Buprenorphine exposure levels to optimize treatment outcomes in opioid use disorder.

The severity of the ongoing opioid crisis, recently exacerbated by the COVID-19 pandemic, emphasizes the importance for individuals suffering from opioid use disorder (OUD) to have access to and receive efficacious, evidence-based treatments. Optimal treatment of OUD should aim at blocking the effects of illicit opioids while controlling opioid craving and withdrawal to facilitate abstinence from opioid use and promote recovery. The present work analyses the relationship between buprenorphine plasma exposure and clinical efficacy in participants with moderate to severe OUD using data from two clinical studies (39 and 504 participants). Leveraging data from placebo-controlled measures assessing opioid blockade, craving, withdrawal and abstinence, we found that buprenorphine plasma concentrations sustained at 2-3 ng/ml (corresponding to ≥70% brain mu-opioid receptor occupancy) optimized treatment outcomes in the majority of participants, while some individuals (e.g., injecting opioid users) needed higher concentrations. Our work also included non-linear mixed effects modeling and survival analysis, which identified a number of demographic, genetic and social factors modulating treatment response and retention. Altogether, these findings provide key information on buprenorphine plasma levels that optimize clinical outcomes and increase the likelihood of individual treatment success. NLM identifiers: NCT02044094, NCT02357901.

Evaluation of Drug-Drug Interaction Liability for Buprenorphine Extended-Release Monthly Injection Administered by Subcutaneous Route.

Buprenorphine extended-release (BUP-XR) formulation is a once-monthly subcutaneous injection for the treatment of opioid use disorder (OUD). Buprenorphine undergoes extensive cytochrome P450 (CYP) 3A4 metabolism, leading to potential drug-drug interactions (DDIs) as reported for sublingual buprenorphine. Sublingual buprenorphine is subject to first-pass extraction, as a significant proportion of the dose is swallowed. Because subcutaneous administration avoids first-pass extraction, the DDI with CYP3A4 inhibitors is expected to be less than the 2-fold increase reported for the sublingual route. The objective of this analysis was to predict the magnitude of DDI following coadministration of BUP-XR with a strong CYP3A4 inhibitor or inducer using physiologically based pharmacokinetic (PBPK) modeling. Models were developed and verified by comparing predicted and observed data for buprenorphine following intravenous and sublingual dosing. Comparison of predicted and observed pharmacokinetic (PK) profiles and PK parameters demonstrated acceptable predictive performance of the models (within 1.5-fold). Buprenorphine plasma concentrations following administration of a single dose of BUP-XR (300 mg) were simulated using a series of intravenous infusions. Daily coadministration of strong CYP3A4 inhibitors with BUP-XR predicted mild increases in buprenorphine exposures (AUC, 33%-44%; Cmax , 17-28%). Daily coadministration of a strong CYP3A4 inducer was also associated with mild decreases in buprenorphine AUC (28%) and Cmax (22%). In addition, the model predicted minimal increases in buprenorphine AUC (8%-11%) under clinical conditions of 2 weeks' treatment with CYP3A4 inhibitors administered after initiation of BUP-XR. In conclusion, the PBPK predictions indicate that coadministration of BUP-XR with strong CYP3A4 inhibitors or inducers would not result in clinically meaningful interactions.

Population Pharmacokinetics of a Monthly Buprenorphine Depot Injection for the Treatment of Opioid Use Disorder: A Combined Analysis of Phase II and Phase III Trials.

BACKGROUND: BUP-XR (a.k.a. RBP-6000 or SUBLOCADE™) is an extended-release subcutaneous buprenorphine formulation for the treatment of opioid use disorder. BUP-XR was designed to provide sustained buprenorphine exposure throughout the monthly dosing interval, at concentrations sufficient to control all aspects of the disease (withdrawal, craving, and blockade of opioid subjective effects). OBJECTIVES: To characterize the population pharmacokinetics of BUP-XR based on phase II and phase III data and to evaluate whether target therapeutic concentrations were reached with the dosing regimens evaluated in the phase III program. METHODS: The population pharmacokinetic analysis included 570 subjects with opioid use disorder who received up to 12 monthly BUP-XR injections following induction with sublingual buprenorphine. RESULTS: In phase III studies, target therapeutic concentrations of buprenorphine were achieved from the first injection and maintained over the entire treatment duration. Buprenorphine plasma concentration-time profiles were well described by a two-compartment model, with first-order absorption for sublingual buprenorphine and a dual absorption submodel for BUP-XR. A covariate analysis evaluated the effects of subjects' demographic characteristics, laboratory data, and genetic status regarding buprenorphine-metabolizing enzymes. Only two covariates, body mass index and body weight, were retained in the final model. Overall, their effects were not of sufficient magnitude to justify a dose adjustment. Finally, pharmacokinetic simulations showed that buprenorphine plasma concentrations decreased slowly after discontinuation of treatment and that a 2-week occasional delay in dosing would not impact efficacy, which translated into labeling claims. DISCUSSION: In conclusion, the present analysis led to the development of a robust population pharmacokinetic model and confirms the ability of BUP-XR to deliver and maintain therapeutic plasma concentrations over the entire treatment duration.

Pharmacokinetics of Sublingual Buprenorphine Tablets Following Single and Multiple Doses in Chinese Participants With and Without Opioid Use Disorder.

BACKGROUND: Two phase I studies assessed the pharmacokinetics of buprenorphine, its metabolite norbuprenorphine, and naloxone following administration of buprenorphine/naloxone sublingual tablets in Chinese participants. METHODS: In the first phase I, open-label, single ascending-dose (SAD) study, 82 opioid-naïve volunteers received a single buprenorphine/naloxone dose ranging from 2 mg/0.5 mg to 24 mg/6 mg while under naltrexone block. In a second phase I, open-label, multiple ascending-dose (MAD) study, 27 patients with opioid dependence in withdrawal received buprenorphine/naloxone doses of either 16 mg/4 mg or 24 mg/6 mg for 9 consecutive days. Serial blood samples were collected after a single dose (SAD study) and at steady-state (MAD study). Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety assessments included adverse events monitoring and laboratory tests. RESULTS: The pharmacokinetic profiles of buprenorphine and naloxone were consistent between single- and multiple-dose studies. Peak plasma concentrations (Cmax) were reached early for buprenorphine (0.75-1.0 h) and naloxone (0.5 h), supporting rapid absorption. In the SAD study, increases in plasma exposures to buprenorphine and naloxone were less than dose proportional, in line with previous observations in Western populations. Buprenorphine-to-naloxone ratios for Cmax and area under the curve (AUC) were constant over the dose range investigated and also consistent with Western populations data. Steady state was reached within 7 days of daily dosing, with slight accumulation over repeated doses. No serious adverse events were observed. CONCLUSIONS: The present data suggest that buprenorphine/naloxone pharmacokinetic profiles in Chinese participants are consistent, overall, with those in Western populations, supporting no differences in dosing. CLINICAL TRIAL REGISTRATION: The protocols were registered on the official website of the China Food and Drug Administration (CFDA): http://www.chinadrugtrials.org.cn/ ; Registration numbers CTR20132963 (RB-CN-10-0012), CTR20140153 (RB-CN-10-0015).

Evaluation of the Effects of a Monthly Buprenorphine Depot Subcutaneous Injection on QT Interval During Treatment for Opioid Use Disorder.

Extensive 12-lead electrocardiogram monitoring and drug concentrations were obtained during development of BUP-XR, a monthly subcutaneous injection for the treatment of opioid use disorder (OUD). Matched QT and plasma drug concentrations (11,925) from 1,114 subjects were pooled from 5 studies in OUD. A concentration-QT model was developed, which accounted for confounding factors (e.g., comedications) affecting heart rate and heart rate-corrected QT interval (QTc). Bias-corrected nonparametric two-sided 90% confidence intervals (CIs) were derived for the mean predicted effect of BUP-XR on QTc (ΔQTc) at therapeutic and supratherapeutic doses. Changes in QTc were associated with age, central vs. noncentral reading, sex, methadone, and barbiturates. The upper 90% CI of ΔQTc was 0.29, 0.67, and 1.34 ms at the steady-state peak concentration (Cmax ) for 100, 300, and 2 × 300 mg doses, respectively. An effect of BUP-XR on QT can be ruled out at therapeutic and supratherapeutic doses of BUP-XR, after accounting for covariates that may influence heart rate and QT interval in OUD.

Effect of Albiglutide on Cholecystokinin-Induced Gallbladder Emptying in Healthy Individuals: A Randomized Crossover Study.

The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) exenatide and lixisenatide reduce cholecystokinin (CCK)-induced gallbladder emptying in healthy subjects. It is unknown if all GLP-1 RAs share this effect; therefore, the effect of the GLP-1 RA albiglutide on gallbladder function was assessed. In this randomized, double-blind, 2-way crossover study, a single dose of subcutaneous albiglutide 50 mg or placebo was administered to 17 healthy subjects, and CCK-induced gallbladder contractility was measured by ultrasonography. CCK (0.003 µg/kg) was infused intravenously over 50 minutes on study day 4 (3 days after dosing, to coincide with albiglutide's expected time to maximum concentration). Gallbladder volume, ejection fraction, and the main pancreatic and common bile-duct diameters were measured before, during, and following CCK infusion. Gallbladder volume was significantly greater in the albiglutide vs placebo groups before, during, and after CCK infusion, and the mean difference from placebo increased numerically during CCK infusion. The area under the volume-effect curve was significantly greater with albiglutide (P = .029). Starting at the 30-minute CCK infusion time point, the gallbladder ejection fraction was significantly lower with albiglutide than placebo. Changes in pancreatic duct diameter and common bile-duct diameter were not significantly different between albiglutide and placebo. Similar incidences of adverse events were observed between the albiglutide and placebo treatment periods. No new albiglutide safety signals were detected, and no serious adverse events were reported. In conclusion, similar to other GLP-1 RAs, albiglutide decreased CCK-induced gallbladder emptying compared with placebo in healthy individuals. Clinical implications of the gallbladder effects are unclear at this time.

Clinical pharmacology of albiglutide, a GLP-1 receptor agonist.

UNLABELLED: Albiglutide is a glucagon-like peptide-1 analogue composed of tandem copies of modified human glucagon-like peptide-1 (7-36) coupled to recombinant human albumin that is approved in adults for the treatment of type 2 diabetes mellitus. After subcutaneous administration, albiglutide is likely primarily absorbed via the lymphatic circulation, with maximum concentrations being reached in 3 to 5 days; steady-state exposures are achieved following approximately 4 to 5 weeks of once-weekly administration. The elimination half-life of albiglutide is approximately 5 days. Clearance of albiglutide is 67 mL/h with between-subject variability of 34.9%; no covariates have been identified that would require dose adjustment of albiglutide. Albiglutide lowers the fasting plasma glucose and reduces postprandial glucose excursions. In addition, ß-cell secretion is enhanced by albiglutide during hyperglycemia, whereas secretion is suppressed during hypoglycemia; α-cell response to hypoglycemia is not impaired by albiglutide. Albiglutide does not prolong the corrected QT interval but has a modest effect on heart rate in patients with type 2 diabetes mellitus. Dose adjustment is not suggested in patients with renal impairment, but experience in patients with severe renal impairment is very limited, and it is recommended that albiglutide be used with care in such patients due to an increased frequency of diarrhea, nausea, and vomiting. No clinically relevant drug interactions have been observed in clinical trials. TRIAL REGISTRATION: NCT00938158, NCT01406262, NCT00537719, NCT01077505, NCT01147731, NCT01147718, NCT01147692, NCT00354536, NCT00394030, NCT00530309, NCT01357889, NCT00518115, NCT01098461, NCT01475734, NCT00849017, NCT00838916, NCT00839527, NCT01098539.

Human absorption, distribution, metabolism and excretion properties of drug molecules: a plethora of approaches.

Human radiolabel studies are traditionally conducted to provide a definitive understanding of the human absorption, distribution, metabolism and excretion (ADME) properties of a drug. However, advances in technology over the past decade have allowed alternative methods to be employed to obtain both clinical ADME and pharmacokinetic (PK) information. These include microdose and microtracer approaches using accelerator mass spectrometry, and the identification and quantification of metabolites in samples from classical human PK studies using technologies suitable for non-radiolabelled drug molecules, namely liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. These recently developed approaches are described here together with relevant examples primarily from experiences gained in support of drug development projects at GlaxoSmithKline. The advantages of these study designs together with their limitations are described. We also discuss special considerations which should be made for a successful outcome to these new approaches and also to the more traditional human radiolabel study in order to maximize knowledge around the human ADME properties of drug molecules.

Effect of renal impairment on the pharmacokinetics, efficacy, and safety of albiglutide.

BACKGROUND: Chronic kidney disease is frequently present in patients with type 2 diabetes mellitus (T2DM). New therapeutic options in this patient subpopulation are needed. OBJECTIVES: Assess the effect of renal impairment on the pharmacokinetics (PK), efficacy, and safety of albiglutide in single- and multiple-dose studies. METHODS: Pharmacokinetics, safety, and efficacy of once weekly albiglutide in patients with T2DM was assessed from a single-dose (30 mg), nonrandomized, open-label study (N = 41) including subjects with normal and varying degrees of renal impairment, including hemodialysis, and a pooled analysis of 4 phase 3, randomized, double-blind (1 open-label), active or placebo-controlled multiple-dose studies. The pooled analysis of the latter 4 studies (N = 1113) was part of the population PK analysis, which included subjects with normal and varying degrees of renal impairment (mild, moderate, severe) treated with albiglutide (30 to 50 mg) to primary end points of 26 to 52 weeks. RESULTS: Single-dose PK showed area-under-the-curve ratios (and 90% CIs) of 1.32 (0.96-1.80), 1.39 (1.03-1.89), and 0.99 (0.63-1.57) for the moderate, severe, and hemodialysis groups, respectively, relative to the normal group. Results indicate that modest increases in plasma concentration of albiglutide were observed with the severity of renal impairment. There was a trend for more glycemic lowering as the estimated glomerular filtration rate decreased. The severe group had a higher frequency of gastrointestinal (eg, diarrhea, constipation, nausea, and vomiting) and hypoglycemic (with background sulfonylurea use) events compared with patients with mild or moderate renal impairment. CONCLUSION: The PK, efficacy, and safety data indicate that albiglutide has a favorable benefit/risk ratio in patients with T2DM and varying degrees of renal impairment, and the need for a dose adjustment is not suggested. Experience in patients with more severe renal impairment is very limited, so the recommendation is to use albiglutide carefully in this population. CLINICAL TRIAL REGISTRATION: (ClinicalTrials.gov):NCT00938158, NCT00849017, NCT00838916, NCT00839527, NCT0198539.

Albiglutide Does Not Prolong QTc Interval in Healthy Subjects: A Thorough ECG Study.

INTRODUCTION: Albiglutide, a selective once-weekly glucagon-like peptide-1 receptor agonist, is being developed for the treatment of type 2 diabetes mellitus. Albiglutide's effect on cardiac repolarization (QTc interval) was assessed in a randomized, double-blind, placebo-controlled, parallel-group study in healthy subjects with a nested crossover comparison for moxifloxacin. METHODS: Subjects were randomized to albiglutide (n = 85) or placebo (n = 89) and received injections of 30 mg albiglutide or placebo on Days 1 and 8 and 50 mg albiglutide or placebo on Days 15, 22, 29, and 36. In the placebo group, moxifloxacin was administered on Day -1 in half the subjects and on Day 40 in the other half. Blood samples for albiglutide plasma concentration were drawn on Days 4 and 39 and serial ECGs were extracted from continuous recordings on Days -2 (baseline), -1, 4, 39, and 40. RESULTS: Demographics were generally similar between albiglutide and placebo subjects: mean age was 29 years and BMI 25 kg/m(2). Mean change-from-baseline QTcI (∆QTcI, which was corrected for individual heart rate) on Day 4 after a single dose of albiglutide 30 mg and on Day 39 after repeat dosing with albiglutide 50 mg once weekly was similar to the placebo response. The placebo-corrected ΔQTcI (ΔΔQTcI) on both albiglutide doses was small with the largest ΔΔQTcI of 1.1 ms (upper bound of 90% CI 3.8 ms) on Day 4 and -0.6 ms (upper bound of CI 1.8 ms) on Day 39. Moxifloxacin caused the largest mean effect on ΔΔQTcI of 10.9 ms and the lower bound of the CI was above 5 ms at all preselected timepoints, thereby demonstrating assay sensitivity. Albiglutide was well tolerated and there were no clinically relevant differences in safety data between albiglutide and placebo. CONCLUSION: Albiglutide at doses up to 50 mg in healthy subjects did not prolong the QTc interval.

From in silico target prediction to multi-target drug design: current databases, methods and applications.

Given the tremendous growth of bioactivity databases, the use of computational tools to predict protein targets of small molecules has been gaining importance in recent years. Applications span a wide range, from the 'designed polypharmacology' of compounds to mode-of-action analysis. In this review, we firstly survey databases that can be used for ligand-based target prediction and which have grown tremendously in size in the past. We furthermore outline methods for target prediction that exist, both based on the knowledge of bioactivities from the ligand side and methods that can be applied in situations when a protein structure is known. Applications of successful in silico target identification attempts are discussed in detail, which were based partly or in whole on computational target predictions in the first instance. This includes the authors' own experience using target prediction tools, in this case considering phenotypic antibacterial screens and the analysis of high-throughput screening data. Finally, we will conclude with the prospective application of databases to not only predict, retrospectively, the protein targets of a small molecule, but also how to design ligands with desired polypharmacology in a prospective manner.

A semi-mechanistic gastric emptying model for the population pharmacokinetic analysis of orally administered acetaminophen in critically ill patients.

PURPOSE: To develop a semi-mechanistic population pharmacokinetic model based on gastric emptying function for acetaminophen plasma concentration in critically ill patients tolerant and intolerant to enteral nutrition before and after prokinetic therapy. METHODS: Acetaminophen plasma concentrations were available from a study with 10 tolerant and 20 intolerant patients before and after prokinetic therapy with either erythromycin or metoclopramide. Population pharmacokinetic modelling was carried out in a nonlinear mixed effects analysis software, NONMEM. RESULTS: A four-compartment semi-mechanistic model for stomach, intestine, central and peripheral compartments was described. The rate of emptying of the stomach was described by a first-order rate parameter. The final model has two gastric emptying rate constant parameters: kg1 (1.30 h(-1), RSE=53.84%, T1/2=0.53 h) for the intolerant group before prokinetic therapy and kg2 (27.8 h(-1), RSE=59.35%, T1/2=0.025 h) for both the intolerant group after prokinetic therapy and the tolerant group. Other parameters and estimates (RSE) in the model were ka=5.12 h(-1) (28.13%), CL=13.0 L/h (19.62%), CLD=22.6 L/h (19.78%), V1=63.8 L (12.79%) and V2=69 L (38.70%). CONCLUSIONS: The four-compartment semi-mechanistic population pharmacokinetic model adequately described the data. The gastric emptying half-time is improved by a factor of about 20 in the patients that are intolerant to enteral nutrition after treatment with prokinetic agents.

An integrated dataset for in silico drug discovery.

Drug development is expensive and prone to failure. It is potentially much less risky and expensive to reuse a drug developed for one condition for treating a second disease, than it is to develop an entirely new compound. Systematic approaches to drug repositioning are needed to increase throughput and find candidates more reliably. Here we address this need with an integrated systems biology dataset, developed using the Ondex data integration platform, for the in silico discovery of new drug repositioning candidates. We demonstrate that the information in this dataset allows known repositioning examples to be discovered. We also propose a means of automating the search for new treatment indications of existing compounds.

The effects of a short course of antibiotics on alvimopan and metabolite pharmacokinetics.

Alvimopan is a novel, oral, peripherally acting mu-opioid receptor (PAM-OR) antagonist that blocks the effects of opioids on the gastrointestinal tract, without blocking opioid-induced analgesic effects. It is metabolized by gut microflora to an active amide-hydrolysis metabolite, which is equipotent to alvimopan. The objective of this study was to characterize the pharmacokinetics of alvimopan and metabolite before, during, and after administration of a short course of antibiotics in healthy adult participants. Simulations were conducted to determine the feasibility for this study. An open-label, sequential drug interaction study was conducted in 45 participants who received twice-daily dosing of alvimopan with and without ciprofloxacin. Metabolite concentrations were reduced by 99.2% (90% confidence interval: 98.8-99.5) in the presence of ciprofloxacin. The interaction occurred rapidly, and recovery was slow. The interaction may be of relevance for patients with relatively high metabolite plasma concentrations prior to antibiotic administration but of little relevance for patients with little or no plasma metabolite exposure initially. Administration of ciprofloxacin decreased alvimopan C(max) by 24%, which is of no clinical relevance. There was no effect of ciprofloxacin on alvimopan trough concentrations or AUC. Alvimopan was well tolerated.

Spatio-temporal prediction and inference by V1 neurons.

In normal vision, visual scenes are predictable, as they are both spatially and temporally redundant. Evidence suggests that the visual system may use the spatio-temporal regularities of the external world, available in the retinal signal, to extract information from the visual environment and better reconstruct current and future stimuli. We studied this by recording neuronal responses of primary visual cortex (area V1) in anaesthetized and paralysed macaques during the presentation of dynamic sequences of bars, in which spatio-temporal regularities and local information were independently manipulated. Most V1 neurons were significantly modulated by events prior to and distant from stimulation of their classical receptive fields (CRFs); many were more strongly tuned to prior and distant events than they were to CRFs bars; and several showed tuning to prior information without any CRF stimulation. Hence, V1 neurons do not simply analyse local contours, but impute local features to the visual world, on the basis of prior knowledge of a visual world in which useful information can be distributed widely in space and time.

Ecological network analysis: an application to the evaluation of effects of pesticide use in an agricultural environment.

Ecological network analysis is used to evaluate the impact of pesticide use on ecological systems in the context of agricultural farmland environments. The aim is to provide support for the design of effective and minimally damaging pest control strategies. The ecological network analysis can identify species that are important to the integrity of the ecological network. The methodology can be used to monitor the impact of shifts in terms of types of pesticide used on the ecological system. The authors' intention is to use this methodology to provide supporting evidence for the UK Voluntary Initiative programme aimed at convincing farmers voluntarily to make improved choices in the use of a wide range of pesticides.

Simulation of robustness against lesions of cortical networks.

Structure entails function, and thus a structural description of the brain will help to understand its function and may provide insights into many properties of brain systems, from their robustness and recovery from damage to their dynamics and even their evolution. Advances in the analysis of complex networks provide useful new approaches to understanding structural and functional properties of brain networks. Structural properties of networks recently described allow their characterization as small-world, random (exponential) and scale-free. They complement the set of other properties that have been explored in the context of brain connectivity, such as topology, hodology, clustering and hierarchical organization. Here we apply new network analysis methods to cortical interareal connectivity networks for the cat and macaque brains. We compare these corticocortical fibre networks to benchmark rewired, small-world, scale-free and random networks using two analysis strategies, in which we measure the effects of the removal of nodes and connections on the structural properties of the cortical networks. The structural decay of the brain networks is in most respects similar to that of scale-free networks. The results implicate highly connected hub-nodes and bottleneck connections as a structural basis for some of the conditional robustness of brain systems. This informs the understanding of the development of connectivity of the brain networks.

Longer fixation duration while viewing face images.

The spatio-temporal properties of saccadic eye movements can be influenced by the cognitive demand and the characteristics of the observed scene. Probably due to its crucial role in social communication, it is argued that face perception may involve different cognitive processes compared with non-face object or scene perception. In this study, we investigated whether and how face and natural scene images can influence the patterns of visuomotor activity. We recorded monkeys' saccadic eye movements as they freely viewed monkey face and natural scene images. The face and natural scene images attracted similar number of fixations, but viewing of faces was accompanied by longer fixations compared with natural scenes. These longer fixations were dependent on the context of facial features. The duration of fixations directed at facial contours decreased when the face images were scrambled, and increased at the later stage of normal face viewing. The results suggest that face and natural scene images can generate different patterns of visuomotor activity. The extra fixation duration on faces may be correlated with the detailed analysis of facial features.

Centre-surround interactions in response to natural scene stimulation in the primary visual cortex.

Centre-surround interaction in the primary visual cortex (area V1) has been studied extensively using artificial, abstract stimulus patterns, such as bars, gratings and simple texture patterns. In this experiment, we extend the study of centre-surround interaction by using natural scene images. We systematically varied the contrast of natural image surrounds presented outside the classical receptive field (CRF), and recorded neuronal response to a natural image patch presented within the CRF in area V1 of awake, fixating macaques. For the majority of neurons (67 out of 111), the natural image surrounds profoundly modulated, mainly by suppressing, neuronal responses to CRF images. These modulatory effects started at the earliest stage of neuronal responses, and often depended on the contrast and higher-order structures of the surrounds. For 47 out of 67 neurons, randomising the phases of the Fourier spectrum of the natural image surround diminished the centre-surround interaction. Our results suggest that the centre-surround interaction in area V1 can be extended to natural vision, and is sensitive to the higher-order structures of natural scene images, such as image contours.