Novel synthesis of [1‐11C]γ‐vinyl‐γ‐aminobutyric acid ([1–11C]GVG) for pharmacokinetic studies of addiction treatment

γ‐Vinyl‐γ‐aminobutyric acid (GVG, Vigabatrin^®), a suicide inhibitor of GABA‐transaminase (GABA‐T), has been suggested as a new drug for the treatment of substance abuse. In order to better understand its pharmacokinetics and potential side effects, we have developed a radiosynthesis of carbon‐11 (t_1/2=20 min) labeled GVG for positron emission tomographic (PET) studies. We report here a novel synthetic strategy to prepare the precursor and to efficiently label GVG with C‐11. 5‐Bromo‐3‐(carbobenzyloxy)amino‐1‐pentene was synthesized in five steps from homoserine lactone, including reduction and methylenation. This was used in a one‐pot, two‐step radiosynthesis. Displacement of bromide with no‐carrier‐added [¹¹C]cyanide followed by acid hydrolysis afforded [1‐¹¹C]GVG with decay corrected radiochemical yields of 27±9% (n=6, not optimized) with respect to [¹¹C]cyanide in a synthesis time of 45 min. Copyright © 2002 John Wiley & Sons, Ltd.     

A new approach for 11C–C bond formation: Synthesis of 17α‐(3′‐[11C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol

A new approach for ¹¹C–C bond formation via a Sonogashira‐like cross‐coupling reaction of terminal alkynes with [¹¹C]methyl iodide was exemplified by the synthesis of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol. The LC‐purified title compound was obtained in decay‐corrected radiochemical yields of 27–47% (n=8) based on [¹¹C]methyl iodide within 21–27 min after EOB. In a typical synthesis starting from 9.6 GBq [¹¹C]methyl iodide, 1.87 GBq of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol was synthesized in radiochemical purity >99%. The specific radioactivity ranged between 10 and 19 GBq/µmol, and the labeling position was verified by ¹³C‐NMR analysis of the corresponding ¹³C‐labeled compound. Copyright © 2003 John Wiley & Sons, Ltd.     

Pharmacokinetic evaluation and studies on the clinical efficacy of guar gum‐–based oral drug delivery systems of albendazole and albendazole‐β‐cyclodextrin for colon‐targeting in human volunteers

The present investigation assessed the in vivo properties of the guar gum–based colon‐targeted matrix tablets of albendazole‐β‐cyclodextrin (KA), albendazole matrix tablet (GA), and an immediate‐release albendazole tablet (CA) in humans. A single oral dose was administered in healthy human volunteers and a completely randomized, two‐way, three‐period crossover design was adopted. The data were statistically analyzed and a value of P<0.05 was considered statistically significant. In healthy human volunteers, guar gum colon‐targeted tablets showed delayed t_max and absorption time, decreased absorption rate constant, and unaltered t_1/2indicating that albendazole is not released in stomach and small intestine, but is delivered to the colon, resulting in a slow absorption of the drug and making the drug available for local action in the colon. The increase in C_max and AUC_0‐∞ of KA shows that the bioavailability of albendazole in humans could be definitely improved by complexing the drug with β‐cyclodextrin. Furthermore, an open, parallel, single‐blind clinical study was conducted in patient volunteers who had helminthiasis. Clinical studies showed that the guar gum colon‐targeted tablets could reduce eggs per gram faster than conventional tablets could, resulting in improved clinical symptoms, Hb content, and decreased total count as compared to conventional tablets of albendazole. The investigation shows that albendazole, when complexed with β‐cyclodextrin, improves in vivo bioavailability of the drug and colon targeting using guar gum ensures drug delivery in the colonic fluids, and therefore improves clinical efficacy in human beings with helminthiasis. Drug Dev. Res. 67:154–165, 2006. © 2006 Wiley‐Liss, Inc.     

Prediction of liver volume – a population‐based approach to meta‐analysis of paediatric,adult and geriatric populations – an update

Liver volume is a critical scaling factor for predicting drug clearance in physiologically based pharmacokinetic modelling and for both donor/recipient graft size estimation in liver transplantation. The accurate and precise estimation of liver volume is therefore essential. The objective here was to extend an existing meta‐analysis using a non‐linear mixed effects modelling approach for the estimation of liver volume to other race groups and paediatric and geriatric populations. Interrogation of the PubMed® database was undertaken using a text string query to ensure as objective a retrieval of liver volume data for the modelling exercise as possible. Missing body size parameters were estimated using simulations from the Simcyp Simulator V13R1 for an age and ethnically appropriate population. Non‐linear mixed effect modelling was undertaken in Phoenix 1.3 (Certara) utilizing backward deletion and forward inclusion of covariates from fully parameterized models. Existing liver volume models based on body surface area (BSA) and body weight and height were implemented for comparison. The extension of a structural model using a BSA equation and incorporating the Japanese race and age as covariates and exponents on LV0 (θ _Baseline) and body surface area (θ _BSA), respectively, delivered a comparatively low objective function value. Bootstrapping of the original dataset revealed that the confidence intervals (2.5–97.5%) for the fitted (theta) parameter estimates were bounded by the bootstrapped estimates of the same. In conclusion, extension and re‐parameterization of the existing Johnson model adequately describes changes in liver volume using the body surface area in all investigated populations. Copyright © 2017 John Wiley & Sons, Ltd.     

Synthesis of (2‐mercaptoacetyl)‐L‐[2‐14C]tryptophan as a selective metallo‐β‐lactamase inhibitor via [2‐14C]indole based on chiral pool strategy

Metallo‐beta‐lactamase enzymes make bacteria resistant to a broad range of commonly used beta‐lactam antibiotics. Several thiol derivatives of L‐amino acids have been shown their inhibitory effects against the metallo‐β‐lactamase IMP‐1. In this study, (2‐mercaptoacetyl)‐L‐tryptophan as a new inhibitor of metallo‐β‐lactamases labeled with carbon‐14 in the 2‐position of the indole ring was prepared from [2‐¹⁴C]indole as a key synthetic intermediate based on chiral pool strategy. The overall synthesis was performed in 10 steps with the overall radiochemical yield 3.6% on the basis of the barium [¹⁴C]carbonate as a starting material.     

Impact of source data verification on data quality in clinical trials: an empirical post hoc analysis of three phase 3 randomized clinical trials

AIM

The aim of this project was to perform an empirical evaluation of the impact of on site source data verification (SDV) on the data quality in a clinical trial database to guide an informed decision on selection of the monitoring approach.

METHODS

We used data from three randomized phase III trials monitored with a combination of complete SDV or partial SDV. After database lock, individual subject data were extracted from the clinical database and subjected to post hoc complete SDV. Error rates were calculated with focus on the degree of on study monitoring and relevance and analyzed for potential impact on end points.

RESULTS

Data from a total of 2566 subjects including more than 3 million data fields were 100% source data verified post hoc. An overall error rate of 0.45% was found. No sites had 0% errors. 100% SDV yielded an error rate of 0.27% as compared with partial SDV having an error rate of 0.53% (P < 0.0001). Comparing partly and fully monitored subjects, minor differences were identified between variables of major importance to efficacy or safety.

CONCLUSIONS

The findings challenge the notion that a 0% error rate is obtainable with on site monitoring. Data indicate consistently low error rates across the three trials analyzed. The use of complete vs. partial SDV offers a marginal absolute error rate reduction of 0.26%, i.e. a need to perform complete SDV of about 370 data points to avoid one unspecified error and does not support complete SDV as a means of providing meaningful improvements in data accuracy.