First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor.

BACKGROUND: This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. METHODS: E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. RESULTS: Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50-800-mg oral dosing. CONCLUSION: The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov code: NCT01618136.

Activity-based costing of health-care delivery, Haiti.

OBJECTIVE: To evaluate the implementation of a time-driven activity-based costing analysis at five community health facilities in Haiti. METHODS: Together with stakeholders, the project team decided that health-care providers should enter start and end times of the patient encounter in every fifth patient's medical dossier. We trained one data collector per facility, who manually entered the time recordings and patient characteristics in a database and submitted the data to a cloud-based data warehouse each week. We calculated the capacity cost per minute for each resource used. An automated web-based platform multiplied reported time with capacity cost rate and provided the information to health-facilities administrators. FINDINGS: Between March 2014 and June 2015, the project tracked the clinical services for 7162 outpatients. The cost of care for specific conditions varied widely across the five facilities, due to heterogeneity in staffing and resources. For example, the average cost of a first antenatal-care visit ranged from 6.87 United States dollars (US$) at a low-level facility to US$ 25.06 at a high-level facility. Within facilities, we observed similarly variation in costs, due to factors such as patient comorbidities, patient arrival time, stocking of supplies at facilities and type of visit. CONCLUSION: Time-driven activity-based costing can be implemented in low-resource settings to guide resource allocation decisions. However, the extent to which this information will drive observable changes at patient, provider and institutional levels depends on several contextual factors, including budget constraints, management, policies and the political economy in which the health system is situated.

Modeling the Potential Economic Impact of the Medicare Comprehensive Care for Joint Replacement Episode-Based Payment Model.

BACKGROUND: The Medicare program has initiated Comprehensive Care for Joint Replacement (CJR), a bundled payment mandate for lower extremity joint replacements. We sought to determine the degree to which hospitals will invest in care redesign in response to CJR, and to project its economic impacts. METHODS: We defined 4 potential hospital management strategies to address CJR: no action, light care management, heavy care management, and heavy care management with contracting. For each of 798 hospitals included in CJR, we used hospital-specific volume, cost, and quality data to determine the hospital's economically dominant strategy. We aggregated data to assess the percentage of hospitals pursuing each strategy; savings to the health care system; and costs and percentages of CJR-derived revenues gained or lost for Medicare, hospitals, and postacute care facilities. RESULTS: In the model, 83.1% of hospitals (range 55.0%-100.0%) were expected to take no action in response to CJR, and 16.1% of hospitals (range 0.0%-45.0%) were expected to pursue heavy care management with contracting. Overall, CJR is projected to reduce health care expenditures by 0.5% (range 0.0%-4.1%) or $14 million (range $0-$119 million). Medicare is expected to save 2.2% (range 2.2%-2.2%), hospitals are projected to lose 3.7% (range 4.7% loss to 3.8% gain), and postacute care facilities are expected to lose 6.5% (range 0.0%-12.8%). Hospital administrative costs are projected to increase by $63 million (range $0-$148 million). CONCLUSION: CJR is projected to have a negligible impact on total health care expenditures for lower extremity joint replacements. Further research will be required to assess the actual care management strategies adopted by CJR hospitals.

A time-driven activity-based costing model to improve health-care resource use in Mirebalais, Haiti.

BACKGROUND: In resource-limited settings, efficiency is crucial to maximise resources available for patient care. Time driven activity-based costing (TDABC) estimates costs directly from clinical and administrative processes used in patient care, thereby providing valuable information for process improvements. TDABC is more accurate and simpler than traditional activity-based costing because it assigns resource costs to patients based on the amount of time clinical and staff resources are used in patient encounters. Other costing approaches use somewhat arbitrary allocations that provide little transparency into the actual clinical processes used to treat medical conditions. TDABC has been successfully applied in European and US health-care settings to facilitate process improvements and new reimbursement approaches, but it has not been used in resource-limited settings. We aimed to optimise TDABC for use in a resource-limited setting to provide accurate procedure and service costs, reliably predict financing needs, inform quality improvement initiatives, and maximise efficiency. METHODS: A multidisciplinary team used TDABC to map clinical processes for obstetric care (vaginal and caesarean deliveries, from triage to post-partum discharge) and breast cancer care (diagnosis, chemotherapy, surgery, and support services, such as pharmacy, radiology, laboratory, and counselling) at Hôpital Universitaire de Mirebalais (HUM) in Haiti. The team estimated the direct costs of personnel, equipment, and facilities used in patient care based on the amount of time each of these resources was used. We calculated inpatient personnel costs by allocating provider costs per staffed bed, and assigned indirect costs (administration, facility maintenance and operations, education, procurement and warehouse, bloodbank, and morgue) to various subgroups of the patient population. This study was approved by the Partners in Health/Zanmi Lasante Research Committee. FINDINGS: The direct cost of an uncomplicated vaginal delivery at HUM was US$62 and the direct cost of a caesarean delivery was US$249. The direct costs of breast cancer care (including diagnostics, chemotherapy, and mastectomy) totalled US$1393. A mastectomy, including post-anaesthesia recovery and inpatient stay, totalled US$282 in direct costs. Indirect costs comprised 26-38% of total costs, and salaries were the largest percentage of total costs (51-72%). INTERPRETATION: Accurate costing of health services is vital for financial officers and funders. TDABC showed opportunities at HUM to optimise use of resources and reduce costs-for instance, by streamlining sterilisation procedures and redistributing certain tasks to improve teamwork. TDABC has also improved budget forecasting and informed financing decisions. HUM leadership recognised its value to improve health-care delivery and expand access in low-resource settings. FUNDING: Boston Children's Hospital, Harvard Business School, and Partners in Health.

Gastrointestinal delivery of propofol from fospropofol: its bioavailability and activity in rodents and human volunteers.

BACKGROUND: Propofol is a safe and widely used intravenous anesthetic agent, for which additional clinical uses including treatment of migraine, nausea, pain and anxiety have been proposed (Vasileiou et al. Eur J Pharmacol 605:1-8, 2009). However, propofol suffers from several disadvantages as a therapeutic outside anesthesia including its limited aqueous solubility and negligible oral bioavailability. The purpose of the studies described here was to evaluate, in both animals and human volunteers, whether fospropofol (a water soluble phosphate ester prodrug of propofol) would provide higher propofol bioavailability through non-intravenous routes. METHODS: Fospropofol was administered via intravenous, oral and intraduodenal routes to rats. Pharmacokinetic and pharmacodynamic parameters were then evaluated. Based on the promising animal data we subsequently conducted an oral and intraduodenal pharmacokinetic/pharmacodynamic study in human volunteers. RESULTS: In rats, bioavailability of propofol from fospropofol delivered orally was found to be appreciable, in the order of around 20-70%, depending on dose. Availability was especially marked following fospropofol administration via the intraduodenal route, where bioavailability approximated 100%. Fospropofol itself was not appreciably bioavailable when administered by any route except for intravenous. Pharmacologic effect following oral fospropofol was confirmed by observation of sedation and alleviation of thermal hyperalgesia in the rat chronic constrictive injury model of neuropathic pain. The human data also showed systemic availability of propofol from fospropofol administration via oral routes, a hereto novel finding. Assessment of sedation in human volunteers was correlated with pharmacokinetic measurements. CONCLUSIONS: These data suggest potential utility of oral administration of fospropofol for various therapeutic indications previously considered for propofol.

Population pharmacokinetic modeling of sotatercept in healthy participants and patients with pulmonary arterial hypertension.

Sotatercept is a breakthrough, first-in-class biologic, that is FDA-approved for the treatment of pulmonary arterial hypertension (PAH). A population pharmacokinetic (PopPK) model was developed using data from two phase 1 studies in healthy participants, and two phase 2 studies and one phase 3 study in participants with PAH. The pooled sotatercept PK data encompassed single intravenous (IV) or subcutaneous (SC) doses ranging from 0.01 to 3.0 mg/kg, as well as multiple SC doses ranging from 0.03 to 1.0 mg/kg, with PK samples collected up to a maximum of ~150 weeks following Q3W and Q4W dosing regimens. The final PopPK analysis included 350 participants, with 30 and 320 participants receiving sotatercept IV and SC, respectively. A two-compartment model with a first-order absorption rate constant and a linear disposition from central compartment well-described sotatercept PK. The estimated bioavailability is ~66%; bioavailability, clearance (CL), and central volume (VC) have low to moderate inter-individual variability. Time-varying body weight and baseline albumin concentration were statistically significant predictors of PK; CL and VC were predicted to increase with increasing body weight, while CL was predicted to decrease with increasing baseline albumin concentration. However, the magnitude of covariate effects is not predicted to meaningfully alter the disposition of sotatercept. Altogether, the PopPK modeling results demonstrate favorable PK characteristics (low to moderate variability and typical bioavailability), supporting sotatercept as a SC biological agent for the treatment of patients with PAH.

Danazol oral absorption modelling in the fasted dog: An example of mechanistic understanding of formulation effects on drug pharmacokinetics.

Oral bioavailability of poorly water soluble (BCS II) drugs like danazol can be minimal without the necessary formulation strategies. Availability of in vitro physicochemical and in vivo pharmacokinetic studies can be valuable when designing these strategies but cannot reveal the drug-formulation-gastrointestinal physiology interplay that impact the successful optimization of intestinal solubilization and resulting oral drug absorption. In silico mechanistic oral drug absorption models can serve as a tool for providing this important perspective and for integrating information generated across various in vivo and in vitro studies. In this work, we detail the development and application of the Simcyp canine ADAM model to nine danazol oral formulations and compare the model predictions to caninein vivo pharmacokinetic data from published literature. The application of this mechanistic approach revealed insights suggesting: (1) complete danazol solubilization in vitro may lead to an over-estimation of oral bioavailability when predictions are not corrected for the in vivo conditions promoting gut luminal precipitation; (2) some solubilizing excipients can influence intestinal physiology in a manner that may reduce danazol absorption; (3) danazol-formulation-luminal bile salts interplay can result in the formation of mixed micelles that negatively impact danazol intestinal permeability; and (4) the magnitude of danazol bioavailability enhancement associated with the use of solubilizing agents can be affected by the presence of saturable gut metabolism that can lead to concentration-dependent differences in its influence in vivo formulation behaviour at high versus low doses.

Time-driven activity-based costing to estimate cost of care at multidisciplinary aerodigestive centers.

OBJECTIVES/HYPOTHESIS: Providing high-value healthcare to patients is increasingly becoming an objective for providers including those at multidisciplinary aerodigestive centers. Measuring value has two components: 1) identify relevant health outcomes and 2) determine relevant treatment costs. Via their inherent structure, multidisciplinary care units consolidate care for complex patients. However, their potential impact on decreasing healthcare costs is less clear. The goal of this study was to estimate the potential cost savings of treating patients with laryngeal clefts at multidisciplinary aerodigestive centers. STUDY DESIGN: Retrospective chart review. METHODS: Time-driven activity-based costing was used to estimate the cost of care for patients with laryngeal cleft seen between 2008 and 2013 at the Massachusetts Eye and Ear Infirmary Pediatric Aerodigestive Center. Retrospective chart review was performed to identify clinic utilization by patients as well as patient diet outcomes after treatment. Patients were stratified into neurologically complex and neurologically noncomplex groups. RESULTS: The cost of care for patients requiring surgical intervention was five and three times as expensive of the cost of care for patients not requiring surgery for neurologically noncomplex and complex patients, respectively. Following treatment, 50% and 55% of complex and noncomplex patients returned to normal diet, whereas 83% and 87% of patients experienced improved diets, respectively. Additionally, multidisciplinary team-based care for children with laryngeal clefts potentially achieves 20% to 40% cost savings. CONCLUSIONS: These findings demonstrate how time-driven activity-based costing can be used to estimate and compare patient costs in multidisciplinary aerodigestive centers. LEVEL OF EVIDENCE: 2c. Laryngoscope, 127:2152-2158, 2017.

Examining the Use of a Mechanistic Model to Generate an In Vivo/In Vitro Correlation: Journey Through a Thought Process.

The attention and interest in establishing in vivo/in vitro correlations (IVIVCs) is grounded in its tremendous utility as a prognostic tool. It can be used to support formulation optimization, predict in vivo drug exposure across a potential patient population, select a biologically relevant in vitro dissolution test condition, and support the use of in vitro dissolution data as a surrogate for in vivo bioequivalence trials. The pharmacological and statistical implications of this correlation are linked to the method by which the IVIVC was determined and to the assumptions and optimization approaches integrated into the estimation procedure. Using previously published data generated in normal healthy volunteers, an IVIVC for metoprolol was established using a mechanistic modeling approach. Within that framework, we explored the consequences of (1) our method of fitting a single Weibull function to the in vivo dissolution, (2) our selection of weighting scheme and optimization approaches, (3) the impact of applying a fixed versus fitted gastric emptying time, and 4) the importance of factoring population variability into our IVIVC estimation and profile reconvolution. We identified those factors found to be critical in terms of their influence on the accuracy of our predicted systemic metoprolol concentration-time profiles. We considered the strengths and weaknesses of our approach and discussed how the results of this study may impact efforts to generate IVIVCs with compounds presenting physicochemical characteristics different from that of metoprolol.

Use of Modeling and Simulation Tools for Understanding the Impact of Formulation on the Absorption of a Low Solubility Compound: Ciprofloxacin.

This study explored the utility of mechanistic absorption models to describe the in vivo performance of a low solubility/low permeability compound in normal healthy subjects. Sixteen healthy human volunteers received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by HPLC. In vitro ciprofloxacin release from the oral tablets was tested under a variety of conditions. A mechanistic model was used to explore in vivo dissolution and intestinal absorption. Although dissolution rate influenced the location of drug release, absorption challenges appeared to be associated with permeability limitations in the lower small intestine and colon. The apparent relationship between drug solubilization within the upper small intestinal and formulation overall bioavailability suggested the presence of an intestinal absorption window in many individuals. Failure to absorb drug within this window appeared to be linked with the likelihood of in vivo drug precipitation. Challenges encountered during this modeling exercise included large intersubject variability in product in vivo dissolution and the apparent limitations in ciprofloxacin absorption. Although transporter activity was not included as a model parameter, this evaluation demonstrated how identifying the location of drug absorption across several formulations provided an opportunity to identify factors to consider when formulating similar low solubility/low permeability compounds. The use of mechanistic models was invaluable for our understanding of in vivo product performance and for the assessment of individual profiles rather than means. The latter was essential for understanding the potential challenges that may be encountered when introducing a formulation into a patient population.

Rethinking the cost of healthcare in low-resource settings: the value of time-driven activity-based costing.

Low-income and middle-income countries account for over 80% of the world's infectious disease burden, but <20% of global expenditures on health. In this context, judicious resource allocation can mean the difference between life and death, not just for individual patients, but entire patient populations. Understanding the cost of healthcare delivery is a prerequisite for allocating health resources, such as staff and medicines, in a way that is effective, efficient, just and fair. Nevertheless, health costs are often poorly understood, undermining effectiveness and efficiency of service delivery. We outline shortcomings, and consequences, of common approaches to estimating the cost of healthcare in low-resource settings, as well as advantages of a newly introduced approach in healthcare known as time-driven activity-based costing (TDABC). TDABC is a patient-centred approach to cost analysis, meaning that it begins by studying the flow of individual patients through the health system, and measuring the human, equipment and facility resources used to treat the patients. The benefits of this approach are numerous: fewer assumptions need to be made, heterogeneity in expenditures can be studied, service delivery can be modelled and streamlined and stronger linkages can be established between resource allocation and health outcomes. TDABC has demonstrated significant benefits for improving health service delivery in high-income countries but has yet to be adopted in resource-limited settings. We provide an illustrative case study of its application throughout a network of hospitals in Haiti, as well as a simplified framework for policymakers to apply this approach in low-resource settings around the world.

Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase.

Several 2'-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2'-Deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys compared to 5. Co-administration of 7a with decitabine, a CDA substrate, boosted the plasma levels of decitabine in rhesus monkeys. These results demonstrate that compound 7a can serve as an acid-stable alternative to 5 as a pharmacoenhancer of drugs subject to CDA-mediated metabolism.

Influence of input rate on the stereospecific and nonstereospecific first pass metabolism and pharmacokinetics of metoprolol extended release formulations.

The purpose of this study was to examine the influence of input rate on the stereoselective and nonstereoselective pharmacokinetics of metoprolol, alpha-hydroxymetoprolol, and its acid metabolite. Extended release formulations (100 mg) of metoprolol with varying release rates (e.g., slow (S), moderate (M), and fast (F)) and an oral solution (OS, 50 mg) were administered to normal, healthy extensive metabolizers. Serial blood samples were collected over 48 h, plasma was obtained, and subsequently analyzed by a validated HPLC method with fluorescence detection. The mean T(max) of metoprolol after the S, M, F (4.43, 4.00, 3.14 h, respectively) was found to be different ( P < 0.05) as compared to the OS (2.07 h). The ratio of alpha-hydroxymetoprolol/metoprolol was higher for the OS (1.26) vs. the S, M, and F (1.02, 0.96, 0.99). The S/R enantiomer ratios of the concentration for metoprolol, ACMB, and alpha-hydroxmetoprolol were calculated at each time point and showed a significant difference ( P < 0.05) in the absorption phase (1-4 h) vs. terminal phase (8-16 h) for fast input (solution and fast extended release formulations). Based on these results, it would appear that input rate influences the pharmacokinetics of metoprolol, its metabolites, and their enantiomers.