question is what is the applicability of QT studies for nucleic acid therapeutics. The DDI and QTc study examples are not the only clinical pharmacology questions unique for nucleic acid therapies. What about characterizing mass balance? Is this necessary for nucleic acid therapies? If so, how should such molecules be radiolabeled, especially those that are double-stranded? Are preclinical studies sufficient? This just highlights some of the other questions that come to mind. In characterizing the ADME properties across a wide variety of drug molecule types, one size does not fit all. In clinical research we need to balance out the question we are addressing with the potential safety risks associated with exposing healthy volunteer subjects and/or patients. Unnecessary exposure of healthy volunteers or patients just to “check a box” is not the ethical or justified. Safety is of foremost importance in drug development. Valid scientific rationale needs to factor into the development of these new agents. Existing guidances focus heavily on small molecules – for good reason – and are not always applicable, and in some cases frankly vague when biologic therapies are mentioned. Biologic therapies in and of themselves vary greatly. From small peptides to larger antibody molecules, there is no one size that fits all. There are also significant economic costs to non-focused “check a box” development strategies. A recent study by the Tufts Center for the Study of Drug Development noted that the cost of developing a drug from R&D through marketing approval is approximately $2,558M8. In order for new innovative therapies to be developed for patients in need, these development costs are passed along in pricing of medicines and ultimately, overall expense of health care. Streamlining the questions that truly need to be addressed will impact the economics. All of us in industry, academics and government agencies, need to continue to collaborate closely, have discussion forums and dialog so that we can efficiently deliver new therapies to the many patients who count on all of us each day. Monette M. Cotreau Waltham, MA

The vascular endothelial growth factor (VEGF) pathway is associated with the promotion of endothelial cell proliferation, migration, and survival necessary for angiogenesis. VEGF and its three receptor isoforms are often overexpressed in many human solid tumors. Tivozanib is a potent, selective inhibitor of VEGF receptors 1, 2, and 3, with a long half-life. The purpose of these studies was to evaluate the effect of ketoconazole, a potent inhibitor of CYP3A4, and rifampin, a potent inducer of CYP3A4, on the pharmacokinetics of tivozanib. Two phase I, open-label, 2-period, single-sequence studies evaluated the effect of steady-state ketoconazole (NCT01363778) or rifampin (NCT01363804) on the pharmacokinetic profile, safety, and tolerability of a single oral 1.5-mg dose of tivozanib. Tivozanib was well tolerated in both studies. Steady-state ketoconazole did not cause a clinically significant change in the pharmacokinetics of a single dose of tivozanib; therefore, dosing of tivozanib with a CYP3A4 pathway inhibitor should not cause a clinically significant change in serum tivozanib levels. However, coadministration of tivozanib with rifampin caused a significant decrease in the area under the curve from 0 to infinity and half-life and an increase in clearance of tivozanib, which suggest increased clearance via the enhanced CYP3A4-mediated metabolism of tivozanib.

Background Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg2 oxaliplatin) regimen in patients with advanced gastrointestinal tumors. Patients and Methods Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6. Results Thirty patients were assigned to tivozanib 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8), fatigue (n = 8), and neutropenia (n = 6). MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease. Conclusion Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors.

Tivozanib hydrochloride (tivozanib) is a potent, selective tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1, 2, and 3, with a long half-life. This Phase I study evaluated the effect of food on tivozanib pharmacokinetics (PK). A single oral dose of tivozanib was administered to healthy subjects in a fasted/fed and a fed/fasted state. Thirty subjects enrolled; 29 completed the study. Maximum concentration (C-max) in the fed state was lower than in the fasted state (geometric means, 14.1 and 18.1 ng/mL). The geometric mean ratio (90% confidence interval) (fed/fasted states) for C-max was 77.5% (72.9-82.4%), indicating a food effect on C-max. There was no difference in tivozanib area under the curve to infinity (AUC(0-infinity)) between states (geometric means, 2,377 and 2,198 ng h/mL). Geometric mean ratios also indicated no food effect on tivozanib AUC(0-infinity). Other PK parameters were similar between states. The most commonly reported adverse events affected the gastrointestinal system and were mild in intensity. There were no clinically significant changes in other safety measures. In conclusion, food does not have an impact on the AUC(0-infinity) of tivozanib but does decrease C-max approximately 23%, suggesting that this agent can be dosed with or without food.

Tivozanib hydrochloride (tivozanib) is a potent, selective tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life. Tivozanib's effects on the QTc interval in patients with advanced solid tumors were assessed. Patients received 1.5 mg of tivozanib orally, once daily, for 21 days. Safety evaluations, serial blood samples for pharmacokinetic measurements, and time-matched, triplicate, 12-lead electrocardiograms (ECG) were collected. Fifty patients were evaluable. The maximum change in QTcF was 9.3 milliseconds (90% confidence interval [CI] 5-13.6), occurring 2.5 hours after dosing on Day 21. The central tendency change across all time points was +2.2 milliseconds. The slope of the exposure-Delta QTcF relationship was 0.08464 ms/ng/mL, with a predicted QTcF change of 8.27 milliseconds at the average tivozanib T-max of 118.1 ng/mL (upper CI 12.6 milliseconds). There were no QTcF values>500 milliseconds or significant changes from baseline observed in heart rate, PR interval, and QRS complex. These data, evaluated along with other tivozanib preclinical and clinical study results, suggest that administration of 1.5 mg tivozanib for 21 days has a minimal effect on cardiac repolarization or ECG morphology in oncology subjects.

Tivozanib is a potent selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. This Phase Ib study investigated the safety/tolerability, pharmacokinetics (PK), and activity of tivozanib with weekly paclitaxel in metastatic breast cancer (MBC). MBC patients with no prior VEGFR TKI treatment received daily oral tivozanib (3 weeks on, 1 week off) with weekly paclitaxel 90 mg/m(2). Standard 3 + 3 dose escalation was used; tivozanib cohorts (C) included C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg. Assessments included Response Evaluation Criteria in Solid Tumors response, PK, and vascular function. Eighteen patients enrolled. Toxicities in >20 % of patients included fatigue, alopecia, nausea, diarrhea, peripheral sensory neuropathy, and hypertension. Grade 3/4 toxicities in >15 % of patients included fatigue and neutropenia. Maximum tolerated dose was tivozanib 1.5 mg with paclitaxel 90 mg/m(2). Four patients withdrew because of toxicity and one due to progressive disease. Thirteen patients were evaluable for response: four (30.8 %) had confirmed partial response; four had stable disease ≥6 months (30.8 %). PK data suggest no influence of paclitaxel on tivozanib concentrations. Tivozanib plus weekly paclitaxel was tolerable at all dose levels, supporting their combination at full dose. Activity in this small population was encouraging.

ABSTRACT Background Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor of VEGF receptors (VEGFRs) 1, 2, and 3, demonstrating activity against advanced RCC in Phase (Ph) II–III trials. This analysis explored the relationship between tivozanib PK and BP, as hypertension is a mechanism-based adverse event and a potential surrogate of response. The relationship between exposure and sVEGFR2 also was explored. Methods Pharmacokinetic, BP, and sVEGRF2 data from tivozanib-treated RCC patients (pts) from a Ph II (n = 21) and a Ph III (n = 259) study were pooled; pts were treated with 1.5 mg tivozanib daily for 21 days followed by a 7-day rest (28-day treatment cycle) in each study. A population PK model of tivozanib was constructed from PK data from Ph I–III studies, to obtain individualized predictions of steady-state values for Cavg. BP was measured at baseline and on Cycle 1 Day 15 (C1D15), C2D1, and C3D1 in the Ph II and Ph III studies, and was binned to the nearest 5 mm Hg. Analysis focused on BP shifts in 5 mm Hg increments. Serum samples for sVEGFR2 (Ph III only) were collected at baseline and on C1D15, C2D1, and C2D22–28. Models of drug exposure as predictors of longitudinal changes in BP and/or sVEGFR2 were constructed by non-linear mixed-effects modeling. Results Across pts, there was a statistically significant median 5 mm Hg increase in diastolic BP on C1D15, with similar increases noted on C2D1. There was a curvilinear decrease in sVEGFR2 with time. An Emax model vs time showed a half-maximal effect occurring in 19.4 (SE = 1.7) days, and a maximal 53% (%CV = 4%) decrease in sVEGFR2. There was a statistically significant effect of Cavg on Emax, with the magnitude of Emax increasing 6% per 10 ng/mL increase in Cavg. Conclusion PK/PD analysis of data from tivozanib Ph II–III studies showed that pts had a median increase in diastolic BP of 5 mm Hg on C1D15 and C2D1. Levels of serum sVEGFR2 were found to decrease significantly with time, and the effect size increased with tivozanib exposure. Relationships between exposure, BP, and sVEGFR2 and outcome are being explored. Disclosure R.J. Motzer: Only disclosure is research funding from AVEO Oncology. J. Loewy: Consulting fee or honoraria from qPharmetra LLC. L. Hodge: Consulting or honoraria from qPharmetra LLC. B. Esteves: AVEO Pharmaceuticals employee with stock options. A. Berkenblit: AVEO Pharmaceuticals employee with stock options. W. Yin: AVEO Pharmaceuticals employee with stock options. K. Dykstra: -Consultancy fee or honorarium: qPharmetra LLC -Fees for participation in review activities such as data monitoring boards, statistical analysis, end point committees and the like: qPharmetra LLC. T.E. Hutson: - Consultancy or honoraria: AVEO Pharmaceuticals - Consultancy: Pfizer, Bayer, GSK, Novartis – Grants, grants pending: Pfizer, Bayer, GSK, Novartis – Payment for lectures includes service on speakers bureau:Pfizer, Bayer, GSK, Novartis. M. Cotreau: AVEO Pharmaceuticals employee with stock options. All other authors have declared no conflicts of interest.

549 Background: Tivozanib (AV-951), a highly potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, has shown additive antitumor activity with fluorouracil (5-FU) in preclinical studies. An open-label phase Ib study was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and antitumor activity of escalating doses of tivozanib combined with standard-dose FOLFOX6 (i.e., oxaliplatin, leucovorin, and 5-FU) in pts with advanced GI tumors. Methods: Tivozanib was administered orally once daily in 4-week cycles (3 weeks on, 1 week off), with FOLFOX6 administered on days 1 and 15 of each cycle. Pts were allowed to continue tivozanib following discontinuation of FOLFOX6. Results: 22 pts (14 male/8 female; median age of 58 years [range, 40-75]) received 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 10) tivozanib plus FOLFOX6. Pts received a median of 8.1 weeks (range, 0.1 - 43.1) of treatment. DLTs were observed in 2 pts receiving 0.5 mg tivozanib (reversible grade 3 diarrhea and grade 3 and 4 transaminase elevations, respectively) and in 2 pts receiving 1.5 mg tivozanib (reversible grade 3 seizures and grade 3 vertigo, respectively). Other grade 3/4 drug-related adverse events (AEs) included neutropenia, fatigue, and hypertension (n = 2 each); and pyrexia, pulmonary embolism, and thrombosis (n = 1 each). There was no indication that drug-related AEs in this study were more frequent or severe than those observed with tivozanib or FOLFOX6 alone. The MTD was 1.5 mg tivozanib with full dose FOLFOX6. The PK profiles of tivozanib, oxaliplatin, and 5-FU will be presented. Several durable partial responses were observed. Additional safety and efficacy data are being obtained in 8 pts currently being treated at the 1.5-mg dose level. Conclusions: The combination of tivozanib and FOLFOX6 is tolerable and safe, with tivozanib given at its recommended dose of 1.5 mg. Observed clinical activity merits further exploration in several GI tumors, and these studies are being planned. [Table: see text]

Background: Tivozanib, a potent, selective, long-half-life tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, has demonstrated antitumor activity in a Phase II study in patients with renal cell carcinoma (RCC), and is currently being studied in clinical trials in patients with RCC and other solid tumors. The goal of this study was to investigate the effect of food on the pharmacokinetics (PK) of a single 1.5 mg dose of tivozanib in healthy subjects. Methods: This was a single-center, open-label, randomized, two-period, crossover Phase I trial. Subjects were admitted to the clinical research unit (CRU) 1 day before dosing, fasted ∼10 hours, and were randomized to fed (standard high-fat breakfast)/fasted or fasted/fed sequence. In each phase of the sequence, subjects received a single oral dose of tivozanib 1.5 mg with a 6-week washout period between doses. Subjects remained at the CRU for at least 48 hours post dose for blood sample collection and safety monitoring, and were assessed on an outpatient basis for up to 504 hours post dose. PK data were analyzed by non-compartmental methods. The effect of food on PK was assessed using standard criteria for bioequivalence based on the exposure parameters AUC 0-α and C max . If the 90% confidence intervals for the fed/fasted AUC 0-α and C max fell within the range of 80% to 125%, it was concluded that food had no effect on exposure. Results: Thirty healthy volunteers were enrolled (19M/11F; mean age 39 years [range 22-53 years]). There was no significant difference in AUC 0-α of serum tivozanib between the fed and fasted states (107.4%; Table 1). Food caused a significant decrease in serum tivozanib levels vs fasted state (C max : 77.5%). Conclusions: These results indicate that dosing tivozanib with food decreases maximal concentrations by ∼ 23%, but does not affect overall exposure. As tivozanib is dosed chronically in oncology patients and accumulates ∼6 to 7 times single-dose levels when at steady-state, these results are not likely to affect dosing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 752. doi:1538-7445.AM2012-752

445 Background: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors-1, -2, and -3 that is currently being tested in a Phase III study in patients with renal cell carcinoma and Phase I/II studies of other solid tumors. Preclinical and retrospective electrocardiogram (ECG) analyses suggest no effect of tivozanib on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. This open-label, non-randomized, single-arm study prospectively investigated the effect of tivozanib on the QTcF interval and its morphology on the ECG and ECG-pharmacokinetic (PK) relationship in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, an ECOG score ≤1 and life expectancy ≥3 months were eligible. Patients received 1.5 mg of tivozanib orally, once daily for 21 days. Serial blood samples and time-matched, triplicate, 12-lead ECGs were collected on: Day 1 20-30 minutes pre-dose (no blood sample collected), immediately pre-dose, and at 2.5, 4, 5, 6, 8, and 10 hours post dose; Day 2 pre-dose evaluation was taken approximately 24 hours post Day 1 dose; Day 8 (±1 day) pre-dose, and at 2.5, 5, and 8 hours post dose; Day 21 pre-dose and at 2.5, 4, 5, 6, 8, and 10 hours post dose; and Day 22 at approximately 24 hours post Day 21 dose. Additional safety parameters were evaluated by assessing clinical laboratory tests, physical examinations, vital signs, and recording of adverse events. Results: Fifty patients with advanced solid tumors (males, 17; median age, 63 years; 94% white) who received ≥ 1 dose of tivozanib were evaluable. Preliminary data showed that there were no clinically significant changes in QTcF from baseline. Further analysis will be completed, and final safety and ECG-PK modeling will be presented. Conclusions: Preliminary data suggest that tivozanib 1.5 mg/d over a 21-day period does not cause clinically significant QT/QTc prolongation over baseline, suggesting that its safety and PK profile is similar to that observed in previous studies, including ECG evaluation in a monkey telemetry study.

Objective: To evaluate the absorption, metabolism, and excretion of tivozanib, a new investigational drug for renal cell carcinoma and solid malignancies. Methods: Eight healthy male participants received a single 1.5-mg (similar to 160 mu Ci) dose of oral [C-14]-tivozanib. Whole blood, serum, urine, and feces were evaluated up to 28 days postdose for pharmacokinetics, radioanalysis, and metabolites. Adverse events were recorded throughout the study. Results: [C-14]-tivozanib concentration peaked at 10.9 +/- 5.84 hours. The mean serum half-life for [C-14]-tivozanib was 89.3 +/- 23.5 hours. The maximum concentration and area under the curve for [C-14]-tivozanib were 12.1 +/- 5.67 ng/mL and 1084 +/- 417.0 ng.h/mL, respectively. Mean recovery of total radioactivity was 91.0% +/- 11.0%; 79.3% +/- 8.82% of the radioactivity was recovered in feces both as unchanged tivozanib and metabolites. In the urine, 11.8% +/- 4.59% was recovered only as metabolites. No unchanged tivozanib was found in the urine. Conclusion: Tivozanib had a long half-life with no major circulating metabolite, was well tolerated as a single dose, and was primarily eliminated via feces with no unchanged tivozanib found in urine. These pharmacokinetic data of [C-14]-tivozanib are consistent with previous studies of unlabeled tivozanib.

Cytochrome P450s (CYPs) are an important family of enzymes in the metabolism of many therapeutic agents and endogenous metabolic reactions. The CYP3A subfamily is especially prominent in these metabolic activities. This review article focuses on how the factors of age and sex may influence the in vivo activity of human CYP3A. The functional activity of CYP3A varies based on issues such as interaction with one or more substrates and between individuals and/or localisation. For CYP3A substrates, intrinsic clearance is the component of total clearance that is contributed by the enzymes. Depending on the route of administration and the contribution of hepatic blood flow to overall clearance, sensitivities to changes in CYP3A activities may differ. Additionally, age may influence the hepatic blood flow and, in turn, affect CYP3A activity. A review of the literature regarding age influences on the clearance of CYP3A substrates does suggest that age can affect the clearance of certain CYP3A substrates. CYP3A is responsible for a large number of endogenous metabolic reactions involving steroid hormones, and enzyme activity has been reported to be induced and/or inhibited in the presence of some sex steroids. Based on published studies for most CYP3A substrates, sex does not appear to influence clearance; however, with certain substrates significant sex-related differences are found. In such cases, women primarily have higher clearance than men.

ABSTRACT Background Study results demonstrated that IFN augments BEV activity and improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a standard first-line treatment option for mRCC. Combining BEV with the mTOR inhibitor EVE may be an efficacious and well-tolerated treatment option. The open-label, phase II RECORD-2 trial compared first-line EVE + BEV and IFN + BEV in mRCC. Patients and methods: Therapy-naive pts with clear cell mRCC and prior nephrectomy were randomized 1:1 to BEV 10 mg/kg IV every 2 weeks with either EVE 10 mg oral daily or IFN (9 MIU SC 3 times/week, if tolerated). Tumour assessments were every 12 weeks. Primary objective was treatment effect on progression-free survival (PFS) per central review based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). Results In EVE + BEV (n = 182) and IFN + BEV (n = 183) arms, median age was 60/60 years, 76/72% of pts were men, MSKCC risk was favourable/intermediate/poor in 36/57/7% and 36/57/7% of pts, and 43/46% of pts had >2 organs involved, respectively. For EVE + BEV and IFN + BEV, median treatment duration was 8.5/8.3 months, respectively; 23/26% of pts discontinued due to AEs. In EVE + BEV and IFN + BEV arms, median PFS by central review was 9.3/10.0 months (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P =0.485), respectively; probability of subsequent phase III success was 5.1%. Results of central and local PFS analysis were consistent. Objective response rate was 27/28% in EVE + BEV and IFN + BEV arms, respectively. Median overall survival (OS) was not reached in the EVE + BEV arm and was 25.9 months (95% CI: 21.1, 30.2) in the IFN + BEV arm. Most frequent AEs (%) were stomatitis (63), proteinuria (49), diarrhoea (39), hypertension (38), and epistaxis (35) in EVE + BEV arm and decreased appetite (45), fatigue (41), proteinuria (37), and pyrexia (35) in IFN + BEV arm. Conclusions In RECORD-2, PFS and tolerability were similar for first-line EVE + BEV and IFN + BEV. Final OS analysis will occur after 2-year follow-up. Disclosure A. Ravaud: Alain Ravaud is a member of global, European, and/or French boards on urological tumors for Pfizer, Novartis, GlaxoSmithKline, Bayer-Schering, and Dendreon, and has received institutional grant support from Pfizer, Novartis, and Roche. O. Anak: Ozlem Anak is an employee of Novartis Pharma AG. D. Pelov: Diana Pelov is an employee of Novartis Pharmaceuticals Corporation. A. Louveau: Anne-Laure Louveau is an employee of Novartis Pharma S.A.S. T. M-H: Tay M-H is a speaker for an advisory board for Novartis Pharmaceuticals Corporation. B. Melichar: Bohuslav Melichar has received honoraria from Novartis and Roche and served on an advisory board for Roche. All other authors have declared no conflicts of interest.