Mathematical and Experimental Validation of Flux Dialysis Method: An Improved Approach to Measure Unbound Fraction for Compounds with High Protein Binding and Other Challenging Properties.

A flux dialysis method to measure unbound fraction (fu) of compounds with high protein binding and other challenging properties was tested and validated. This method is based on the principle that the initial flux rate of a compound through a size-excluding dialysis membrane is proportional to the product of the compound initial concentration, fu, and unbound dialysis membrane permeability (Pmem). Therefore, fu can be determined from the initial concentration and flux rate, assuming membrane Pmem is known. Compound initial flux rates for 14 compounds were determined by dialyzing human plasma containing compound (donor side) versus compound-free plasma (receiver side) and measuring the rate of compound appearance into the receiver side. Eleven compounds had known fu values obtained from conventional methods (ranging from 0.000013 to 0.22); three compounds (bedaquiline, lapatinib, and pibrentasvir) had previously qualified fu values (e.g., <0.001).Pmem estimated from flux rates and known fu values did not meaningfully differ among the compounds and were consistent with previously published values, indicating that Pmem is a constant for the dialysis membrane. This Pmem constant and the individual compound flux rates were used to calculate fu values. The flux dialysis fu values for the 11 compounds were in good agreement with their reported fu values (all within 2.5-fold; R2 = 0.980), confirming the validity of the method. Furthermore, the flux dialysis method allowed discrete fu to be estimated for the three compounds with previously qualified fu Theoretical and experimental advantages of the flux dialysis method over other dialysis-based protein binding methods are discussed.

Metabolism and disposition of ABT-894, a novel α4ß2 neuronal acetylcholine receptor agonist, in mice and monkeys.

1. Metabolism and disposition of ABT-894 was investigated in hepatocytes, in mice and monkeys receiving [(14)C]ABT-894. 2. In hepatocytes, turnover rate of ABT-894 was slow in all species with more than 90% of parent remaining. M3 (carbamoyl glucuronide) and M6 (mono-oxidation) were detected across species. 3. ABT-894 showed species-specific disposition profiles. ABT-894 was primarily eliminated by renal secretion in mice. Whereas, monkey mainly cleared ABT-894 metabolically. 4. ABT-894 underwent two primary routes of metabolism in monkeys: N-carbamoyl glucuronidation to form M3 and oxidation product M1. M3 was the major metabolite in monkey excreta. M3 was observed in mice urine. Circulating levels of M3 in terms of M3/ABT-894 ratios were essentially absent in mice, but were high in monkeys. 5. Understanding the species difference in the clearance mechanism is the key to the accurate projection of the human clearance and preclinical safety assessment. Lack of species difference in the metabolism of ABT-894 in hepatocytes certainly creates a challenge in predicting its metabolism and pharmacokinetics in human. Based on available metabolism and pharmacokinetic data of ABT-894 in human, monkey is the preferred species in predicting human clearance since it presents a similar clearance mechanism from that observed in human.

Species-dependent metabolism of a novel selective α7 neuronal acetylcholine receptor agonist ABT-107.

Metabolism of ABT-107 was investigated in in vitro hepatic systems, in rat and monkey receiving [¹4C]ABT-107, and in vivo plasma in rat, dog, monkey and human. In in vitro hepatic systems, ABT-107 was primarily cleared via oxidative metabolism, and proceeded via two parallel pathways. Pathway 1, ABT-107 was oxidized at the nitrogen of quinuclidine moiety to form M1. Pathway 2, oxidation occurred at indole-containing moiety to form M2. Metabolism via N-oxidation was predominant in dog and rat, while in monkey and human, metabolism proceeded primarily via oxidation of indole-containing moiety. ABT-107 was extensively metabolized in vivo in rat and monkey. M1 was primarily found in rat urine and bile; whereas, M2 was the major metabolite in monkey urine and feces. M1 was the predominant circulating metabolite in dog and rat. M2 was the primary circulating metabolite in monkey and human. Enzymatic studies suggested M1 formation was primarily mediated by renal FMO1. CYP3A4, 1A2, 2J2 and 2D6 were primary enzymes catalyzing M2 formation. Biotransformation of ABT-107 in human and monkey is markedly different from that in dog and rat, suggesting that monkey is an appropriate model for predicting human biotransformation and toxicology of ABT-107.

Mechanistic Physiologically Based Pharmacokinetic Modeling of the Dissolution and Food Effect of a Biopharmaceutics Classification System IV Compound-The Venetoclax Story.

Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system class IV compound. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion formulation of venetoclax in humans. A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism, and plasma protein binding. A middle-out approach was used to define permeability. Model predictions of oral venetoclax pharmacokinetics were verified against clinical studies of fed and fasted healthy volunteers, and clinical drug interaction studies with strong CYP3A inhibitor (ketoconazole) and inducer (rifampicin). Model verification demonstrated accurate prediction of the observed food effect following a low-fat diet. Ratios of predicted versus observed Cmax and area under the curve of venetoclax were within 0.8- to 1.25-fold of observed ratios for strong CYP3A inhibitor and inducer interactions, indicating that the venetoclax elimination pathway was correctly specified. The verified venetoclax PBPK model is one of the first examples mechanistically capturing absorption, food effect, and exposure of an amorphous solid dispersion formulated compound. This model allows evaluation of untested drug-drug interactions, especially those primarily occurring in the intestine, and paves the way for future modeling of biopharmaceutics classification system IV compounds.

Web-based triage in a college health setting.

The authors describe the initiation and use of a Web-based triage system in a college health setting. During the first 4 months of implementation, the system recorded 1,290 encounters. More women accessed the system (70%); the average age was 21.8 years. The Web-based triage system advised the majority of students to seek care within 24 hours; however, it recommended self-care management in 22.7% of encounters. Sore throat was the most frequent chief complaint (14.2%). A subset of 59 students received treatment at student health services after requesting an appointment via e-mail. The authors used kappa statistics to compare congruence between chief complaint and 24/7 WebMed classification (kappa = .94), between chief complaint and student health center diagnosis (kappa = .91), and between 24/7 WebMed classification and student health center diagnosis (kappa = .89). Initial evaluation showed high use and good accuracy of Web-based triage. This service provides education and advice to students about their health care concerns.

Reducing the risks of diabetes complications through diabetes self-management education and support.

People with diabetes are at risk of developing complications that contribute to substantial morbidity and mortality. In 2011, the American Association of Diabetes Educators convened an invitational Reducing Risks Symposium, during which an interdisciplinary panel of 11 thought leaders examined current knowledge about the reduction and prevention of diabetes-related risks and translated evidence into diabetes care and self-management education. Symposium participants reviewed findings from the literature and engaged in a moderated roundtable discussion. This report summarizes the discussion and presents recommendations to incorporate into practice to improve outcomes. The objective of the symposium was to develop practical advice for diabetes educators and other members of the diabetes care team regarding the reduction of diabetes-related risks. Optimal diabetes management requires patients to actively participate in their care, which occurs most effectively with a multidisciplinary team. Diabetes education is an integral part of this team approach because it not only helps the patient understand diabetes, its progression, and possible complications, but also provides guidance and encouragement to the patient to engage in proactive risk-reduction decisions for optimal health. A variety of tools are available to help the diabetes educator develop an individualized, patient-centered plan for risk reduction. More research is needed regarding intervention efficacy, best practices to improve adherence, and quantification of benefits from ongoing diabetes support in risk reduction. Diabetes educators are urged to stay abreast of evolving models of care and to build relationships with health care providers both within and beyond the diabetes care team.

Recommendations for managing patients with diabetes mellitus in cardiopulmonary rehabilitation: an American Association of Cardiovascular and Pulmonary Rehabilitation statement.

Diabetes mellitus is a highly prevalent condition in patients participating in cardiopulmonary rehabilitation. However, research and subsequent guidelines specifically applicable to patients with diabetes, participating in cardiopulmonary rehabilitation, are limited. Recognizing this limitation, the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) initiated this statement, with the goal of developing a template that incorporated recommendations provided in the AACVPR Core Components and the American Association of Diabetes Educators 7 Self-Care Behaviors. This statement describes key processes regarding evaluation, interventions, and expected outcomes in each of the core components for the management of patients with diabetes in a cardiopulmonary rehabilitation program.

Inhibitors of hepatitis C virus polymerase: synthesis and biological characterization of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines.

The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.