In advanced cancer patients the CYP3A4-mediated clearance of drugs is dependent on the severity of inflammation. In a study in patients with advanced cancer (n = 44) with solid tumors, prior to cancer treatment, high inter-patient variability was observed in the plasma pharmacokinetic (PK) parameters of the CYP3A4 substrate midazolam. The neutrophil-to-lymphocyte ratio (NLR) was used to categorize the degree of inflammation of each patient and in turn to correlate increases in NLR to decreases in CYP3A4 expression. Patients with NLR ≥ 5 were categorized as having high inflammation, and patients with NLR < 5 as having low-to-moderate inflammation. A physiologically-based PK (PBPK) model of midazolam PK and a top-down approach was used to determine the reductions in CYP3A4 abundance in the liver and gut wall needed to match the PK parameters of midazolam in the NLR ≥ 5 and NLR < 5 groups of patients. The midazolam mean CL/F was 33 L/h in the NLR < 5 group, and midazolam CL/F was 20 L/h in the NLR ≥ 5 group. To match the PK of midazolam in the NLR < 5 group, the CYP3A4 expression was reduced 40

Cyclosporine (cyclosporin A or CsA), a clinically relevant but nonspecific inhibitor of hepatic organic anion transporting polypeptides (OATPs), is used for assessing transporter-mediated drug-drug interactions (DDIs) at varying dosing regimens. We developed a physiologically based pharmacokinetic model to reproduce CsA pharmacokinetics (PK) and effect of CsA on substrates of OATPs and cytochrome P450 (CYP)3A4. The model was built using intravenous and oral CsA clinical PK and DDI data in healthy volunteers. The model reproduces single- and multiple-dose clinical CsA PK from numerous studies with simulated/observed AUC and Cmax within 0.59-1.75 following oral CsA dosing. As an object of CYP3A4, the model reproduces the observed effect of ketoconazole and grapefruit juice on CsA PK. CsA inhibition constants against CYP3A4 and hepatic OATPs were estimated to reproduce clinical DDIs with CYP3A index substrate midazolam (MDZ) and OATP1B biomarker coproporphyrin-I, and confirmed with felodipine and pitavastatin, verifying the model for inhibition of hepatic CYP3A4 and OATPs in healthy volunteers. A review of clinical data herein indicates that most clinical DDI studies utilize a single dose of CsA and for certain clinical substrates, a counterintuitive decrease in half-life following CsA administration has been observed (similar to single-dose rifampin DDIs). Using the currently developed CsA model, we predicted the effect of various single- and multiple-dose CsA regimens against OATP1B substrate and MDZ models. Depending on the OATP1B substrate characteristics, 200 mg CsA twice daily or a single 600 mg dose reasonably mimic simulated continuous OATP1B inhibition and single-dose rifampin, albeit with predicted weak-to-moderate CYP3A4 inhibition.

Imlunestrant (LY3484356) is a next‐generation orally bioavailable selective estrogen receptor degrader being investigated for the treatment of estrogen receptor–positive advanced breast and endometrial cancers. This Phase 1, open‐label, 2‐part study evaluated the disposition and absolute bioavailability of [ 14 C]‐imlunestrant in 16 US‐based healthy women (aged 36‐65 years) of non–childbearing potential. Part 1 participants (N = 8) received an oral dose of 400‐mg [ 14 C]‐imlunestrant solution (100 µCi). Part 2 participants (N = 8) received an oral dose of 2 × 200‐mg imlunestrant tablets followed by approximately 45 µg [ 14 C]‐imlunestrant (approximately 1 µCi) given as a 15‐minutes infusion 4 hour later. Blood, fecal, and urine samples were collected. Total radioactivity was primarily eliminated in feces (97.3%) with trace amounts recovered in urine (0.278%), suggesting minimal renal clearance. Imlunestrant accounted for most of the radioactive dose in feces (61.8%), followed by metabolite M2 (20.9%), metabolites M5 + M10 (coeluted), M7, M8, M9, and M11 (5.1% or less for each). Absolute bioavailability of imlunestrant after oral administration relative to intravenous administration was 10.9% based on dose‐normalized area under the concentration–time curve from time zero to infinite time. Imlunestrant was well tolerated as an oral solution or as a tablet/intravenous dose. Eight participants reported mild/moderate treatment‐related adverse events that resolved by the end of the study.

Dulaglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, is approved for improving glycemic control and reducing cardiovascular risks in patients with type 2 diabetes mellitus (T2DM). This research investigates the effect of dulaglutide on gastric emptying and its impact on the pharmacokinetics (PK) of orally administered molecules utilizing a combination of population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) modeling approaches. In clinical studies, the gastric emptying delay (GED) was evaluated in healthy participants and patients with T2DM at various dose levels of dulaglutide. A PopPK model estimated the exposure-dependent delay in gastric emptying, which was then input into the orally administered small molecule PBPK models. These PBPK models, informed by internal clinical studies and publicly available data, quantified the effect of dulaglutide-induced GED on the area under the curve (AUC), maximum concentration (Cmax), and time to maximum concentration (tmax) of the co-administered drugs. The modeling approach was verified for reproducing observed GED-mediated drug-drug interactions (DDIs) at low doses of dulaglutide and to predict DDIs at a 4.5 mg dulaglutide dose. The clinical studies demonstrated that the 1.5 mg dulaglutide dose has no clinically relevant effect on the pharmacokinetics of small molecules, and the modeling led to a similar conclusion at 4.5 mg dulaglutide. This work demonstrates that modeling approaches can be used to predict potential GLP-1-mediated DDIs related to gastric emptying delay, increasing the efficiency of the clinical pharmacology programs.

Pirtobrutinib is a reversible Bruton tyrosine kinase (BTK) inhibitor. In vitro, pirtobrutinib is metabolized by cytochrome P450 (CYP) 3A4 and uridine 5'-diphosphoglucuronosyl transferases (UGTs) and causes reversible and time-dependent inhibition and induction of CYP3A4. Coadministration of itraconazole, a strong CYP3A4 inhibitor, with pirtobrutinib in healthy human subjects, resulted in a pirtobrutinib area under the plasma concentration-time curve (AUC) ratio of 1.49, while rifampin, a strong CYP3A4 inducer, decreased pirtobrutinib AUC by 71%. Oral administration of pirtobrutinib 200 mg once daily (QD) increased the AUC of oral and intravenous midazolam by 1.70- and 1.12-fold, respectively. A physiologically based pharmacokinetic (PBPK) model was developed for pirtobrutinib using physicochemical properties, in vitro data, and clinical pharmacology study results. The PBPK model captured the clinically observed interactions for itraconazole, rifampin, and midazolam, with predicted pirtobrutinib and midazolam AUC ratios within 0.91- to 1.16-fold of observed. The model predicted 1.20- to 1.73-fold increases in the pirtobrutinib AUC with strong and moderate CYP3A4 inhibitors. Furthermore, the predicted pirtobrutinib AUC ratios were within 0.51-0.86 with moderate and weak CYP3A4 inducers. The predicted effects of CYP3A4 modulators on pirtobrutinib pharmacokinetics, together with the known exposure-response relationships for safety and efficacy in patients with hematological malignancies, were used for recommending appropriate dosing regimens during coadministration.

The US Food and Drug Administration 2024 guidance prefers regression analysis over categorical analysis for pharmacokinetic data for studies that assess pharmacokinetics in patients with impaired renal functions. The objective of this study was to compare these two statistical methods for pharmacokinetic data analysis of renal impairment studies. Baseline data from seven renal impairment studies were pooled to estimate the impact of three creatinine-based equations (Cockcroft-Gault, CKD-EPI2009, and absolute CKD-EPI2009) on classification of participants into different renal impairment categories. Retrospective analyses were performed on two renal impairment studies with three distinct analytes (predominantly renally cleared; and predominantly metabolized by hepatic cytochrome P450 enzymes, or by systemic peptidase) using regression or categorical statistical analysis methods and creatine-based equations. While the three equations were highly correlated, the use of a different equation may result in up to 50% of participants being reclassified into different renal impairment groups. Categorical analysis with analysis of variance provided different point estimates and precision of exposure difference for a given renal impairment group based on the equation used. The use of regression analysis without inclusion of data from participants on hemodialysis, as recommended by the Food and Drug Administration, showed most consistent estimate of the relationship between renal impairment and exposure of three analytes. These retrospective analyses support the Food and Drug Administration recommendations of using regression analysis without data from participants on hemodialysis as the primary analysis of data for renal impairment study; and established a modeling strategy for such analysis.

Predictions of drug-drug interactions resulting from time-dependent inhibition (TDI) of CYP3A4 have consistently overestimated or mispredicted (ie, false positives) the interaction that is observed in vivo. Recent findings demonstrated that the presence of the allosteric modulator progesterone (PGS) in the in vitro assay could alter the in vitro kinetics of CYP3A4 TDI with inhibitors that interact with the heme moiety, such as metabolic-intermediate complex forming inhibitors. The impact of the presence of 100 μM PGS on the TDI of molecules in the class of macrolides typically associated with metabolic-intermediate complex formation was investigated. The presence of PGS resulted in varied responses across the inhibitors tested. The TDI signal was eliminated for 5 inhibitors, and unaltered in the case of 1, fidaxomicin. The remaining molecules erythromycin, clarithromycin, and troleandomycin were observed to have a decrease in both potency and maximum inactivation rate ranging from 1.7- to 6.7-fold. These changes in TDI kinetics led to a >90% decrease in inactivation efficiency. To determine in vitro conditions that could reproduce in vivo inhibition, varied concentrations of PGS were incubated with clarithromycin and erythromycin. The resulting in vitro TDI kinetics were incorporated into dynamic physiologically based pharmacokinetic models to predict clinically observed interactions. The results suggested that a concentration of ∼45 μM PGS would result in TDI kinetic values that could reproduce in vivo observations and could potentially improve predictions for CYP3A4 TDI. SIGNIFICANCE STATEMENT: The impact of the allosteric heterotropic modulator progesterone on the CYP3A4 time-dependent inhibition kinetics was quantified for a set of metabolic-intermediate complex forming mechanism-based inhibitors. We identify the in vitro conditions that optimally predict time-dependent inhibition for in vivo drug-drug interactions through dynamic physiologically based pharmacokinetic modeling. The optimized assay conditions improve in vitro to in vivo translation and prediction of time-dependent inhibition.

Current drug discovery screens to assess the drug-drug interaction (DDI) risk caused by time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 are known to overpredict or produce false positives that do not translate in vivo. Recent work identified that inclusion of the allosteric modulator progesterone (PGS), at a concentration of 45 μM to human liver microsomal incubations, generated in vitro TDI values that replicated clinical DDI predictions for 2 well established mechanism-based inhibitors. Further application of this approach across a diverse set of compounds was undertaken in this study, with 56 molecules reported in literature as time-dependent inhibitors in vitro tested in the human liver microsomal TDI kinetic assay in the absence and presence of 45 μM PGS. No TDI signal was observed for 15 molecules under control conditions despite literature reports. For the remaining compounds observed to have a TDI signal under control conditions, presence of PGS modified the inactivation efficiency for 36 compounds and eliminated the TDI signal for 5 compounds that were false positives. In vitro kinetic values were incorporated into mechanistic static and dynamic physiologically based pharmacokinetic models to project DDIs. TDI parameters established in the presence of PGS decreased the magnitude of overprediction while maintaining a high sensitivity (96% and 100%) for the detection of TDI with improved specificity (69% and 89%) when using mechanistic static and dynamic models, respectively. Inclusion of PGS into in vitro TDI assays provides a simple, rapid, and cost-effective solution for identifying true CYP3A4 TDIs and improving TDI-related DDI predictions. SIGNIFICANCE STATEMENT: The impact of the previously determined optimal concentration of the allosteric modulator progesterone (45 μM) was evaluated across a set of 56 compounds reported to be time-dependent inhibitors in vitro. In vitro generated values were incorporated into mechanistic static and physiologically based pharmacokinetic models to predict extent of drug-drug interactions and compared to clinical reports. Inclusion of progesterone into the assay identified in vitro false positives and improved risk predictions.

The current study was designed to investigate the influence of allosteric effectors on the metabolism of the prototypical cytochrome P450 (CYP) 3A4 substrate midazolam (MDZ), and on the determination in vitro time-dependent inhibition (TDI) of CYP3A4 using human liver microsomes (HLM). As the concentration of midazolam increased to 250 µM in HLMs, homotropic cooperativity resulted in a decrease in the 1'-hydroxymidazolam to 4-hydroxymidazolam ratio to a maximum of 1.1. The presence of varying concentrations of testosterone, progesterone (PGS), or carbamazepine (CBZ) in HLMs with MDZ could recapitulate the effect of homotropic cooperativity such that the formation rates of the 1'hydroxymidazolam and 4-hydroxymidazolam were equal even at low concentrations of MDZ. The presence of PGS (10 or 100 µM) and CBZ (100 or 1000 µM) in in vitro TDI determination of four known CYP3A4 time-dependent inactivators (clarithromycin, troleandomycin, mibefradil, raloxifene) simultaneously decreased potency and inactivation rate constant, resulting in fold changes in inactivation efficiency on average of 1.6-fold and 13-fold for the low and high concentrations of allosteric modulator tested, respectively. The formation of a metabolic-intermediate complex (MIC) for clarithromycin and troleandomycin decreased in the presence of the allosteric modulators in a concentration-dependent manner, reaching a new steady state formation that could not be overcome with increased incubation time. Maximum reduction of the MIC formed by clarithromycin was up to ∼91%, while troleandomycin MIC decreased up to ∼31%. These findings suggest that the absence of endogenous allosteric modulators may contribute to the poor translation of HLM-based drug-drug interaction predictions. SIGNIFICANCE STATEMENT: The reported overprediction of in vitro human liver microsome time-dependent inhibition of CYP3A4 and observed drug interactions in vivo remains an issue in drug development. We provide characterization of allosteric modulators on the CYP3A4 metabolism of the prototypical substrate midazolam, demonstrating the ability of the modulators to recapitulate the homotropic cooperativity of midazolam. Furthermore, we demonstrate that allosteric heterotropic cooperativity of CYP3A4 can impact the time-dependent inhibition kinetics of known mechanisms-based inhibitors, providing a potential mechanism to explain the overprediction.

Most domestic energy retrofit policies in the UK are designed to incentivise economically rational consumers. Logically, this should mean that applicants to domestic energy incentives are those who can financially benefit the most from these subsidies. Here, we test this logic by asking the question 'what types of households apply for domestic energy incentives in the UK?'. To answer this question, we systematically assess the characteristics of households who apply for incentives and develop a GB neighbourhood level household typology bringing together data sets on domestic energy incentives and household geo-demographics. We discover that some types of households are much more likely to apply for incentives than others. In particular, we find that Asian origin, owner-occupier households of low income living in energy inefficient terraces apply for ECO incentives at a rate twelve times higher than expected. This phenomenon is even more pronounced when we look at applications by geographic area, with these households applying in very high numbers in the industrial north of England. Building on recent work on energy consumption and social relations, we argue that understanding the increased likelihood of these household types to apply for domestic energy incentives demands a relational perspective. These households share geo-demographic and dwelling characteristics, which suggests the spread of uptake of policy through the community through networks of social relations, as opposed to uptake purely on the basis of perceived cost-benefit. We conclude by offering insights for policy makers about the possibilities for mobilising social relations in the delivery of energy efficiency projects.

The objective of this work was to demonstrate that clinical OAT1-mediated DDIs can be predicted using physiologically based pharmacokinetic (PBPK) modeling. LY404039 is a metabotropic glutamate receptor 2/3 agonist and the active moiety of the prodrug pomaglumetad methionil (LY2140023). After oral administration, pomaglumetad methionil is rapidly taken up by enterocytes via PEPT1 and once absorbed, converted to LY404039 via membrane dehydropeptidase 1 (DPEP1). LY404039 is renally excreted by both glomerular filtration and active secretion and in vitro studies showed that the active secretion of LY404039 was mediated by the organic anion transporter 1 (OAT1). Both clinical and in vitro data were used to build a PBPK model to predict OAT1-mediated DDIs. In vitro inhibitory potencies (IC50) of the known OAT inhibitors, probenecid and ibuprofen, were determined to be 4.00 and 2.63 µM, respectively. Subsequently, clinical drug-drug interaction (DDI) study showed probenecid reduced the renal clearance of LY404039 by 30 to 40

On September 25 and 26, 2021, the Alzheimer's Association hosted the first meeting focused on people with early-onset Alzheimer's disease (EOAD)-sometimes referred to as younger onset Alzheimer's disease (AD). Though a diagnosis of AD can be devastating at any age, those with a younger onset-defined as symptoms developing prior to 65 years of age-face unique challenges. EOAD occurs when people are in the prime of their lives, often with multiple responsibilities including careers, community activities, and raising children and caring for older family members. These challenges warrant special consideration and study, yet people with EOAD are often excluded from AD research because of their atypical age of onset. To help fill this gap, we designed and launched the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) to enroll and follow 500 people with EOAD from > 15 sites in the United States, which the National Institute on Aging funded in 2018. The September 2021 meeting was designed to inform people with EOAD and their family members and caregivers about the latest research on the biology of EOAD, treatments in the pipeline, practical considerations about legal and financial arrangements for families, and the support networks available to them. More than 217 registrants attended.

The vast majority of older adults who are chronically ill rely on informal caregivers for support. Caregivers often require additional support to facilitate their role. To the best of our knowledge, there has yet to be a collation of caregiver-identified priorities for support. Using existing research, this scoping review provides a comprehensive picture of what caregivers have indicated as priorities for support. Arksey and O'Malley's scoping review framework guides this review. We searched MEDLINE, CINAHL and PsycINFO databases on July 2, 2021. We selected databases based on their relevance to nursing, health and social science. Inclusion criteria were peer-reviewed research of any design, a sample population of caregivers to older adults (>55 years), manuscripts published in English and the priorities for caregiver support identified by caregivers themselves. We screened a total of 3591 records, and 33 articles met the inclusion criteria. These studies were from geographic settings across the globe and used various quantitative, qualitative and mixed-method study designs. In our synthesis, we quantified the identified priorities within the studies using coding and content analysis. We present the following list of caregiver-identified priorities: (1) orientation to the caregiving role; (2) self-care and respite; (3) adapting healthcare; (4) improved supports; (5) information needs; (6) access to resources; (7) financial assistance. Policymakers, healthcare professionals and non-profit organisations can use evidence from this review to guide decisions when developing support services and interventions for caregivers.

The predictive performance of physiologically‐based pharmacokinetics (PBPK) models for pharmacokinetics (PK) in renal impairment (RI) and hepatic impairment (HI) populations was evaluated using clinical data from 29 compounds with 106 organ impairment study arms were collected from 19 member companies of the International Consortium for Innovation and Quality in Pharmaceutical Development. Fifty RI and 56 HI study arms with varying degrees of organ insufficiency along with control populations were evaluated. For RI, the area under the curve (AUC) ratios of RI to healthy control were predicted within twofold of the observed ratios for > 90% (N = 47/50 arms). For HI, > 70% (N = 43/56 arms) of the hepatically impaired to healthy control AUC ratios were predicted within twofold. Inaccuracies, typically overestimation of AUC ratios, occurred more in moderate and severe HI. PBPK predictions can help determine the need and timing of organ impairment study. It may be suitable for predicting the impact of RI on PK of drugs predominantly cleared by metabolism with varying contribution of renal clearance. PBPK modeling may be used to support mild impairment study waivers or clinical study design.

Modelinformed drug development (MIDD) tools including physiologically based pharmacokinetic (PBPK) modeling can improve the mechanistic understanding of a drug’s pharmacology and potentially translate into development efficiencies. This article summarizes viewpoints from the November 18, 2019, US Food and Drug Administration (FDA) public workshop titled “Development of Best Practices in Physiologically Based Pharmacokinetic Modeling to Support Clinical Pharmacology Regulatory DecisionMaking,” which discussed best practices in PBPK model development and evaluation, case studies, and research needs.1

The transition to a low-carbon future based on renewable energy sources is leading to a new role for citizens, from passive energy consumers to active energy citizens - the so-called renewable energy (RE) prosumers. Recent EU energy policy seeks to mainstream RE prosumers in each Member State. This study carries out a cross-country comparison between the regulatory frameworks of nine countries and regions - Belgium (Flanders region only), Croatia, France, Germany, Italy, Portugal, Spain, Netherlands and the United Kingdom - to reveal the main challenges and opportunities that these have posed to collective RE prosumers (i.e. renewable energy communities, citizen energy communities and jointly-acting renewable self-consumers). Four countries have had more favourable frameworks for collective prosumers: France, Germany, Netherlands and United Kingdom. The results indicate that the current legal framework at the EU level represents a clear opportunity for collective prosumers. Spain and Portugal have both already shifted from a restrictive regulation to implementing in 2019 a legal framework for collectives. The study provides a starting point to distil policy implications for improving legal frameworks relevant for collective RES prosumers across Europe.

'What needs to change in the United Kingdom energy system, to allow low carbon business models to thrive?' Earlier work by the authors has reported that up to 21bn pound of new financial value could be available to electricity utilities by 2050, in a low-carbon UK power sector. This represents up to 30% of future electricity markets. To capture new value, electricity utility business models need to evolve. This research used an elite 'decision theatre' method, in the UK, USA, and Europe, to decide on the most important changes required to the energy system to enable new [low-carbon] utility business models to thrive. The results show that there is substantial agreement on the five requirements for change, these are: (1) Clear national heat and electric transport strategies; (2) Commitment to sufficient carbon prices; (3) Simpler, principles-based regulation across the energy value chain; (4) Accessible markets for flexibility and other energy services; and (5) Managing consumers' exposure to risk. These were the changes that participants considered most important to foster low-carbon utility business model innovation. This work suggests focusing on business model innovation as opposed to technological innovation could accelerate decarbonisation, and extends the use of the Decision Theatre method in social science energy research.

cfDNA has the potential to be used as diagnostic, predictive, prognostic and pharmacodynamic biomarker for NSCLC. Next Generation Sequencing of cfDNA is moving from the research setting to routine clinical use. As tumour genomics and burden will differ in the clinic from trials it is important to determine performance in this setting. 17ml of blood was taken from 230 patients with known or suspected NSCLC treated at The Christie and Newcastle upon Tyne Hospitals NHS Trusts from June 2019. Samples were transported to Foundation Medicine and analysed on a commercial hybrid-capture NGS platform for 70 oncogenes. Clinical details and rationale for test were extracted from clinical notes. Most patients were either untreated or had received 1 line of therapy (54% and 25% respectively). Histology was adenocarcinoma in 68%; squamous cancer in 13%, other in 9% and no histology in 10%. In 35% the rationale for testing was to avoid a contemporaneous biopsy (either failure of initial biopsy or inability to safely perform 15%, or rebiopsy on progression of targeted therapy 20%). Median time from collection to report was 13 days (range 4 to 21) with 85% received within 14 days; the failure rate was 5%, mostly due to cfDNA levels <20ng/ml. The number of abnormalities reported was 0 in 13%, 1 in 22%, 2 in 28% and 3 or more in 36% of patients. The median variant allele fraction (VAF) was 1.6% (range 0.11-91); however, 25% of cases had less than 0.5% VAF. Potentially actionable findings using the ESCAT scale were found for Tier 1: 22% (20% already known) Tier 2:14% and Tier 3: 4% of patients. 5 known fusions were not detected (4 ALK; 1 ROS-1) although 3 patients were on therapy at sampling. In community practice results of cfDNA sampling are similar to reported in previous research series. 18% of patients either had failed analysis or no detectable abnormality. Only patients with EGFR mutations were able to access standard of care treatments but some patients were able to avoid biopsies or be routed to appropriate trials.

ABSTRACT Background Anxiety, evoked by continuous inspiration of a 5 – 8% CO 2 mixture, has been found to have an analgesic eLect on self-reported pain. The precise mechanism whereby this effect obtains remains unknown. Methods The present study tested whether temporal summation, the psychological counterpart of wind-up, is involved in hypercapnic analgesia. 21 healthy participants received painful transcutaneous electrical stimuli of varied intensity, during continuous inhalation of 7.5% CO 2 mixture and medical air, presented in a single-blinded counterbalanced order. Continuous pain ratings were acquired to measure the temporal development of the pain response. Several points and events of interest that characterise the pain response profile were extracted from the continuous data. Results Mixed-eLects modelling demonstrated a reduction of all pain measures during inspiration of the anxiogenic mixture, but not air. This was accompanied by an increase in the psychological and physiological measures of anxiety. Analyses of the characteristic measures of temporal summation suggested that the hypercapnic mixture has an analgesic property evident from the start of the pain response. The same was true for the remainder of the response, the adaptation period, where pain ratings were also inhibited. The reduced pain ratings persisted during the remainder of the response. Anxiety was found to be a mediating factor for summative pain ratings but not the temporally sensitive TS measures, suggesting an overall, cumulative effect. Conclusions The findings provide an explanation for the previously observed low self-reported pain during the inhalation of an anxiogenic hypercapnic mixture.