Jürgen Venitz

2‐Methoxyestradiol, a Promising Anticancer Agent

Estrogens occurring naturally in the body are metabolized to catecholestrogens (2‐ and 4‐hydroxyestradiol) by the cytochrome P450 enzymes. 2‐Hydroxy catecholestrogens are further metabolized by catechol‐O‐methyltransferase to 2‐methoxyestradiol, which is known to be protective against tumor formation. 2‐Methoxyestradiol exhibits potent apoptotic activity against rapidly growing tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the colchicine‐binding site, have been reported. The exact mechanism of action of 2‐methoxyestradiol is still unclear, but it has been shown to be effective in preventing tumor growth in a variety of cell lines. 2‐Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for estrogen receptor α compared with that of estradiol, and its affinity for estrogen receptor β is even lower than that of estrogen receptor α, thus it has minimal estrogenic activity. 2‐Methoxyestradiol is distinct because of its inability to engage estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of estrogen receptors α and β. A phase I clinical trial of 2‐methoxyestradiol 200, 400, 600, 800, and 1000 mg/day in 15 patients with breast cancer showed significant reduction in bone pain and analgesic intake in some patients, with no significant adverse effects. Another phase I study of 2‐methoxyestradiol 200–1000 mg/day in combination with docetaxel 35 mg/m2/week for 4–6 weeks performed in 15 patients with advanced refractory metastatic breast cancer showed no serious drug‐related adverse effects. A phase II randomized, double‐blind trial of 2‐methoxyestradiol 400 and 1200 mg/day in 33 patients with hormone‐refractory prostate cancer showed that it was well tolerated and showed prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1000 mg/day.

A Phase II Clinical Trial of Sorafenib in Androgen-Independent Prostate Cancer

Purpose: To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC). Experimental Design: Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles. Results: Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimenn. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC0-12) and maximum concentration (Cmax) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration (tmax) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively. Conclusions: Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.

Pharmacokinetic/Pharmacodynamic Modeling in Drug Research and Development

The two domains in clinical pharmacology dealing with optimizing dosing recommendations are pharmacokinetics and pharmacodynamics. However, the usefulness of these disciplines is limited if viewed in isolation. Pharmacokinetic/pharmacodynamic (PK/PD) relationships and modeling builds the bridge between these two classical disciplines of clinical pharmacology. It links the concentration‐time profile as assessed by pharmacokinetics to the intensity of observed response as quantified by pharmacodynamics. Thus, the resulting so‐called integrated PK/PD‐models allow the description of the complete time course of the desired and/or undesired effects in response to a drug therapy. PK/PD‐modeling can elucidate the causative relationship between drug exposure and response and provide a better understanding of the sequence of events that result in the observed drug effect. This information can then be used to streamline the drug development process and dose optimization. This consensus paper presents an update on the current state of PK/PD‐modeling from an academic, industrial and regulatory perspective.

The role of vascular endothelial growth factor SNPs as predictive and prognostic markers for major solid tumors

Angiogenesis is crucial for development and metastasis of tumors, and vascular endothelial growth factor (VEGF) is a key mediator of this process. The importance of VEGF in tumorigenesis and tumor progression makes it an attractive target for the development of anticancer therapies. Inhibition of angiogenesis has shown promising clinical efficacy; however, not all patients treated with antiangiogenic agents derive benefit from them. Some patients are predisposed to refractory disease, whereas others develop resistance after initial response. Patients may also have different severity of drug-related adverse events. Optimization of drug administration based on disease status and individual responsiveness is important in limiting the treatment failure and minimization of side-effects. Single nucleotide polymorphisms (SNP) in VEGF may alter VEGF protein concentrations, influence the process of angiogenesis, and may relate to interindividual variation in the risk and progression of selected tumors, and their resistance to treatments. This review examines the role of SNPs in the VEGF gene as predictive and prognostic markers for major solid tumors, including the breast, non-small cell lung, colorectal, and prostate cancers. Selected VEGF SNPs seem to be associated with risk of these cancers; however, there is lack of unanimity in findings, in part influenced by differences in study design and analysis. [Mol Cancer Ther 2009;8(9):2496–508]

Phase I Clinical Trial of Oral 2-Methoxyestradiol, an Antiangiogenic and Apoptotic Agent, in Patients with Solid Tumors

Purpose: To determine the maximum-tolerated dose (MTD) and toxicity profile of the novel anticancer agent, 2-methoxyestradiol (2ME2) administered orally, in patients with solid tumors. Patients and Methods: Twenty patients with refractory solid tumors were enrolled. 2ME2 was given orally starting at 400 mg bid with dose escalation until 3000 mg bid. Tumor biopsies were taken before and after starting the drug to assess for microvessel density by CD 31 and cell proliferation by Ki67 immunohistochemistry. Serial plasma samples collected up to 50 hours after first single oral dose for characterization of pharmacokinetics, were analyzed using liquid chromatography tandem mass-spectrometry. Results: Eleven men and nine women received 2ME2 at dose levels of 400 mg bid (n=3), 800 mg bid (n=3), 1600 mg bid (n=6), 2200 mg bid (n=5) and 3000 mg bid (n=3). There were no dose limiting toxicities, therefore the MTD was not defined. There was one episode of grade 4 angioedema in the 1600 mg bid dose level 38 days into 2ME2 treatment. Other toxicities were mild to moderate. A patient with clear cell carcinoma of the ovary had a partial response at 1600 mg bid dose level lasting over 3 years. Conclusion: MTD for 2ME2 was not reached at dose of 3000 mg bid. The trial was closed due to extremely low plasma concentrations of 2ME2 relative to the doses administered. 2ME2 treatment had no effect on microvessel density (CD31 immunostaining) and cell proliferation (Ki-67 immunostaining). A new formulation of 2ME2 with improved bioavailability is currently being developed.

Final analysis of a phase II trial using sorafenib for metastatic castration-resistant prostate cancer.

To determine if sorafenib is associated with an improved 4‐month probability of progression‐free survival, using radiographic and clinical criteria alone, in patients with metastatic castration‐resistant prostate cancer. Secondary endpoints included pharmacokinetics, toxicity analysis and overall survival.

Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib

BackgroundHypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes.MethodsToxicities (≥ grade 2 HT or HFSR), progression-free survival (PFS), and overall survival (OS) following treatment initiation were evaluated. Toxicity incidence and VEGFR2 H472Q and V297I status were compared to clinical outcomes.ResultsIndividuals experiencing HT had longer PFS following bevacizumab therapy than those without this toxicity in trials utilizing bevacizumab in patients with prostate cancer (31.5 vs 14.9 months, n = 60, P = 0.0009), and bevacizumab and sorafenib in patients with solid tumors (11.9 vs. 3.7 months, n = 27, P = 0.052). HT was also linked to a > 5-fold OS benefit after sorafenib and bevacizumab cotherapy (5.7 versus 29.0 months, P = 0.0068). HFSR was a marker for prolonged PFS during sorafenib therapy (6.1 versus 3.7 months respectively, n = 113, P = 0.0003). HT was a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib (OR(95%CI) = 3.2(1.5-6.8), P = 0.0024). Carriers of variant alleles at VEGFR2 H472Q experienced greater risk of developing HT (OR(95%CI) = 2.3(1.2 - 4.6), n = 170, P = 0.0154) and HFSR (OR(95%CI) = 2.7(1.3 - 5.6), n = 170, P = 0.0136).ConclusionsThis study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, and VEGFR2 alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib.

Population pharmacokinetic analysis of sorafenib in patients with solid tumours

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Sorafenib is a multikinase inhibitor with activity against B-raf, C-raf, VEGFR2, PDGFRβ and FGFR1. Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). The pharmacokinetics (PK) of sorafenib are highly variable between subjects. Sorafenib exposure increases less than dose proportionally (likely due to limited solubility). Sorafenib undergoes enterohepatic recycling (EHC). WHAT THIS STUDY ADDS This is the first study to characterize the PK of sorafenib using a model based on sorafenibs known disposition characteristics such as delayed/solubility-limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying. This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5 on sorafenib PK. No clinically important covariates were identified. This model can be used to simulate and explore alternative dosing regimens and to develop exposure-response relationships for sorafenib. AIMS To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib. METHODS PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis. RESULTS A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h(-1) (3.6-22.3 l h(-1) ), volume 213 l (50-1000 l), mean absorption transit time 1.98 h (0.5-13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h. CONCLUSIONS Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.

The Pharmacokinetics of Subcutaneous Enoxaparin in End‐Stage Renal Disease

Study Objective. To evaluate the pharmacokinetics of enoxaparin in end‐stage renal disease (ESRD), and determine if dosage reduction is necessary to maintain antifactor Xa activity concentrations within the therapeutic range.

Pharmacokinetics and Safety of Ambrisentan in Combination With Sildenafil in Healthy Volunteers

The pharmacokinetic interaction between sildenafil, a phosphodiesterase type 5 (PDE‐5) inhibitor, and ambrisentan, an ETA‐selective, propanoic acid—based endothelin receptor antagonist (ERA), was studied in a 2‐period crossover study in 19 healthy volunteers, with ambrisentan exposure (AUC0‐∞) and maximum plasma concentration (Cmax) determined over 24 hours for a 10‐mg dose of ambrisentan alone and again after 7 days of sildenafil 20 mg 3 times daily. The AUC0‐∞ and Cmax for sildenafil and N‐desmethyl sildenafil (active metabolite) were determined over 24 hours for a 20‐mg dose of sildenafil alone and again after 7 days of dosing with ambrisentan 10 mg once daily. There was no clinically relevant pharmacokinetic interaction between ambrisentan and sildenafil or N‐desmethyl sildenafil. Ambrisentan Cmax was unchanged (96.3% [90% confidence interval: 86.0%‐107.8%]), with a minor increase in AUC0‐∞(108.5% [102.6%‐111.7%]) with sildenafil coadministration. Sildenafil Cmax was increased slightly (113.4% [99.6%‐129.1%]), and AUC0‐∞ was unchanged (98.7% [91.2%‐110.5%]) with ambrisentan coadministration. N‐desmethyl sildenafil was unaltered. Dose adjustment of either drug is not necessary compared with administration alone.