Effect of a High-Fat Meal on Single-Dose Rencofilstat (CRV431) Oral Bioavailability in Healthy Human Subjects.

Rencofilstat (RCF) is a novel cyclophilin inhibitor under development for the treatment of nonalcoholic steatohepatitis and hepatocellular carcinoma. This phase 1, randomized, open-label study in healthy participants assessed the relative bioavailability of a single dose of RCF 225-mg soft gelatin capsules in both fasted and high-fat conditions. Forty-four participants were enrolled to either the fasted (n = 24) or the high-fat fed (n = 20) arm. Noncompartmental pharmacokinetics were evaluated following a single 225-mg oral dose. Administration of RCF with a high-fat meal led to increases in maximum concentration, area under the concentration-time curve (AUC) from time 0 to 24 hours, and AUC from time 0 to infinity fed-to-fasted geometric mean ratios of 102.2%, 114.5%, and 132.9%, respectively. All AUC geometric mean ratios were outside of the 80% to 125% range, suggesting that a high-fat meal can increase the extent of RCF exposure. Time to maximum concentration increased from 1.5 to 1.8 hours in the fasted and high-fat groups, respectively, suggesting slightly delayed absorption. High fat intake may delay gastric emptying while increasing the absorption and bioavailability of RCF. No treatment-emergent adverse events were observed in the fasted group, and 1 treatment-emergent adverse event occurred in the high-fat meal group. The differences in observed whole-blood concentrations are unlikely to have clinically relevant effects given the wide therapeutic index of RCF demonstrated in previous phase 1 studies.

Rencofilstat, a cyclophilin inhibitor: A phase 2a, multicenter, single-blind, placebo-controlled study in F2/F3 NASH.

Rencofilstat (RCF) demonstrated antifibrotic effects in preclinical models and was safe and well tolerated in Phase 1 studies. The aim of this Phase 2a study was safety, tolerability, pharmacokinetics, and exploration of efficacy biomarkers in subjects with nonalcoholic steatohepatitis (NASH). This Phase 2a, multicenter, single-blind, placebo-controlled study randomized 49 presumed F2/F3 subjects to RCF 75 mg once daily (QD), RCF 225 mg QD, or placebo for 28 days. Primary safety and tolerability endpoints were explored using descriptive statistics with post hoc analyses comparing active to placebo groups. Pharmacokinetics were evaluated using population pharmacokinetics methods. Efficacy was explored using biomarkers, transcriptomics, and lipidomics. RCF was safe and well tolerated, with no safety signals identified. The most frequently reported treatment-emergent adverse events were constipation, diarrhea, back pain, dizziness, and headache. No clinically significant changes in laboratory parameters were observed, and RCF pharmacokinetics were unchanged in subjects with NASH. Alanine transaminase (ALT) reduction was greater in active subjects than in placebo groups. Nonparametric analysis suggested that ALT reductions were statistically different in the 225-mg cohort compared with matching placebo: -16.3 ± 25.5% versus -0.7 ± 13.4%, respectively. ProC3 and C6M reduction was statistically significant in groups having baseline ProC3 > 15.0 ng/ml. RCF was safe and well tolerated after 28 days in subjects with presumed F2/F3 NASH. Presence of NASH did not alter its pharmacokinetics. Reductions in ALT, ProC3, and C6M suggest direct antifibrotic effects with longer treatment duration. Reductions in key collagen genes support a mechanism of action via suppression and/or regression of collagen deposition. Conclusion: These results support advancement of rencofilstat into a larger and longer Phase 2b study.

Clinical Pharmacists' Knowledge of and Attitudes toward Older Adults.

BACKGROUND: Although pharmacy literature suggests that pharmacists have a positive attitude towards older adults, there is a paucity of studies that have measured pharmacists' knowledge or attitudes towards older people. The purpose of our study was to assess the knowledge and attitudes of hospital pharmacists toward older adults. METHODS: An electronic survey was distributed over two months to clinical hospital pharmacists across the province of Alberta, Canada. The survey was composed of two validated tools, the Palmore Facts of Aging Quiz (PFAQ) and Kogan's Attitude toward Old People Scale (KOPS). PFAQ is scored from 0 (poor knowledge) to 25 (high knowledge) and KOPS from 34 to 204, with higher than 119 indicating a positive attitude. RESULTS: A total of 153 pharmacists completed the survey (response rate of 24%). The mean age was 39 (SD 10.8) years; the average years practiced was 15 (SD 11), and the majority of respondents (n = 65) reported that >50% of patients in their practice were geriatrics. The mean correct responses on the PFAQ were 18.8 (SD 2.6). KOPS had a mean score of 156.8 (SD 14), with only one pharmacist score falling below 119, indicating a negative attitude. There was a statistically significant, positive correlation between attitudes and knowledge (r = 0.38, p < 0.05), as well as the increasing age of the respondents (r = 0.18, p = 0.03). The remaining measured categories (i.e., gender, years of pharmacy practice) had no significant effect. CONCLUSION: Clinical hospital pharmacists in Alberta have a positive attitude toward geriatric patients, as well as a satisfactory knowledge of older adults.

Structurally distinct cyclosporin and sanglifehrin analogs CRV431 and NV556 suppress established HCV infection in humanized-liver mice.

We previously reported that the non-immunosuppressive cyclophilin inhibitors (CypIs)-cyclosporin A analog CRV431 and sanglifehrin analog NV556-efficiently inhibit HCV replication in vitro. In this study, we asked whether they can also reduce HCV replication in vivo. We found that a single oral administration of CRV431 and NV556 to HCV-infected humanized-liver mice drastically reduced HCV blood levels. The antiviral effect was observed when CRV431 or NV556 were each individually administered with HCV, 3, 6 weeks or even 3 months post-infection when viral replication is robust. These results were confirmed in chimeric mice implanted with human hepatocytes isolated from three distinct donors. Remarkably, no viral rebound was observed 5 months after a single dose administration of 50 mg/kg of CRV431 or NV556 four weeks post-HCV infection, indicating the possibility of suppression of an established viral infection. Since we recently demonstrated that both CRV431 and NV556 also inhibit the development of liver fibrosis and hepatocellular carcinoma in nonviral-induced non-alcoholic steatohepatitis mouse models, our present data suggest that the two entirely structurally different CypIs-CRV431 and NV556-derived from unrelated natural products, represent attractive partners to current direct-acting agent (DAA) regimens for the treatment of hepatitis C and liver diseases.

The impact of palliative care consults on deprescribing in palliative cancer patients.

PURPOSE: The transition from active cancer treatment to palliative care often results in a shift in drug risk-benefit assessment which requires the deprescribing of various medications. Deprescribing in palliative cancer patients can benefit patients by reducing their pill burden, decrease potential side effects, and potentially decrease healthcare costs. In addition, a change in patients' goals of care (GOC) necessitates the alteration of drug therapy which includes both deprescribing and the addition of medications intended to improve quality of life. Depending on a patient's GOC, a medication can be considered as inappropriate. OBJECTIVES: Primary: Comparison between potentially inappropriate medications (PIMs) prior to the palliative care consult (PCC) versus after the PCC. Secondary: Association between PIMs and GOC. METHODS: The study was a 1-year retrospective database review. The study included cancer patients seen by the PCC team at the University of Alberta Hospital. The OncPal guidelines were used to identify and determine the number of PIMs prior to the PCC and after the PCC. RESULTS: The reduction in PIMs prior to PCC versus after the PCC was statistically significant (p value < 0.001), demonstrating the PCC has a positive significant impact on deprescribing PIMs. For our secondary outcome, an overall decrease in PIMs was observed with the changes of GOC. The strength of the correlations was low (r < 0.1), and the p value was 0.056. CONCLUSION: This study shows the positive impact a PCC has on deprescribing and reveals the importance of using guidelines for deprescribing in palliative cancer patients.

Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH).

Introduction: Cyclophilins are a family of diverse regulatory enzymes that have been studied for over 30 years; they participate in many pathophysiological processes. Genetic deletion or pharmacologic inhibition of cyclophilins has shown therapeutic effects in a wide spectrum of disease models, including liver disorders, and hence may be beneficial in treating nonalcoholic steatohepatitis (NASH).Areas Covered: This articles briefly describes cyclophilin isomerases and the main classes of cyclophilin antagonists; it then summarizes data showing cyclophilin participation in the major pathophysiological activities that occur in NASH.Expert Opinion: Optimization of therapeutic outcomes in the treatment of NASH may be best realized by targeting multiple pathologic pathways, especially when treating advanced stages of the disease. A preferred approach for achieving this goal is to use compounds such as cyclophilin inhibitors that simultaneously target multiple disease processes. The pleiotropic benefits of this drug class derive from the extraordinary functionality of prolyl isomerization as a regulatory mechanism and its evolutionary diversification into many biochemical pathways. Nonimmunosuppressive analogs of cyclosporine A are the most thoroughly characterized cyclophilin inhibitors and show significant potential to attenuate several of the major pathophysiological events in NASH - mitochondrial dysfunction, cellular injury and death, inflammation, and in particular, fibrosis.

A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models.

Previous studies show that cyclophilins contribute to many pathologic processes, and cyclophilin inhibitors demonstrate therapeutic activities in many experimental models. However, no drug with cyclophilin inhibition as the primary mode of action has advanced completely through clinical development to market. In this study, we present findings on the cyclophilin inhibitor, CRV431, that highlight its potential as a drug candidate for chronic liver diseases. CRV431 was found to potently inhibit all cyclophilin isoforms tested-A, B, D, and G. Inhibitory constant or IC50 values ranged from 1 to 7 nM, which was up to 13 times more potent than the parent compound, cyclosporine A (CsA), from which CRV431 was derived. Other CRV431 advantages over CsA as a nontransplant drug candidate were significantly diminished immunosuppressive activity, less drug transporter inhibition, and reduced cytotoxicity potential. Oral dosing to mice and rats led to good blood exposures and a 5- to 15-fold accumulation of CRV431 in liver compared with blood concentrations across a wide range of CRV431 dosing levels. Most importantly, CRV431 decreased liver fibrosis in a 6-week carbon tetrachloride model and in a mouse model of nonalcoholic steatohepatitis (NASH). Additionally, CRV431 administration during a late, oncogenic stage of the NASH disease model resulted in a 50% reduction in the number and size of liver tumors. These findings are consistent with CRV431 targeting fibrosis and cancer through multiple, cyclophilin-mediated mechanisms and support the development of CRV431 as a safe and effective drug candidate for liver diseases. SIGNIFICANCE STATEMENT: Cyclophilin inhibitors have demonstrated therapeutic activities in many disease models, but no drug candidates have yet advanced completely through development to market. In this study, CRV431 is shown to potently inhibit multiple cyclophilin isoforms, possess several optimized pharmacological properties, and decrease liver fibrosis and tumors in mouse models of chronic liver disease, which highlights its potential to be the first approved drug primarily targeting cyclophilin isomerases.

Population Pharmacokinetics of Mycophenolic Acid Co-Administered with Tacrolimus in Corticosteroid-Free Adult Kidney Transplant Patients.

BACKGROUND AND OBJECTIVE: Mycophenolic acid is commonly prescribed to adult kidney transplant recipients. Mycophenolic acid is extensively metabolized to mycophenolic acid-glucuronide (major metabolite) and mycophenolic acid-acyl-glucuronide (minor metabolite). We hypothesized that (1) adult kidney transplant patients on corticosteroid-free regimens exhibit unique mycophenolic acid population pharmacokinetics compared with patients receiving corticosteroid-based therapy, and (2) mycophenolic acid clearance is directly dependent on glucuronide metabolite formation. METHODS: Non-linear mixed-effects modeling was conducted with MonolixSuite-2018R1 (n = 27). Optimal pharmacokinetic models were selected based on objective function values, standard errors, and biological plausibility. RESULTS: Clinical demographic data were sex (female, 16), age (47 ± 13 years, mean ± standard deviation), weight (70 ± 16 kg), height (165 ± 9 cm), albumin (43 ± 4 g/L), serum creatinine (102 ± 27 µmol/L), estimated glomerular filtration rate (61 ± 16 mL/min/1.73 m2), mycophenolic acid dosage (1.4 ± 0.5 g/day, as mycophenolate mofetil), and tacrolimus dosage (5 ± 3 mg/day, immediate release). The population pharmacokinetics of mycophenolic acid can be described by a two-compartment first-order absorption with lag time, and a linear elimination structural model. The apparent oral clearance estimate in the final model (population mean, relative standard error) was 2.87 L/h, 42.3%, which is lower than that reported for similar patients on corticosteroid-based regimens (11.9-26.3 L/h). Other pharmacokinetic parameters were comparable to historical data obtained in corticosteroid-based patients. Both mycophenolic acid-acyl-glucuronide trough concentration and the area under the concentration-time curve ratio were significant covariates that reduced mycophenolic acid apparent oral clearance from 16.5 (base model) to 2.87 L/h. The model was evaluated based on bootstrapping, visual predictive checks, and diagnostic plots. CONCLUSIONS: Our novel findings suggest the potential need to reduce mycophenolic acid dosage in subjects on corticosteroid-free regimens. Corticosteroid-free subjects may also be more sensitive to drug/gene interactions.

Population Pharmacokinetic Analysis of Immediate-Release Oral Tacrolimus Co-administered with Mycophenolate Mofetil in Corticosteroid-Free Adult Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVE: Tacrolimus is the mainstay calcineurin inhibitor frequently administered with mycophenolic acid with or without corticosteroids to prevent graft rejection in adult kidney transplant recipients. The primary objective of this study was to develop and evaluate a population pharmacokinetic model characterizing immediate-release oral tacrolimus co-administered with mycophenolate mofetil (a pro-drug of mycophenolic acid) in adult kidney transplant recipients on corticosteroid-free regimens. The secondary objective was to investigate the effects of clinical covariates on the pharmacokinetics of tacrolimus, emphasizing the interacting effects of mycophenolic acid. METHODS: Population modeling and evaluation were conducted with Monolix (Suite-2018R1) using the stochastic approximation expectation-maximization algorithm in 49 adult subjects (a total of 320 tacrolimus whole-blood concentrations). Effects of clinical variables on tacrolimus pharmacokinetics were determined by population covariate modeling, regression modeling, and categorical analyses. RESULTS: A two-compartment, first-order absorption with a lag-time, linear elimination, and constant error model best represented the population pharmacokinetics of tacrolimus. The apparent clearance value for tacrolimus was 17.9 l/h (6.95% relative standard error) in our model, which is lower compared with similar subjects on corticosteroid-based therapy. The glomerular filtration rate had significant effects on the apparent clearance and central compartment volume of distribution. Conversely, mycophenolic acid did not affect the apparent clearance of tacrolimus. CONCLUSION: We have developed and internally evaluated a novel population pharmacokinetic model for tacrolimus co-administered with mycophenolate mofetil in corticosteroid-free adult kidney transplant patients. These findings are clinically important and provide further reasons for conducting therapeutic drug monitoring in this specific population.

Dietary-Induced Obesity and Changes in the Biodistribution and Metabolism of Amiodarone in the Rat.

The metabolism and biodistribution of the antiarrhythmic drug amiodarone (AM) was assessed in male Sprague-Dawley rats given either normal chow or high-fat and high-fructose diets for 14 weeks. After the feeding period, microsomes were prepared from liver and intestine, and the metabolism of AM to desethylamiodarone was determined. Intrinsic clearance (CL) was reduced by hepatic microsomes isolated from rats given high-calorie diets. In intestinal microsomes, there was no change or a small increase in metabolic rate in obese rats. A biodistribution study was also undertaken in a group of control and high-fat + high fructose-fed rats. Excess calories led to a significant increase in plasma AM compared to normal chow-fed control animals. A population pharmacokinetic analysis of AM confirmed that its oral CL was reduced. In plasma, there was a decrease in the metabolite to drug ratio. Some tissue:plasma ratios of AM in high calorie-fed rats were aligned with a decrease in plasma unbound fraction. It is concluded that the findings reinforced those of a recent report where we found decreases in expressions of enzymes involved in AM dealkylation, in showing greater exposure and lower oral CL, and generally decreases in liver microsomal metabolism of AM after high-calorie diets.

Clinical prediction survival of advanced cancer patients by palliative care: a multi-site study.

AIMS: This study examined (1) accuracy of clinician prediction of survival (CPS) by palliative practitioners on first assessment with the use of standardised palliative tools, (2) factors affecting accuracy, (3) potential impact on clinical care. METHODS: A multi-site prospective study (n=1530) was used. CPS was divided into four time periods (<=2wks, >2 to 6wks, >6 to 12wks and >12wks). Multivariate analysis was assessed on six predictor variables. RESULTS: Overall, median survival of the sample was only 5 weeks. CPS category was accurate only 38.6% of the time, with 44.6% patients dying before the predicted time period. Of six candidate variables, on multivariate analysis only (i) the clinical time periods themselves and (ii) Palliative Performance Scale <=50 predicted for prognostic accuracy. CONCLUSION: CPS, even by palliative practitioners, remains overly optimistic with the existence of the horizon effect. This raises the question in that these individuals may have been potentially overtreated.

Cytochrome P450 3A and P-glycoprotein drug-drug interactions with voclosporin.

AIMS: Voclosporin is a novel calcineurin inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. Pharmacokinetic drug interactions between voclosporin and a CYP3A inhibitor, inducer and substrate and a P-glycoprotein inhibitor and substrate were evaluated. METHODS: Voclosporin 0.4 mg kg(-1) was administered to 24 subjects in each of five studies, as follows: every 12 h (Q12H) alone and concomitantly with ketoconazole 400 mg once daily (QD); single dose before and single dose after rifampin 600 mg QD; Q12H where midazolam 7.5 mg was administered as a single dose alone before voclosporin and with last the dose of voclosporin; Q12H alone and concomitantly with verapamil 80 mg every 8 h; and Q12H with digoxin 0.25 mg QD. The noncompartmental pharmacokinetic parameters maximal concentration (Cmax ) and area under the concentration-time curve (AUC) were obtained, and geometric least squares mean ratios and 90% confidence intervals were evaluated. RESULTS: Ketoconazole increased voclosporin Cmax (6.4-fold) and AUC (18-fold); rifampin reduced voclosporin AUC (0.9-fold); voclosporin did not change exposure of midazolam or α-hydroxy-midazolam; verapamil increased voclosporin Cmax (2.1-fold) and AUC (2.7-fold); and voclosporin increased digoxin Cmax (0.5-fold), AUC (0.25-fold) and urinary excretion (0.2-fold). CONCLUSIONS: Administration of voclosporin concomitantly with strong inhibitors and inducers of CYP3A resulted in increased and decreased exposures, respectively, and should be considered contraindicated. Drug-drug interactions involving voclosporin and CYP3A substrates are not expected. Administration of voclosporin concomitantly with inhibitors and substrates of P-glycoprotein resulted in increased voclosporin and substrate exposures, respectively. Appropriate concentration and safety monitoring is recommended with co-administration of voclosporin and P-glycoprotein substrates and inhibitors.

Voclosporin food effect and single oral ascending dose pharmacokinetic and pharmacodynamic studies in healthy human subjects.

Voclosporin (VCS) is a novel calcineurin (CN) inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the single ascending dose pharmacokinetics (PK) and pharmacodynamics (PD, CN activity) of VCS and the effect of food. VCS was administered orally in single doses of 0.25 through 4.5 mg/kg in 62 subjects in the single ascending dose study and as a single oral 1.5 mg/kg dose to 18 subjects after fasting, consumption of a low-fat and high-fat meal. Non-compartmental PK, PD, and PKPD correlation were evaluated. Following single oral doses, systemic exposure increased in a linear manner and demonstrated 1:1 dose-proportional, first-order linear PK above 1.5 mg/kg. VCS inhibited CN activity in a dose-related fashion with maximal inhibition peaking at 3.0 mg/kg. PKPD correlation indicated an EC50 of 78.3 ± 6.8 ng/mL. Administration of VCS with a low-fat and high-fat meal decreased C(max) by 29% and 53%, respectively, and AUC(inf) by 15% and 25%, respectively. Following ascending single doses of VCS, exposure increased in a linear fashion. A food effect on exposure was demonstrated, with a more pronounced effect following a high-fat meal. VCS concentrations were also found to correlate with CN activity.

Pain management in chronic kidney disease: the pharmacokinetics and pharmacodynamics of hydromorphone and hydromorphone-3-glucuronide in hemodialysis patients.

OBJECTIVE: To describe the pharmacokinetics of hydromorphone (HM) and its primary metabolite hydromorphone-3-glucuronide (H3G) both on and off dialysis in relation to the pharmacodynamic measurements of pain. DESIGN: Prospective, open-label, observational study. SETTING: Canadian, university-based renal program. PARTICIPANTS: Twelve anuric hemodialysis patients with chronic pain, established on immediate-release HM. MAIN OUTCOME MEASURES: HM and H3G plasma concentrations were measured during and between hemodialysis treatments using a reverse-phase high-performance liquid chromatography assay with liquid chromatography/mass spectrometer/mass spectrometer detection. The McGill Pain Questionnaire (MPQ) and a Visual Analogue Scale (VAS) were used to measure pain. Noncompartmental analyses were conducted. Adverse effects were recorded. RESULTS: HM did not substantially accumulate (accumulation factor R = 2.7 (1.6)), most likely due to the rapid conversion to H3G. Conversely, H3G accumulated between dialysis treatments (R = 12.5 (12.1)) but appeared to be effectively removed during hemodialysis (1.8 (0.7), p = 0.03). HM resulted in > 65 percent reduction in pain over dosing intervals. Mean MPQ pain scores decreased from 39.8 (18.2) to 12.3 (16.2) on dialysis and from 35.0 (18.5) to 15.5 (13.6) between dialysis treatments. Mean VAS pain scores decreased from 7.5 (2.5) to 3.0 (1.5) on dialysis and from 5.9 (3.2) to 4.4 (1.6) between dialysis treatments. No clinically significant opioid toxicity was observed. The accumulation of H3G between hemodialysis treatments was associated with greater sensory-type pain (r = 0.76, p < 0.0001) and reduced duration of analgesia. CONCLUSIONS: HM may be a safe and effective opioid for use in selected hemodialysis patients.

A randomized, multicenter, double-blind, placebo-controlled phase 2 trial of ISA247 in patients with chronic plaque psoriasis.

BACKGROUND: Use of current oral calcineurin inhibitors for the treatment of psoriasis is limited by toxicity. OBJECTIVE: Evaluate the safety and efficacy of ISA247, a new oral calcineurin inhibitor, in plaque psoriasis patients. METHODS: This 12-week, randomized, double-blind, placebo-controlled, parallel-group study included 201 plaque psoriasis patients with > or = 10% body surface area involvement. Patients were randomized to placebo, ISA247 0.5 mg/kg/d, and ISA247 1.5 mg/kg/d groups. End points included a 2-point reduction in the Static Global Assessment score and a 75% reduction in the Psoriasis Area and Severity Index. RESULTS: A 2-point SGA reduction was achieved in 0% (placebo), 15.6% (0.5 mg/kg/d), and 45.1% (1.5 mg/kg/d) (P < .0001). A 75% reduction in the Psoriasis Area and Severity Index was achieved in 0% (placebo), 18.2% (0.5 mg/kg/d), and 66.7% (1.5 mg/kg/day) (P < .0001). While serum creatinine increased in patients treated with ISA247 1.5 mg/kg/d, it remained within the normal range. LIMITATIONS: Longer-term studies are needed to evaluate the effect of ISA247 on renal function. CONCLUSION: ISA247 appears safe and effective for treating moderate to severe psoriasis.