Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4′-Oglucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P < 0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity. Cancer Res; 70(22); 9003-11. ©2010 AACR.
OBJECTIVES Aprepitant is effective for the prevention of chemotherapy-induced or postoperative nausea and vomiting (CINV/PONV). The aim of this study was to develop a population pharmacokinetic (PK) model of aprepitant in pediatric patients and to support dosing recommendations for oral aprepitant in pediatric patients at risk of CINV. METHODS A population PK model was constructed based on data from 3 clinical studies in which children (6 months to 12 years) and adolescents (12–19 years) were treated with a 3-day regimen of oral aprepitant (capsules or suspension), with or without intravenous fosaprepitant on day 1 (CINV), or a single dose of oral aprepitant (capsules or suspension; PONV). Nonlinear mixed-effects modeling was used for model development, and a stepwise covariate search determined factors influencing PK parameters. Simulations were performed to guide final dosing strategies of aprepitant in pediatric patients. RESULTS The analysis included 1326 aprepitant plasma concentrations from 147 patients. Aprepitant PK was described by a 2-compartment model with linear elimination and first-order absorption, with allometric scaling for central and peripheral clearance and volume using body weight, and a cytochrome P450 3A4 maturation component for the effect of ontogeny on systemic clearance. Simulations established that application of a weight-based (for those <12 years) and fixed-dose (for those 12–17 years) dosing regimen results in comparable exposures to those observed in adults. CONCLUSIONS The developed population PK model adequately described aprepitant PK across a broad pediatric population, justifying fixed (adult) dosing for adolescents and weight-based dosing of oral aprepitant for children.
CPX‐351, a dual‐drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, is approved in the United States for adults with newly diagnosed therapy‐related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia‐related changes. Population pharmacokinetics analyses were performed using nonlinear mixed‐effect modeling on pooled data from 3 clinical studies, and the impact of CPX‐351 exposures on efficacy and safety was assessed. The pharmacokinetics of cytarabine and daunorubicin were described using 2‐compartment models with linear elimination. None of the evaluated covariates had a clinically significant impact on plasma exposure to total cytarabine or daunorubicin, while bilirubin and formulation showed statistically significant effects on pharmacokinetic parameters of cytarabine and daunorubicin, respectively. In patients with mild/moderate renal impairment or serum bilirubin ≤3 mg/dL, plasma exposures to cytarabine and daunorubicin following CPX‐351 were within the variability range for patients with normal kidney function or serum bilirubin levels. Exposure‐response analysis demonstrated that better efficacy outcomes were associated with higher CPX‐351 exposure quartiles. Early mortality rates in all CPX‐351 exposure quartiles were lower vs the 7 + 3 control group, and lower mortality rates were associated with higher exposure quartiles. A trend toward greater frequency of grade 3 treatment‐emergent adverse events (but not grade 4/5 events) was observed at higher CPX‐351 exposure quartiles. Overall, the population pharmacokinetic analyses indicate no adjustments to the recommended dose and schedule of CPX‐351 are warranted for patients with mild/moderate renal impairment or serum bilirubin ≤3 mg/dL. Results from the exposure‐response analyses suggest the current CPX‐351 regimen provides a favorable risk‐benefit profile.
Rationale:In developing an alternative formulation of formoterol fumarate (FF), systemic exposure from the new product must be similar to an approved formulation and maintain a similar pharmacodynamic (PD) response. In order to evaluate dose-response, and assure assay sensitivity, doses higher than the approved product should be administered to demonstrate superior PD response relative to the approved dose. Pearl has previously demonstrated bioequivalence between FF-MDI and Foradil® Aerolizer® (Foradil). Pearl conducted a single dose crossover study to compare FF-MDI to Foradil at the approved and higher doses. Methods: In a randomized, double-blind, six period, crossover study conducted in patients with moderate to severe COPD that were reversible to albuterol, 3 doses of FF-MDI (7.2, 9.6 and 19.2µg) were compared to placebo MDI, and Foradil (12 and 24 µg). Pharmacokinetic (PK) and PD assessments were conducted for 12 hours following each dose. The primary efficacy endpoint was FEV AUC relative to pre-dose 1 0-12 baseline at the start of each treatment day. Secondary endpoints included Peak FEV , morning trough FEV and safety assessments. Full 1 1 PK profiles were obtained throughout the 12â€'hour observation period. An ANOVA was used in the analyses of the ln-transformed PK parameters AUC , and C . The resulting mean estimates (Geometric Least-Squares Means, Geometric LSM) for each treatment were 0-12 max computed. Results: Fifty patients were randomized. All doses of FF-MDI and Foradil were superior to placebo for the primary endpoint (P<0.0001 for all comparisons). FF-MDI 7.2 µg and FF-MDI 9.6 µg were non-inferior to Foradil 12 µg. Foradil 24 µg was superior to Foradil 12 µg (mean difference = 52 mL) and FF-MDI 19.2 µg was superior to FF-MDI 9.6 µg (mean difference = 42 mL), demonstrating assay sensitivity across both formulations. Bioequivalence between FF-MDI 9.6 µg and Foradil 12 µg was demonstrated by the ratio of Geometric LSMs and 90% CI for AUC (0.98, 0.90-1.07, respectively), and for Cmax (0.96, 0.87-1.07, respectively). Similar PK results were observed for the 0-12 comparison between FF-MDI 19.2 µg and Foradil 24 µg. All products were safe and well tolerated with no substantial differences across formulations. Conclusion: This is the second study in which Pearl Therapeutics' formulation of FF-MDI 9.6 µg demonstrated bioequivalence and comparable efficacy and safety to Foradil® Aerolizer® 12 µg. In this study, assay sensitivity was achieved with comparable findings across the two higher doses.
Background: rVWF (vonicog alfa; Vonvendi ®,Baxalta US Inc, a Takeda company, Lexington, MA, USA) is a purified recombinant VWF concentrate approved for on-demand (OD) treatment of hemorrhage and management of surgical bleeding in adults with VWD. The efficacy and safety of rVWF prophylaxis has also been evaluated in a recent open-label phase 3 trial in adults with severe VWD (NCT02973087). Aims: To evaluate the exposure-response (ER) relationship between VWF activity (measured by VWF:ristocetin cofactor [RCo]), endogenous factor VIII (FVIII) activity (measured by FVIII:C), and spontaneous bleeding events (sBEs) in patients with severe VWD receiving rVWF prophylaxis for up to 1 year. Methods: The modeling framework involved developing population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models and conducting simulations to characterize VWF activity/PK and FVIII activity/PD, then developing an ER model for VWF and FVIII activities in association with sBEs. The population PK and PK/PD models were developed using data from 100 unique patients receiving intravenous rVWF in 4 completed clinical studies (NCT00816660; NCT01410227; NCT02283268; NCT02973087). The PK and PK/PD analyses were used to generate model parameters and evaluate predictors of heterogeneity for PK/VWF:RCo and PD/FVIII:C time profiles. The ER relationship was evaluated using sBEs from the phase 3 rVWF prophylaxis trial (NCT02973087) in 23 adults with severe VWD (VWF:RCo <20 IU/dL) requiring VWF therapy to manage BEs during the year before study entry: 13/23 patients were previously treated OD with a VWF (Prior OD group) and 10/23 had received plasma-derived VWF (pdVWF) prophylaxis (Switch group). For this ER evaluation, a repeated time-to-event (RTTE) model was used, including a piecewise exponential additive model, and the covariate effect of previous treatment (OD with a VWF or prophylaxis with pdVWF) was explored. Model selection was performed by comparing the goodness of fit of linear and nonlinear ER models based on the PK and PK/PD models' predicted values for 1) VWF:RCo and FVIII:C trough levels; 2) average VWF:RCo and FVIII:C levels in dosing interval; and 3) average VWF:RCo and FVIII:C levels over 24 h following rVWF treatment, with comparisons of these levels before sBE onset in patients with and without sBEs. The PK and PK/PD models were also used to derive the VWF:RCo and FVIII:C levels for pdVWF, and these were applied to the ER model. The impact of the dosing regimens (twice weekly [BIW] or once weekly [QW]) on the ER for rVWF and pdVWF were investigated based on population simulations. Hazard ratios (HRs) for the probability of bleeding were generated as a function of median VWF activity at steady state for patients with type 3 VWD. Results: The RTTE model with a linear ER function linking the average levels of VWF:RCo or FVIII:C over 24 h before sBE onset was selected as the best model. A statistically significant ER relationship was observed (p<0.05) for the ER model with VWF:RCo, in which higher exposure to VWF:RCo was associated with a lower risk of sBE occurrence. The covariate effect of previous treatment (OD with a VWF or prophylaxis with pdVWF) was not statistically significant (p=0.6732). Simulations suggested that the HR per 10 IU/dL increment in the average exposure of VWF:RCo 24 h before an sBE was 0.673 (95% CI: 0.454-0.999). The HR per 20 IU/dL increment in the average exposure of VWF:RCo 24 h before an sBE was 0.453 (95% CI: 0.206-0.998). In addition, the predicted risk of a sBE for the 50 IU/kg QW regimen of rVWF and pdVWF was 30% and 43% higher, respectively, compared with the 50 IU/kg BIW regimen of rVWF (ie, reference regimen). The predicted risk of bleeding with the 50 IU/kg BIW regimen of pdVWF was 20% higher compared with the 50 IU/kg BIW regimen of rVWF. A trend was observed for the ER relationship based on FVIII:C (average levels of FVIII over 24 h before the sBE) suggesting a lower risk of sBEs with increased FVIII:C, which was however not statistically significant. Conclusions: Analysis of exposure to VWF:RCo or FVIII:C vs sBE occurrence indicated a causal association between VWF:RCo and sBEs; higher VWF:RCo was associated with a lower sBE risk. This relationship was independent of the patients' previous treatment (OD with a VWF or prophylaxis with pdVWF). Once further supported with additional data, this ER model could be utilized for individualized dosing strategies to optimize patient outcomes with rVWF prophylaxis. Disclosures Wang: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Özen: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Mellgård: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Marier: Certara Strategic Consulting: Current Employment. Barriere: Certara Strategic Consulting: Current Employment. Vasilinin: Certara Strategic Consulting: Current Employment. Bhattacharya: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc.: Current Employment. OffLabel Disclosure: Abstract reports results from a population ER analysis using data from a clinical trial investigating the efficacy and safety of rVWF prophylaxis. rVWF is not currently authorized for use as a prophylactic treatment.
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