The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.

Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia (MLL) gene rearrangements (MLL-r) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.

Geospatial patterns of comorbidity prevalence among people with osteoarthritis in Alberta Canada.

BACKGROUND: Knowledge of geospatial pattern in comorbidities prevalence is critical to an understanding of the local health needs among people with osteoarthritis (OA). It provides valuable information for targeting optimal OA treatment and management at the local level. However, there is, at present, limited evidence about the geospatial pattern of comorbidity prevalence in Alberta, Canada. METHODS: Five administrative health datasets were linked to identify OA cases and comorbidities using validated case definitions. We explored the geospatial pattern in comorbidity prevalence at two standard geographic areas levels defined by the Alberta Health Services: descriptive analysis at rural-urban continuum level; spatial analysis (global Moran's I, hot spot analysis, cluster and outlier analysis) at the local geographic area (LGA) level. We compared area-level indicators in comorbidities hotspots to those in the rest of Alberta (non-hotspots). RESULTS: Among 359,638 OA cases in 2013, approximately 60% of people resided in Metro and Urban areas, compared to 2% in Rural Remote areas. All comorbidity groups exhibited statistically significant spatial autocorrelation (hypertension: Moran's I index 0.24, z score 4.61). Comorbidity hotspots, except depression, were located primarily in Rural and Rural Remote areas. Depression was more prevalent in Metro (Edmonton-Abbottsfield: 194 cases per 1000 population, 95%CI 192-195) and Urban LGAs (Lethbridge-North: 169, 95%CI 168-171) compared to Rural areas (Fox Creek: 65, 95%CI 63-68). Comorbidities hotspots included a higher percentage of First Nations or Inuit people. People with OA living in hotspots had lower socioeconomic status and less access to care compared to non-hotspots. CONCLUSIONS: The findings highlight notable rural-urban disparities in comorbidities prevalence among people with OA in Alberta, Canada. Our study provides valuable evidence for policy and decision makers to design programs that ensure patients with OA receive optimal health management tailored to their local needs and a reduction in current OA health disparities.

Pharmacokinetic and Pharmacodynamic Considerations for Drugs Binding to Alpha-1-Acid Glycoprotein.

According to the free drug hypothesis only the unbound drug is available to act at physiological sites of action, and as such the importance of plasma protein binding primarily resides in its impact on pharmacokinetics and pharmacodynamics. Of the major plasma proteins, alpha-1-acid glycoprotein (AAG) represents an intriguing one primarily due to the high affinity, low capacity properties of this protein. In addition, there are marked species and age differences in protein expression, homology and drug binding affinity. As such, a thorough understanding of drug binding to AAG can help aid and improve the translation of pharmacokinetic/pharmacodynamic (PK/PD) relationships from preclinical species to human as well as adults to neonates. This review provides a comprehensive overview of our current understanding of the biochemistry of AAG; endogenous function, impact of disease, utility as a biomarker, and impact on PK/PD. Experimental considerations are discussed as well as recommendations for understanding the potential impact of AAG on PK through drug discovery and early development.

Implications for Metabolite Quantification by Mass Spectrometry in the Absence of Authentic Standards.

Quantification of metabolites by mass spectrometry in the absence of authentic reference standards or without a radiolabel is often called "semiquantitative," which acknowledges that mass spectrometric responses are not truly quantitative. For many researchers, it is tempting to pursue this practice of semiquantification in early drug discovery and even preclinical development, when radiolabeled absorption, distribution, metabolism, and excretion studies are being deferred to later stages of drug development. The caveats of quantifying metabolites based on parent drug response are explored in this investigation. A set of 71 clinically relevant drugs/metabolites encompassing common biotransformation pathways was subjected to flow injection analysis coupled with electrospray ionization (ESI) mass spectrometry. The results revealed a large variation in ESI response even for structurally similar parent drug/metabolite pairs. The ESI response of each metabolite was normalized to that of the parent drug to generate an ESI relative response factor. Overall, relative response factors ranged from 0.014 (>70-fold lower response than parent) to 8.6 (8.6-fold higher response than parent). Various two-dimensional molecular descriptors were calculated that describe physicochemical, topological, and structural properties for each drug/metabolite. The molecular descriptors, along with the ESI response factors, were used in univariate analyses as well as a principal components analysis to ascertain which molecular descriptors best account for the observed discrepancies in drug/metabolite ESI response. This investigation has shown that the practice of using parent drug response to quantify metabolites should be used with caution.

A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models.

Protein arginine methyltransferase-5 (PRMT5) is reported to have a role in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell lymphoma (MCL). Here we describe the identification and characterization of a potent and selective inhibitor of PRMT5 with antiproliferative effects in both in vitro and in vivo models of MCL. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases.

Mechanistic investigations into the species differences in pinometostat clearance: impact of binding to alpha-1-acid glycoprotein and permeability-limited hepatic uptake.

1. The plasma clearance of the first-in-class DOT1L inhibitor, EPZ-5676 (pinometostat), was shown to be markedly lower in human compared to the preclinical species, mouse, rat and dog. 2. This led to vertical allometry where various interspecies scaling methods were applied to the data, with fold-errors between 4 and 13. We had previously reported the elimination and metabolic pathways of EPZ-5676 were similar across species. Therefore, the aim of this work was to explore the mechanistic basis for the species difference in clearance for EPZ-5676, focusing on other aspects of disposition. 3. The protein binding of EPZ-5676 in human plasma demonstrated a non-linear relationship suggesting saturable binding at physiologically relevant concentrations. Saturation of protein binding was not observed in plasma from preclinical species. Kinetic determinations using purified serum albumin and alpha-1-acid glycoprotein (AAG) confirmed that EPZ-5676 is a high affinity ligand for AAG with a dissociation constant (Kd) of 0.24 µM. 4. Permeability limited uptake was also considered since hepatocyte CLint was much lower in human relative to preclinical species. Passive unbound CLint for EPZ-5676 was estimated using a correlation analysis of logD and data previously reported on seven drugs in sandwich cultured human hepatocytes. 5. Incorporation of AAG binding and permeability limited hepatic uptake into the well-stirred liver model gave rise to a predicted clearance for EPZ-5676 within 2-fold of the observed value of 1.4 mL min-1 kg-1. This analysis suggests that the marked species difference in EPZ-5676 clearance is driven by high affinity binding to human AAG as well as species-specific hepatic uptake invoking the role of transporters.

Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development.

Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia-rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field.

Species differences in metabolism of EPZ015666, an oxetane-containing protein arginine methyltransferase-5 (PRMT5) inhibitor.

1. Metabolite profiling and identification studies were conducted to understand the cross-species differences in the metabolic clearance of EPZ015666, a first-in-class protein arginine methyltransferase-5 (PRMT5) inhibitor, with anti-proliferative effects in preclinical models of Mantle Cell Lymphoma. EPZ015666 exhibited low clearance in human, mouse and rat liver microsomes, in part by introduction of a 3-substituted oxetane ring on the molecule. In contrast, a higher clearance was observed in dog liver microsomes (DLM) that translated to a higher in vivo clearance in dog compared with rodent. 2. Structure elucidation via high resolution, accurate mass LC-MS(n) revealed that the prominent metabolites of EPZ015666 were present in hepatocytes from all species, with the highest turnover rate in dogs. M1 and M2 resulted from oxidative oxetane ring scission, whereas M3 resulted from loss of the oxetane ring via an N-dealkylation reaction. 3. The formation of M1 and M2 in DLM was significantly abrogated in the presence of the specific CYP2D inhibitor, quinidine, and to a lesser extent by the CYP3A inhibitor, ketoconazole, corroborating data from human recombinant isozymes. 4. Our data indicate a marked species difference in the metabolism of the PRMT5 inhibitor EPZ015666, with oxetane ring scission the predominant metabolic pathway in dog mediated largely by CYP2D.

Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.

Rearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness; thus, there is a pressing need for new therapies for this disease. Genetic and small molecule inhibitor studies have demonstrated that the histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged leukemia in model systems. Here we describe the characterization of EPZ-5676, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity. The compound has an inhibition constant value of 80 pM, and demonstrates 37 000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676 inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous IV infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is therefore a potential treatment of MLL-rearranged leukemia and is under clinical investigation.

Structural and Kinetic Characterization of a Novel N-acetylated Aliphatic Amine Metabolite of the PRMT Inhibitor, EPZ011652.

Pharmacokinetic and metabolite identification studies were conducted to understand the clearance pathways of EPZ011652 [(2-aminoethyl)(methyl)({3-[4-(propan-2-yloxy)phenyl]-1H-pyrazol-4-yl}methyl)amine], a potent protein arginine N-methyltransferase inhibitor. Metabolic clearance was the major pathway of EPZ011652 elimination in rats with structural elucidation of metabolites via liquid chromatography - mass spectrometry (LC-MS(n)) accurate mass measurement revealing the formation of a novel aliphatic N-acetylated metabolite (M1) located on the terminal nitrogen of the ethylene-diamine side chain. EPZ015564, a synthetic standard of the N-acetyl product, was prepared and was also generated by human and rat, but not dog hepatocytes. In rat hepatocytes, on incubation with EPZ011652, the concentration of EPZ015564 initially increased before decreasing with incubation time, suggesting that the metabolite is itself a substrate for other metabolizing enzymes, in agreement with the identification of metabolites M2, M3, and M4 in rat bile, all N-acetylated metabolites, undergoing sequential phase I (demethylation, oxidation) or phase II (sulfation) reactions. Reaction phenotyping with recombinant human N-acetyltransferase (NAT) isoforms revealed that both NAT1 and NAT2 are capable of acetylating EPZ011652, although with different catalytic efficiencies. Kinetic profiles of EPZ015564 formation followed classic Michaelis-Menten behavior with apparent Km values of >1000 µM for NAT1 and 165 ± 14.1 µM for NAT2. The in vitro intrinsic clearance for EPZ011652 by NAT2 (110 µL/min/mg) was 500-fold greater than by NAT1. In summary, we report the unusual N-acetylation of an aliphatic amine and discuss the implications for drug discovery and clinical development.

Evaluation of drug-drug interactions for oncology therapies: in vitro-in vivo extrapolation model-based risk assessment.

AIMS: Understanding drug-drug interactions (DDI) is a critical part of the drug development process as polypharmacy has become commonplace in many therapeutic areas including the cancer patient population. The objectives of this study were to investigate cytochrome P450 (CYP)-mediated DDI profiles available for therapies used in the oncology setting and evaluate how models based on in vitro-in vivo extrapolation performed in predicting CYP-mediated DDI risk. METHODS: A dataset of 125 oncology therapies was collated using drug label and approval history information, incorporating in vitro and clinical PK data. The predictive accuracy of the basic and net effect mechanistic static models was assessed using this oncology drug dataset, for both victim and perpetrator potential of CYP3A-mediated DDI. RESULTS: The incidence of CYP3A-mediated interaction potential was 47%, 22% and 11% for substrates, inhibitors and inducers, respectively. The basic models for precipitants gave conservative predictions with no false negatives, whilst the mechanistic static models provided reasonable quantitative predictions (2.3-3-fold error). Further analysis revealed that incorporating DDI at the level of the intestine was in most cases over-predicting interaction magnitude due to overestimates of the rate and extent of oral absorption of the precipitant. Quantifying victim DDI potential was also demonstrated using fmCYP3A estimates from ketoconazole clinical DDI studies to predict the magnitude of interaction on co-administration with the CYP3A inducer, rifampicin (1.6-3.3 fold error). CONCLUSIONS: This work illustrates the utility and limitations of current DDI risk assessment approaches applied to a range of contemporary anti-cancer agents, and discusses the implications for therapeutic combination strategies.

Risk factors associated with human Rift Valley fever infection: systematic review and meta-analysis.

OBJECTIVE: To identify risk factors for human Rift Valley fever virus (RVFV) infection. METHODS: A systematic review identified 17 articles reporting on 16 studies examining risk factors for RVFV. Pooled odds ratios (pOR) were calculated for exposures examined in four or more studies. RESULTS: Being male [pOR = 1.4 (1.0, 1.8)], contact with aborted animal tissue [pOR = 3.4 (1.6, 7.3)], birthing an animal [pOR = 3.2 (2.4, 4.2)], skinning an animal [pOR = 2.5 (1.9, 3.2)], slaughtering an animal [pOR = 2.4 (1.4, 4.1)] and drinking raw milk [pOR = 1.8 (1.2, 2.6)] were significantly associated with RVF infection after meta-analysis. Other potential risk factors include sheltering animals in the home and milking an animal, which may both involve contact with animal body fluids. CONCLUSIONS: Based on the identified risk factors, use of personal protective equipment and disinfectants by animal handlers may help reduce RVFV transmission during outbreaks. Milk pasteurisation and other possible preventive methods require further investigation.

Novel ROCK inhibitors for the treatment of pulmonary arterial hypertension.

A novel class of selective inhibitors of ROCK1 and ROCK2 has been identified by structural based drug design. PK/PD experiments using a set of highly selective Rho kinase inhibitors suggest that systemic Rho kinase inhibition is linked to a reversible reduction in lymphocyte counts. These results led to the consideration of topical delivery of these molecules, and to the identification of a lead molecule 7 which shows promising PK and PD in a murine model of pulmonary hypertension after intra-tracheal dosing.

Past residence outside of the United States is associated with diet quality in adults currently residing in the United States.

OBJECTIVE: To evaluate healthy dietary factors in relation to prior residence outside the United States (US) among university-affiliated individuals currently residing in the US. METHODS: Current diet information was collected via a 4-day food record and residential history data were collected by in-person interview for 114 individuals. RESULTS: Residence outside of the US at any point during the interviewee's life was associated with higher diet quality (Healthy Eating Index-2005: 50.0 vs. 46.8) and lower added sugar intake (25.8 vs. 34.9 g/d). Concordance of residence as a child (≤12 years of age) and within the prior 5 years was more strongly associated with higher HEI-2005 score (52.7) than if childhood was outside of the US and recent within the US (47.1), compared with individuals who have only resided within the US (46.9). Results were similar when also accounting for self-reported current residence as permanent residence. Current diet quality, food groups, and nutrient intakes differed depending on where in the world region individuals resided as a child. Restricting the analyzes to a subgroup of individuals of younger age and similar education attenuated associations. CONCLUSIONS: Lower added sugar intake and higher overall diet quality were most consistently associated with residence outside of the US, and recent residence outside of the US may be more strongly associated than childhood residence. Some of these differences may be explained by demographic or socioeconomic factors. Future studies could evaluate explanatory factors for these observations, including detailed socioeconomic factors, exposure to diverse foods, and accessibility of processed foods.

Nonclinical pharmacokinetics and metabolism of EPZ-5676, a novel DOT1L histone methyltransferase inhibitor.

(2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol (EPZ-5676) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL-rearranged leukemias. This report describes the preclinical pharmacokinetics and metabolism of EPZ-5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. The in vivo pharmacokinetics in mouse, rat and dog were characterized following i.v. and p.o. administration; EPZ-5676 had moderate to high clearance, low oral bioavailability with a steady-state volume of distribution 2-3 fold higher than total body water. EPZ-5676 showed biexponential kinetics following i.v. administration, giving rise to a terminal elimination half-life (t1/2 ) of 1.1, 3.7 and 13.6 h in mouse, rat and dog, respectively. The corresponding in vitro ADME parameters were also studied and utilized for in vitro-in vivo extrapolation purposes. There was good agreement between the microsomal clearance and the in vivo clearance implicating hepatic oxidative metabolism as the predominant elimination route in preclinical species. Furthermore, low renal clearance was observed in mouse, approximating to fu -corrected glomerular filtration rate (GFR) and thus passive glomerular filtration. The metabolic pathways across species were studied in liver microsomes in which EPZ-5676 was metabolized to three monohydroxylated metabolites (M1, M3 and M5), one N-dealkylated product (M4) as well as an N-oxide (M6).

Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors.

Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest in oncology, both for treating with a single agent and in combination with a KRAS inhibitor. We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of GDC-1971 (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.

In silico prediction of total human plasma clearance.

The prediction of the total human plasma clearance of novel chemical entities continues to be of paramount importance in drug design and optimization, because it impacts both dose size and dose regimen. Although many in vivo and in vitro methods have been proposed, a well-constructed, well-validated, and less resource-intensive computational tool would still be very useful in an iterative compound design cycle. A new completely in silico linear PLS (partial least-squares) model to predict the human plasma clearance was built on the basis of a large data set of 754 compounds using physicochemical descriptors and structural fragments, the latter able to better represent biotransformation processes. The model has been validated using the "ELASTICO" approach (Enhanced Leave Analog-Structural, Therapeutic, Ionization Class Out) based on ten therapeutic/structural analog classes. The model yields a geometric mean fold error (GMFE) of 2.1 and a percentage of compounds predicted within 2- and 3-fold error of 59% and 80%, respectively, showing an improved performance when compared with previous published works in predicting clearance of neutral compounds, and a very good performance with ionized molecules at pH 7.5, able to compare favorably with fairly accurate in vivo methods.

A validation of ground ambulance pre-hospital times modeled using geographic information systems.

BACKGROUND: Evaluating geographic access to health services often requires determining the patient travel time to a specified service. For urgent care, many research studies have modeled patient pre-hospital time by ground emergency medical services (EMS) using geographic information systems (GIS). The purpose of this study was to determine if the modeling assumptions proposed through prior United States (US) studies are valid in a non-US context, and to use the resulting information to provide revised recommendations for modeling travel time using GIS in the absence of actual EMS trip data. METHODS: The study sample contained all emergency adult patient trips within the Calgary area for 2006. Each record included four components of pre-hospital time (activation, response, on-scene and transport interval). The actual activation and on-scene intervals were compared with those used in published models. The transport interval was calculated within GIS using the Network Analyst extension of Esri ArcGIS 10.0 and the response interval was derived using previously established methods. These GIS derived transport and response intervals were compared with the actual times using descriptive methods. We used the information acquired through the analysis of the EMS trip data to create an updated model that could be used to estimate travel time in the absence of actual EMS trip records. RESULTS: There were 29,765 complete EMS records for scene locations inside the city and 529 outside. The actual median on-scene intervals were longer than the average previously reported by 7-8 minutes. Actual EMS pre-hospital times across our study area were significantly higher than the estimated times modeled using GIS and the original travel time assumptions. Our updated model, although still underestimating the total pre-hospital time, more accurately represents the true pre-hospital time in our study area. CONCLUSIONS: The widespread use of generalized EMS pre-hospital time assumptions based on US data may not be appropriate in a non-US context. The preference for researchers should be to use actual EMS trip records from the proposed research study area. In the absence of EMS trip data researchers should determine which modeling assumptions more accurately reflect the EMS protocols across their study area.

Rural-Urban Differences in Non-Local Primary Care Utilization among People with Osteoarthritis: The Role of Area-Level Factors.

The utilization of non-local primary care physicians (PCP) is a key primary care indicator identified by Alberta Health to support evidence-based healthcare planning. This study aims to identify area-level factors that are significantly associated with non-local PCP utilization and to examine if these associations vary between rural and urban areas. We examined rural-urban differences in the associations between non-local PCP utilization and area-level factors using multivariate linear regression and geographically weighted regression (GWR) models. Global Moran's I and Gi* hot spot analyses were applied to identify spatial autocorrelation and hot spots/cold spots of non-local PCP utilization. We observed significant rural-urban differences in the non-local PCP utilization. Both GWR and multivariate linear regression model identified two significant factors (median travel time and percentage of low-income families) with non-local PCP utilization in both rural and urban areas. Discontinuity of care was significantly associated with non-local PCP in the southwest, while the percentage of people having university degree was significant in the north of Alberta. This research will help identify gaps in the utilization of local primary care and provide evidence for health care planning by targeting policies at associated factors to reduce gaps in OA primary care provision.

Rural-Urban Disparities in Realized Spatial Access to General Practitioners, Orthopedic Surgeons, and Physiotherapists among People with Osteoarthritis in Alberta, Canada.

Rural Canadians have high health care needs due to high prevalence of osteoarthritis (OA) but lack access to care. Examining realized access to three types of providers (general practitioners (GPs), orthopedic surgeons (Ortho), and physiotherapists (PTs)) simultaneously helps identify gaps in access to needed OA care, inform accessibility assessment, and support health care resource allocation. Travel time from a patient's postal code to the physician's postal code was calculated using origin-destination network analysis. We applied descriptive statistics to summarize differences in travel time, hotspot analysis to explore geospatial patterns, and distance decay function to examine the travel pattern of health care utilization by urbanicity. The median travel time in Alberta was 11.6 min (IQR = 4.3-25.7) to GPs, 28.9 (IQR = 14.8-65.0) to Ortho, and 33.7 (IQR = 23.1-47.3) to PTs. We observed significant rural-urban disparities in realized access to GPs (2.9 and IQR = 0.0-92.1 in rural remote areas vs. 12.6 and IQR = 6.4-21.0 in metropolitan areas), Ortho (233.3 and IQR = 171.3-363.7 in rural remote areas vs. 21.3 and IQR = 14.0-29.3 in metropolitan areas), and PTs (62.4 and IQR = 0.0-232.1 in rural remote areas vs. 32.1 and IQR = 25.2-39.9 in metropolitan areas). We identified hotspots of realized access to all three types of providers in rural remote areas, where patients with OA tend to travel longer for health care. This study may provide insight on the choice of catchment size and the distance decay pattern of health care utilization for further studies on spatial accessibility.