Pharmacokinetics Of Bevacizumab Research Articles

Intraperitoneal pharmacokinetics of systemic oxaliplatin, 5-fluorouracil and bevacizumab in patients with colorectal peritoneal metastases

BackgroundPeritoneal metastases (PM) commonly occur in colorectal cancer patients. Systemic chemotherapy yields poor outcomes for these patients. It is hypothesised that traditional systemic chemotherapy is not very effective for this patient population. This study investigates to what extent systemic anti-cancer therapy crosses the peritoneal barrier. MethodsIn a Phase I study, eighteen patients received systemic oxaliplatin, 5-FU, and bevacizumab. Plasma and peritoneal fluid samples were collected to measure drug concentrations. A non-compartmental analysis determined the Area Under the Curve (AUC) for oxaliplatin and 5-FU in both matrices. Intraperitoneal (IP) and intravenous (IV) exposure ratios were calculated, along with the bevacizumab concentration IP/IV ratio. The relationship between tumour load and IP/IV ratios and the correlation between the IP/IV ratios of different treatments were assessed statistically. ResultsA total of 438 5-FU samples and 578 oxaliplatin samples were analysed in plasma and peritoneal fluid. Bevacizumab was quantified with 17 measurements in plasma and 15 measurements IP. Median IP/IV ratios were 0.143, 0.352 and 0.085 for 5-FU, oxaliplatin and bevacizumab, respectively. Oxaliplatin exhibited a longer IP half-life than 5-FU. A correlation was found between oxaliplatin and bevacizumab IP/IV ratios (R=0.69, p=0.01). No statistical correlations were found between the other investigated drugs. ConclusionsOur findings indicate that only a small percentage of systemically administered anti-cancer treatment reaches the IP cavity, questioning their efficacy against PM. This strengthens the hypothesis for repeated intraperitoneal chemotherapy to reach adequate anti-cancer drug levels.

PemBOv trial: Pembrolizumab plus bevacizumab with or without pegylated liposomal doxorubicin-based chemotherapy in patients with platinum-resistant ovarian cancer.

5575 Background: Few platinum resistant ovarian cancer (PROvC) patients respond to anti-PD1 monotherapy (ORR 7.6%) with little impact on survival (OS 10.1 mo). Among responders the median duration of response is impressive (18.7 mo) (Hamanishi 2021). Methods: We have evaluated the combination of pembrolizumab (200mg), with bevacizumab (400mg) for 6 cycles plus minus peglyated liposomal doxorubicin (PLD) q3w in PROvC patients with no limit in previous treatment lines, allowed to be previously treated with bevacizumab. An initial safety run evaluated the dual combination of pembrolizumab plus PLD (cohort A). The triple combination was evaluated at MTD-1 and at MTD of PLD (30mg/m2 q3w) (cohort C). The dual combination of pembrolizumab + bevacizumab was run in parallel (cohort B). This is an open label phase I trial with a modified toxicity probability interval design. The evaluation criteria endpoints were safety and efficacy. Pharmacokinetics of bevacizumab were evaluated. NCT03596281 Results: A total of 47 patients (pts) were enrolled between January 2019 and February 2021. Median age was 70 years (38-77). 30/12 pts (63.8/25.5%) had an initial FIGO stage III/IV, 44 pts (93.6%) had a HGSOC. 40 pts (85.1%) underwent surgery, out of which 13 pts (32.5%) had a primary debulking. BRCA mutations were present in 9 pts (19.1%). Pts had a median of 3 previous treatment lines (0-13), including pretreatment with antiangiogenic agents in 36 (76.6%) and PARP inhibitors in 21 pts (44.7%). No DLT was reported. Grade 3/4 treatment-related adverse events were reported in 2 pts (30%), 4 (20%) and 11 (50%) in cohorts A, B and C respectively. The ORR was 0, 26.3 (95% CI 6.5-46.1) and 30% (9.9-50.1) with a DCR of 0, 78.9 and 75% in cohorts A, B and C respectively. According to investigator assessment, the median PFS was 2.1, 4.7 and 4.8 mo (table). The blinded independent central review is currently under evaluation. A large inter-patient variability in bevacizumab plasma concentrations was observed among patients. The 400 mg flat dosing achieved residual concentrations similar to that of 5 mg/kg Q2W or 7.5 mg/kg q3w (51± 30 μg/ml in cohort B and 63 ± 55 μg/ml in cohort C (p>0.05) after C1). Overall, 22 % of pts of cohort B and 18 % of cohort C showed trough levels below the targeted threshold (i.e. < 25 μg/ml). Correlative studies are ongoing. Conclusions: Short-term flat dose bevacizumab potentiates the response to anti-PD1 therapy even in the absence of chemotherapy in heavily pre-treated PROvC patients. The long-term treatment with bevacizumab could potentially improve the outcome. The combination of anti-PD-1 plus anti-angiogenic agents should be a backbone for the treatment of PROvC patients. Clinical trial information: NCT03596281. [Table: see text]

Population pharmacokinetics and exposure-response relationship of trastuzumab and bevacizumab in early-stage breast cancer.

To describe the sources of interindividual variability of bevacizumab and trastuzumab pharmacokinetics in early-stage breast cancer, and to study the relationship between exposure and both early clinical response and specific adverse events. Patients (n = 86) received 6 cycles of docetaxel + trastuzumab. Early tumour response was assessed by determination of the maximum standard uptake value (SUVmax) variation (ΔSUVmax) after 1 cycle using [18F]-fluorodeoxyglucose (FDG) PET. Early poor responders (ΔSUVmax < 70%) also received bevacizumab from cycle 3 to cycle 6. Sources of interindividual variability in pharmacokinetics of both antibodies were studied by population compartment modelling. Exposure as assessed by area under the concentration-versus-time curve (AUC) was compared between responders and non-responders and between patients experiencing specific adverse events or not. A two-compartment model described the pharmacokinetics of both antibodies satisfactorily. Their central volume of distributions (Vc) increased with body surface area and their elimination half-lives were shorter (~14days) than previously reported (~26-28days). There was a time-dependent increase in trastuzumab Vc, positively correlated to baseline SUVmax. Bevacizumab elimination rate (k10) was positively correlated with ΔSUVmax measured at the end of the first cycle. Bevacizumab had no significantly influence on trastuzumab pharmacokinetics. No relationship between exposure and clinical response or occurrence of adverse events was found. Tumour uptake as assessed by SUVmax influences the pharmacokinetics of bevacizumab and trastuzumab. In early-stage breast cancer, elimination half-lives of these therapeutic monoclonal antibodies may be shorter than those previously reported in more advanced disease.

Atezolizumab and bevacizumab for hepatocellular carcinoma: mechanism, pharmacokineticsand future treatment strategies.

Hepatocellular carcinoma (HCC) is a common cancer globally and a leading cause of cancer-related deaths. Although early-stage disease may be curable by resection, liver transplantation or ablation, many patients present with unresectable disease and have a poor prognosis. Combination treatment with atezolizumab (targeting PD-L1) and bevacizumab (targeting VEGF) in the recent IMbrave150 study was shown to be effective with an acceptable safety profile in patients with unresectable HCC. Herein, we discuss this novel combination in the context of the liver immune environment, summarize the mechanism and pharmacokinetics of atezolizumab and bevacizumab, and examine recent data on other immune checkpoint inhibitor combination strategies as well as future directions in the treatment of patients with advanced HCC.

PET study of ocular and blood pharmacokinetics of intravitreal bevacizumab and aflibercept in rats

Intravitreal injections are the standard procedure in the treatment of retinal pathologies, such as the administration of the anti-VEGF antibodies in age-related macular degeneration. The aim of this study is to evaluate the intraocular and blood pharmacokinetics after an intravitreal injection of 89Zr-labelled bevacizumab and 89Zr-labelled aflibercept in Sprague-Dawley rats using Positron Emission Tomography. First, both antibodies were radiolabelled to zirconium-89 with a maximum specific activity of 15 Mbq/mg for bevacizumab and 10 Mbq/mg for aflibercept. Four µL containing 1–1.2 Mq of 89Zr-labelled compound were injected into the vitreous through a 35 G needle. A microPET acquisition was carried out immediately after the injection and at different time points through a 12-day study and blood samples were obtained through the tail vein. Radiolabelling was successfully performed with a radiochemical purity after ultrafiltration above 95% for both agents. Both antibodies ocular curves followed a two-compartment model in which an intraocular elimination half-life of 16.44 h was found for 89Zr-bevacizumab and 4.51 h for 89Zr-aflibercept, considering the alpha phase as the elimination phase. Regarding the beta phase, a half-life of 3.23 days for 89Zr-bevacizumab and 4.69 days for 89Zr-aflibercept were observed. With regards to blood concentration, 89Zr-bevacizumab showed a blood half-life of 7.08 days, whereas 89Zr-aflibercept’s was 3.18 days, by a one-compartment model with first-order absorption kinetics. In conclusion, this study shows for the first time the ocular and blood pharmacokinetic analysis after intravitreal injection of aflibercept and bevacizumab in rats.

A New Model to Describe the Single-dose Pharmacokinetics of Bevacizumab and Predict Its Multiple-Dose Pharmacokinetics in Beagle Dogs.

Complex pharmacokinetic (PK) properties including nonlinear elimination were encountered by some monoclonal antibodies (mAbs), and classic compartment models sometimes failed to appropriately describe those properties. In this work, a new model was built on a comprehensive analysis of the complex elimination of mAbs. This new model was firstly utilized to fit with the single-dose plasma concentration data of bevacizumab in beagle dogs receiving an intravenous administration of 2.5 mg/kg bevacizumab. Then, the optimal PK parameters from fitting with the single-dose PK data were employed into the multiple-dose mathematical expressions to predict bevacizumab’s multiple-dose PK profiles. One-compartment model recommended as the optimal classic model by DAS 2.0 software was set as a control. As a result, new model fitted better with the single-dose PK profiles of bevacizumab with smaller weighted residual sum of squares and higher fitting degree compared with the classic model. Importantly, new model also accurately predicted the multiple-dose PK profiles of bevacizumab and performed well at the single-to-multiple transition. In conclusion, the new model reasonably explained the complex elimination of bevacizumab, and it might play a big role in the PK studies of bevacizumab and other mAbs.

A Minimal Physiologically Based Pharmacokinetic Model with a Nested Endosome Compartment for Novel Engineered Antibodies.

We proposed here a minimal physiologically based pharmacokinetic (mPBPK) model for a group of novel engineered antibodies in mice and humans. These antibodies are designed with altered binding properties of their Fc domain with neonatal Fc receptor (FcRn) or the Fab domain with their cognate targets (recycling antibodies) in acidic endosomes. To enable simulations of such binding features in the change of antibody pharmacokinetics and its target suppression, we nested an endothelial endosome compartment in parallel with plasma compartment based on our previously established mPBPK model. The fluid-phase pinocytosis rate from plasma to endothelial endosomes was reflected by the clearance of antibodies in FcRn dysfunctional humans or FcRn-knockout mice. The endosomal recycling rate of FcRn-bound antibodies was calculated based on the reported endosomal transit time. The nonspecific catabolism in endosomes was fitted using pharmacokinetic data of a human wild-type IgG1 adalimumab in humans and B21M in human FcRn (hFcRn) transgenic mice. The developed model adequately predicted the pharmacokinetics of infliximab, motavizumab, and an Fc variant of motavizumab in humans and the pharmacokinetics of bevacizumab, an Fc variant of bevacizumab, and a recycling antibody PH-IgG1 and its non-pH dependent counterpart NPH-IgG1 in hFcRn transgenic mice. Our proposed model provides a platform for evaluation of the pharmacokinetics and disposition behaviors of Fc-engineered antibodies and recycling antibodies.

Pharmacokinetics of Bevacizumab in Three Patients Under the Age of 3 Years with CNS Malignancies

BackgroundBevacizumab is a recombinant antibody that is increasingly used in pediatric malignancies. The pharmacokinetics of bevacizumab in pediatric patients have been shown to be influenced by tumor localization and body weight. In this report, we present data on the pharmacokinetics and safety of bevacizumab in children under the age of 3 years with central nervous system (CNS) malignancies.MethodsThree patients (mean age 22 months) were treated with intravenous bevacizumab 10 mg/kg every 2 weeks. In total, 20 trough and peak bevacizumab concentrations of 10 treatment cycles were obtained at steady state.ResultsBevacizumab was generally well-tolerated in this age group. The mean trough concentration was 127 ± 29 µg/ml (range 77–155), and the mean peak concentration was 149 ± 13 µg/ml (range 113–157). Trough and peak levels were stable upon repeated treatment cycles in the same patient. In contrast, we determined strong interindividual variations in trough levels. Whereas the plasma concentration of the oldest patient matched the prediction of a previously published model, younger patients showed markedly higher trough levels.ConclusionsSerum peak concentrations of bevacizumab in children under the age of 3 years with CNS malignancies are in a similar magnitude to that found in older children and adults. Thus, a dosing schedule of bevacizumab 10 mg/kg every 2 weeks can be considered sufficient and safe, even in very young children. We further show that very young children with CNS malignancies show a markedly reduced plasma clearance, possibly related to lower body weight or differences in clearance mechanisms of antibodies.

Population pharmacokinetics of bevacizumab in cancer patients with external validation.

BackgroundBevacizumab is approved for various cancers. This analysis aimed to comprehensively evaluate bevacizumab pharmacokinetics and the influence of patient variables on bevacizumab pharmacokinetics.MethodsRich and sparse bevacizumab serum concentrations were collected from Phase I through IV studies in early and metastatic cancers. Bevacizumab was given intravenously as single agent or in combination with chemotherapy for single- and multiple-dose schedules.ResultsModel-building used 8943 bevacizumab concentrations from 1792 patients with colon/colorectal, non-small cell lung, kidney, pancreatic, breast, prostate and brain cancer. Bevacizumab doses ranged from 1 to 20 mg/kg given once every 1, 2 or 3 weeks. A two-compartment model best described the data. The population estimates of clearance (CL), central volume of distribution (V1) and half-life for a typical 70-kg patient were 9.01 mL/h, 2.88 L and 19.6 days. CL and V1 increased with body weight and were higher in males than females by 14 and 18 %, respectively. CL decreased with increasing albumin and decreasing alkaline phosphatase. The final model was externally validated using 1670 concentrations from 146 Japanese patients that were not used for model-building. Mean prediction errors were −2.1, 3.1 and 1.0 % for concentrations, CL and V1, respectively, confirming adequate predictive performance.ConclusionsA robust bevacizumab pharmacokinetic model was developed and externally validated, which may be used to simulate bevacizumab exposure to optimize dosing strategies. Asian and non-Asian patients exhibited similar bevacizumab pharmacokinetics. Given the similarity in pharmacokinetics among monoclonal antibodies, this may inform pharmacokinetic studies in different ethnic groups for other therapeutic antibodies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3079-6) contains supplementary material, which is available to authorized users.

Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation.

The aim of the present study was to evaluate the pharmacokinetics of bevacizumab and various dosing strategies for this agent in paediatric patients. Data were collected from 232 paediatric patients (1971 concentrations) in five studies, with a wide range of age (0.5-21 years), body weight (BWT; 5.9-125 kg), and regimens (5-15 mg kg(-1) biweekly or triweekly). Data from 152 patients (1427 concentrations) and 80 patients (544 concentrations) were used for model building and external validation, respectively. Steady-state exposure was simulated under BWT-based, body surface area (BSA)-based, ideal body weight (IBW)-based, and tier-based doses. NONMEM and R were used for analyses. Typical estimates of clearance, central volume of distribution (V1), and median half-life were 9.04 ml h(-1) , 2851 ml, and 19.6 days, respectively. Clearance decreased with increasing albumin. Clearance and V1 increased with BWT and were higher in male patients. Clearance and V1 were lower in children with primary central nervous system (CNS) tumours than in children with sarcomas, resulting in 49% higher trough (C min) and 29% higher peak (Cmax) concentrations. BWT-adjusted clearance and V1 remained unchanged across ages. Paediatric C min was similar to adult C min under all dosing strategies. Paediatric Cmax exceeded adult Cmax under tier-based doses. BWT-adjusted pharmacokinetic parameter estimates in paediatric patients were similar to those in adults, and similar across ages. Bevacizumab exposure was higher in children with primary CNS tumours than in children with sarcomas. BSA-based, IBW-based, and tier-based doses offered no substantial advantage over the BWT-based dose currently used in adults for bevacizumab. Given the similarity in pharmacokinetics among many monoclonal antibodies, this may help to develop practical paediatric dosing guidelines for other therapeutic antibodies.

A pharmacokinetic binding model for bevacizumab and VEGF165 in colorectal cancer patients.

Purpose To characterize the population pharmacokinetics of bevacizumab, its binding properties to VEGF165 and the effect of demographic data and VEGF-A polymorphisms on the interplay between bevacizumab serum pharmacokinetics and VEGF165 serum concentrations in patients with colorectal cancer stage IV.MethodsBevacizumab and VEGF165 data were collected from 19 adult patients with metastatic colorectal cancer enrolled in an observational clinical study. Bevacizumab was administered with one of the following combinations: 5-FU/Leucovorin/Irinotecan, 5-FU/Leucovorin/Oxaliplatin, Capecitabine/Irinotecan at doses ranging from 5 to 10 mg/kg every 2 or 3 weeks. Data analysis was performed using nonlinear mixed-effects modeling implemented in NONMEM 7.3.ResultsA target-mediated drug disposition model adequately described bevacizumab concentration changes over time and its binding characteristics to VEGF165. The estimated clearance of bevacizumab was 0.18 L/day, the free VEGF165 levels at baseline were 212 ng/L, and the elimination rate constant of free VEGF165 was 0.401 day−1. Body weight was allometrically included in all PK parameters.ConclusionThe final model adequately described the pre- and post-dose concentrations of total bevacizumab and free VEGF165 in patients with colorectal cancer. Model parameters were consistent with those previously reported for patients with solid tumors. Correlations between the binding affinity of bevacizumab and the VEGF-2578C/A and VEGF-634G/C polymorphisms were noticed.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-015-2701-3) contains supplementary material, which is available to authorized users.

Pharmacokinetics of bevacizumab and its effects on serum VEGF and IGF-1 in infants with retinopathy of prematurity.

To measure serum levels of bevacizumab and to compare serum levels of free vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) in infants who were treated with either intravitreal injection of bevacizumab (IVB) or laser for type 1 retinopathy of prematurity (ROP). Twenty-four infants with type 1 ROP were randomized into three treatment groups: IVB at 0.625 mg per eye per dose, IVB at 0.25 mg per eye per dose, and laser. Blood samples were collected prior to treatment and on posttreatment days 2, 14, 42, and 60. Weekly body weights were documented from birth until 60 days post treatment. Serum levels of bevacizumab, free VEGF, and IGF-1 were measured with enzyme-linked immunosorbent assay (ELISA). Serum bevacizumab was detected 2 days after the injection, peaked at 14 days, and persisted for up to 60 days with half-life of 21 days. Area under the curve (AUC) analysis showed that systemic exposure to bevacizumab was variable among the subjects and was dose dependent. Serum free VEGF levels decreased in all three subgroups 2 days post treatment, with more significant reductions found in both IVB-treated groups, P = 0.0001. Serum IGF-1 levels were lower in both IVB-treated groups. Clearance of bevacizumab from the bloodstream in premature infants takes at least 2 months. Although serum free VEGF levels decreased following either laser or bevacizumab treatment, the reductions were more significant in the IVB-treated groups. Potential long-term effects of systemic exposure to bevacizumab in infants need to be studied further.

Similar exposure and pharmacokinetics of bevacizumab in pediatric and adult cancer patients: Analysis of individual data of 152 pediatric patients.

10062 Background: Bevacizumab (BEV) is approved for various cancers. BEV pharmacokinetics (PK) is well established by a population PK (PPK) model in adults, but has not been comprehensively evaluat...

Population Pharmacokinetics of Bevacizumab in Children with Osteosarcoma: Implications for Dosing

To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Bevacizumab concentration-time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults, with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space, 49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure, as body mass index percentile was significantly (P < 0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure before primary tumor resection was associated with increased risk of major wound healing complications after surgery (P < 0.05). A population pharmacokinetic model for bevacizumab was developed, which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications.

Pharmacokinetics of bevacizumab after topical and intravitreal administration in human eyes

BackgroundTopical bevacizumab is a potential treatment modality for corneal neovascularization, and several recent studies have demonstrated its efficacy. No previous study of the pharmacokinetics of topical bevacizumab has been performed in human eyes. The purpose of this study is to investigate the pharmacokinetics of topical administration of bevacizumab in human eyes, and also to compare the pharmacokinetics of intravitreal bevacizumab injections with previously reported data.MethodsTwenty-two (22 eyes) were included in this study, and divided into four groups: eight patients received topical bevacizumab and aqueous samples were obtained 1 hour later during cataract extraction surgery (group 1), eight patients received topical bevacizumab and vitreous samples were obtained 1 day later during pars-plana vitrectomy (PPV) (group 2), three patients received intravitreal bevacizumab and vitreous samples were obtained during PPV (group 3). Vitreous samples from three patients who received no bevacizumab served as controls (group 4). All samples underwent enzyme-linked immunosorbent assay to detect bevacizumab.ResultsNo bevacizumab was detected in the aqueous or vitreous of any topically treated eyes. The mean vitreal half-life for intravitreally injected bevacizumab was 4.9 days in four non-vitrectomized eyes and 0.66 days in one previously vitrectomized eye.ConclusionsTopically administered bevacizumab does not penetrate the cornea into the anterior chamber and vitreous cavity, indicating that topical use for treating corneal neovascularization has minimal risk of intraocular penetration and adverse events related to intraocular vascular endothelial growth factor inhibition. The half-life following intravitreal bevacizumab injection measured in this study is comparable to that of previous reports, and includes the first demonstration of a significantly reduced half-life following intravitreal injection in a previously vitrectomized eye.

A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer

Background:This phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC).Methods:Patients with refractory stage IV CRC were treated with bevacizumab 5 mg kg−1 i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured.Results:Thirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50 mg q.d., imatinib 400 mg q.d., and bevacizumab 5 mg kg−1 i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival.Conclusion:The combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.

A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC). Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions. A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab. Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.

Characterization of the long-term pharmacokinetics of bevacizumab following last dose in patients with resected stage II and III carcinoma of the colon

The study characterizes the long-term pharmacokinetics (PK) following last dose of bevacizumab as adjuvant therapy in patients with resected stage II and III colon carcinoma in a Phase III clinical study (AVF3077s). Patients in AVF3077s received bevacizumab (5 mg/kg every 2 weeks) as adjuvant therapy for 1 year. Following the last dose bevacizumab concentration, data at 3 and 6 months were used to characterize long-term bevacizumab PK based on the population-modeling approach. The long-term bevacizumab PK were consistent with previously reported results based on short-term bevacizumab PK. The clearance (CL), central volume of distribution (V(1)), intercompartmental clearance (Q), and the peripheral volume of distribution (V(2)) were 214 mL/day, 2,830 mL, 636 mL/day, and 2,490 mL, which correspond to a disposition and elimination half-life of 1.33 and 19.1 days, respectively. The empirical Bayes estimates of median post-treatment bevacizumab drug levels at 3 and 6 months were 6.14 and 0.23 μg/mL, respectively. For test covariates, the change in CL and V(1) of bevacizumab was less than 20% of the typical value. Body weight is the important covariate explaining the inter-individual variability on CL and V(1). Long-term bevacizumab PK in this study was predictable based on short-term PK data from metastatic settings in other tumor types. An exploratory analysis demonstrated no apparent association of the tested covariates with bevacizumab PK. Further, the extended serum persistence of bevacizumab following last dose should be considered in clinical study designs and post-treatment evaluations that may be affected by bevacizumab.

Ocular Pharmacokinetics of Bevacizumab in Vitrectomized Eyes with Silicone Oil Tamponade

We characterized the ocular pharmacokinetics of bevacizumab in vitrectomized eyes with silicone oil tamponade. A total of 18 pigmented rabbits underwent vitrectomy and silicone oil tamponade before an intra-silicone oil injection of 1.25 mg bevacizumab. At post-injection days 1, 7, 14, 28, 42, and 56, 3 rabbits were sacrificed and enucleated, and bevacizumab concentrations were measured in various ocular tissues and plasma. The bevacizumab peak concentration was reached at day 14 in the aqueous humor (4030.70 ng/mL), retina (42,171.7 ng/g), and choroid (56,243.33 ng/g). In the iris/ciliary body and plasma, the peak concentration was reached at day 7 with 52,648.30 ng/g and 197.70 ng/mL, respectively. The choroid had the maximum exposure to bevacizumab with an area under the curve calculated from time zero to the last observed time (AUC(last)) of 1,151,633.40 ng/day/g and the aqueous humor had the minimum exposure (AUC(last) = 74,611.28 ng/day/g) among the ocular tissues, while the drug exposure to the plasma was the smallest of all tissues studied (AUC(last) = 3795.17 ng/day/g). The terminal half-lives and the mean residence time of bevacizumab in the ocular tissues ranged from 3-5 and 10-13 days, respectively. The peak concentration of bevacizumab in various ocular tissues and plasma was delayed and lower than that found in normal rabbit eyes; however, the terminal half-lives were similar to those found in the eyes with native vitreous following an intravitreal injection. Oil may have impacted the distribution of bevacizumab and led to an altered profile of drug level in the ocular tissues.

Intraperitoneal bevacizumab combined with cytoreductive surgery: a pre-clinical study of tolerance and pharmacokinetics in an animal model

Cytoreductive Surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is currently the only potentially curative treatment for peritoneal carcinomatosis (PC). Systemic administration of bevacizumab improves survival in patients with metastatic colorectal or ovarian cancer. Intraperitoneal administration of bevacizumab has been shown to be safe and effective in treating malignant ascites. The combination of CRS with intraperitoneal (IP) bevacizumab could maximize local control and survival from PC, but the associated morbidity from this is unknown. The aim of this study was to evaluate the safety of the combination of CRS with IP bevacizumab and to determine the pharmacokinetics of the drug in a rabbit model. Twenty healthy rabbits underwent a standardized procedure of debulking surgery, including peritonectomy and gastrointestinal anastomosis and were randomized to receive IP bevacizumab (25mg/kg) or placebo. Another group of three rabbits underwent an instillation of IP bevacizumab (25mg/kg) without surgery. One rabbit that received IP bevacizumab died with no complication associated with the use of bevacizumab at autopsy. There was no significant difference between IP bevacizumab and placebo in weight loss, length of surgery or morbidity. The plasma concentration of bevacizumab increased to a peak at 24h post IP administration. Bevacizumab was not detected in the plasma of animals without surgery. This study suggests that IP bevacizumab does not increase morbidity and mortality of debulking surgery in an animal model. When surgery is performed, the pharmacokinetics of IP bevacizumab are modified in plasma.