Inhibition of fatty acid synthase with FT-4101 safely reduces hepatic de novo lipogenesis and steatosis in obese subjects with non-alcoholic fatty liver disease: Results from two early-phase randomized trials.

AIMS: To assess the therapeutic potential of fatty acid synthase (FASN) inhibition with FT-4101, a potent, selective, orally bioavailable, small-molecule by (a) evaluating the dose-response of single FT-4101 doses (3, 6 and 9 mg) on hepatic de novo lipogenesis (DNL) in healthy participants (Study 1) and (b) demonstrating the safety, tolerability and efficacy on hepatic steatosis after 12 weeks of FT-4101 dosing in patients with non-alcoholic fatty liver disease (NAFLD; Study 2). MATERIALS AND METHODS: In Study 1, three sequential cohorts of healthy men (n = 10/cohort) were randomized to receive a single dose of FT-4101 (n = 5/cohort) or placebo (n = 5/cohort) followed by crossover dosing after 7 days. Hepatic DNL was assessed during fructose stimulation from 13 C-acetate incorporation. In Study 2, men and women with NAFLD (n = 14) randomly received 12 weeks of intermittent once-daily dosing (four cycles of 2 weeks on-treatment, followed by 1 week off-treatment) of 3 mg FT-4101 (n = 9) or placebo (n = 5). Steady-state DNL based on deuterated water labelling, hepatic steatosis using magnetic resonance imaging-proton density fat fraction and sebum lipids and circulating biomarkers were assessed. RESULTS: Single and repeat dosing of FT-4101 were safe and well tolerated. Single FT-4101 doses inhibited hepatic DNL dose-dependently. Twelve weeks of 3 mg FT-4101 treatment improved hepatic steatosis and inhibited hepatic DNL. Decreases in sebum sapienate content with FT-4101 at week 11 were not significant compared to placebo and rebounded at week 12. Biomarkers of liver function, glucose and lipid metabolism were unchanged. CONCLUSIONS: Inhibition of FASN with 3 mg FT-4101 safely reduces hepatic DNL and steatosis in NAFLD patients.

Clinical disposition, metabolism and in vitro drug-drug interaction properties of omadacycline.

1. Absorption, distribution, metabolism, transport and elimination properties of omadacycline, an aminomethylcycline antibiotic, were investigated in vitro and in a study in healthy male subjects. 2. Omadacycline was metabolically stable in human liver microsomes and hepatocytes and did not inhibit or induce any of the nine cytochrome P450 or five transporters tested. Omadacycline was a substrate of P-glycoprotein, but not of the other transporters. 3. Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300 mg oral dose of [14C]-omadacycline (36.6 µCi). Absorption was rapid with peak radioactivity (∼610 ngEq/mL) between 1-4 h in plasma or blood. The AUClast of plasma radioactivity (only quantifiable to 8 h due to low radioactivity) was 3096 ngEq h/mL and apparent terminal half-life was 11.1 h. Unchanged omadacycline reached peak plasma concentrations (∼563 ng/mL) between 1-4 h. Apparent plasma half-life was 17.6 h with biphasic elimination. Plasma exposure (AUCinf) averaged 9418 ng h/mL, with high clearance (CL/F, 32.8 L/h) and volume of distribution (Vz/F 828 L). No plasma metabolites were observed. 4. Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.

A Diacylglycerol Transferase 1 Inhibitor Is a Potent Hepatitis C Antiviral in Vitro but Not in Patients in a Randomized Clinical Trial.

Hepatitis C virus (HCV) infection is a significant cause of liver disease affecting 80-150 million people globally. Diacylglycerol transferase 1 (DGAT-1), a triglyceride synthesis enzyme, is important for the HCV life cycle in vitro. Pradigastat, a potent DGAT-1 inhibitor found to lower triglycerides and HgbA1c in patients, was investigated for safety and efficacy in patients with HCV. This was a two-part study. In the in vitro study, the effect of pradigastat on virus production was evaluated in infected cells in culture. In the clinical study ( https://clinicaltrials.gov/ct2/show/NCT01387958 ), 32 patients with HCV infection were randomized to receive pradigastat or placebo (26:6) once daily for 14 days. Primary efficacy outcomes were serum viral RNA and alanine aminotransferase levels. In vitro, pradigastat significantly reduced virus production, consistent with inhibition of viral assembly and release. However, the clinical study was prematurely terminated for lack of efficacy. There was no significant change in serum viral RNA levels after dosing with pradigastat or placebo for 14 days. Pradigastat was safe and well-tolerated in this population. Most treatment-emergent adverse events were gastrointestinal; there were no hepatic adverse events. Although pradigastat had a potent antiviral effect in vitro, no significant antiviral effect was observed in patients at predicted efficacious exposures.

A First-in-Human Study To Assess the Safety and Pharmacokinetics of Monoclonal Antibodies against Human Cytomegalovirus in Healthy Volunteers.

Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the function of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. Here, we evaluated the safety, tolerability, and pharmacokinetics of a single intravenous dose of LJP538 or LJP539 or their combination in healthy volunteers. Adverse events and laboratory abnormalities occurred sporadically with similar incidence between antibody and placebo groups and without any apparent relationship to dose. No subject who received antibody developed a hypersensitivity, infusion-related reaction or anti-drug antibodies. After intravenous administration, both LJP538 and LJP539 demonstrated typical human IgG1 pharmacokinetic properties, with slow clearances, limited volumes of distribution, and long terminal half-lives. The pharmacokinetic parameters were linear and dose proportional for both antibodies across the 50-fold range of doses evaluated in the study. There was no apparent impact on pharmacokinetics when the antibodies were administered alone or in combination. CSJ148 and the individual monoclonal antibodies were safe and well tolerated, with pharmacokinetics as expected for human immunoglobulin.

Evaluation of an Automated Falls Detection Device in Nursing Home Residents.

OBJECTIVES: To determine the concordance between falls recorded using an investigational fall detection device and falls reported by nursing staff in a nursing home. DESIGN: Six-month prospective study. SETTING: Hebrew SeniorLife nursing home units in Boston, Massachusetts. PARTICIPANTS: Nursing home residents with a documented history of at least one fall within 12 months before consent (N = 62, mean age 86.2 ± 8.1, 66% female). INTERVENTION: Subjects continuously wore an automated falls detection device on a pendant around their neck. The device contained triaxial accelerometers set to detect a rapid change in position that was interpreted as a fall. MEASUREMENTS: Healthcare staff reported daily falls, defined as unexpected events in which residents were found on the floor, and the number of these falls was compared with the number of falls recorded according to the device. RESULTS: Seven of 37 residents whom nursing staff found on the floor had a fall recorded according to the device (19%). The device did not identify any of the clinical fall events in 23 of the 37 fallers (62%). The device detected 17 of 89 total falls that nursing staff recorded (sensitivity 19%) within an 8-hour time window. Of 128 fall events that the device recorded, 17 were concordant with nursing reports (13%) within an 8-hour time window, and 111 (87%) were false positives. CONCLUSION: There is poor concordance between falls recorded using the investigational fall detection device and falls to the floor that nursing home staff report.

The effects of CYP3A4 induction and inhibition on the pharmacokinetics of alisporivir in humans.

In vitro data suggest that alisporivir is a substrate and inhibitor of CYP3A4 and P-gp. Hence, the potential for drug-drug interactions when alisporivir is co-administered with CYP3A4 and/or P-gp inhibitors such as ketoconazole, azithromycin and CYP3A4 inducers such as rifampin were evaluated in three separate clinical studies. Co-administration with ketoconazole (a strong CYP3A4 inhibitor) increased the Cmax , AUC and terminal elimination half-life of alisporivir by approximately two-, eight- ,and threefold, respectively. Co-administration with azithromycin (a putative weak CYP3A4 inhibitor and substrate) had no impact on the Cmax and AUC of alisporivir. Rifampin (a CYP3A4 inducer) caused an approximate 90% reduction in alisporivir Cmax and AUC and a fourfold reduction in alisporivir terminal elimination half-life. Alisporivir as an inhibitor of CYP3A4 caused a 39% increase in azithromycin exposure. The results from these studies establish alisporivir as a sensitive CYP3A4 substrate in vivo. Consequently, co-administered potent CYP3A4 inhibitors and inducers are likely to cause clinically significant changes in the exposure to alisporivir.

Sex differences in cyclosporine pharmacokinetics and ABCB1 gene expression in mononuclear blood cells in African American and Caucasian renal transplant recipients.

Cyclosporine exhibits pharmacokinetic and pharmacodynamic variability in renal transplant recipients (RTR) attributed to P-glycoprotein (P-gp), an ABCB1 efflux transporter that influences bioavailability and intracellular distribution. Data on race and sex influences on P-gp in RTR are lacking. We investigated sex and race influences on cyclosporine pharmacokinetics and ABCB1 gene expression in peripheral blood mononuclear cells (PBMC). Fifty-four female and male African American and Caucasian stable RTR receiving cyclosporine and mycophenolic acid completed a 12-hour study. ABCB1 gene expression was assessed in PBMCs pre-dose and 4 hours after cyclosporine. Statistical analysis used mixed effects models on transformed, normalized ABCB1 expression and cyclosporine pharmacokinetics. Sex and race differences were observed for the dose-normalized area under the concentration curve (AUC0-12 /Dose) [P = .0004], apparent clearance [P = .0004] and clearance/body mass index (CL/BMI) [P = .027] with slowest clearance and greatest drug exposure in females. Sex and race differences were found pre-dose and 4 hours for ABCB1 [P < .0001] with females having less expression than males. ABCB1 differences were observed between pre-dose and 4 hours [P = .0009]. Female RTR had slower cyclosporine clearance and lower ABCB1 gene expression in PBMC suggesting reduced efflux activity and greater intracellular drug exposure.

Mycophenolic acid pharmacokinetics during maintenance immunosuppression in African American and Caucasian renal transplant recipients.

Renal transplant recipients exhibit variability in mycophenolic acid (MPA) and MPA glucuronide (MPAG) pharmacokinetics, which are influenced by clinical and demographic factors. Racial influence on MPA and MPAG pharmacokinetics was investigated in 53 patients: 17 African American males, 22 Caucasian males, and 14 females receiving mycophenolate mofetil (MMF) and cyclosporine. A 12-hour steady-state pharmacokinetic study was conducted. Enterohepatic circulation of MPA was characterized by a second plasma concentration peak and was included in a novel statistical model with MPAG. MPA clearance in African American males was 26.5 ± 14.4 L/h versus 17.9 ± 6.1 L/h in Caucasian males (P = .035) and 16.1 ± 4.6 L/h in Caucasian females (P = .024) with no difference noted in MPA troughs. Enterohepatic circulation occurred less frequently in African American males (23%) compared with Caucasian males (42%) and Caucasian females (50%) (P > .05). Cyclosporine exposure was correlated with MPA and MPAG pharmacokinetics, whereas creatinine clearance influenced MPAG pharmacokinetics. A racial difference was noted with more rapid MPA clearance in African American males compared with Caucasians. The results support differential MPA dosing and the role of therapeutic drug monitoring in addition to considering the influence of renal function and concurrent immunosuppressives on MPA and MPAG pharmacokinetics.

Ketoconazole increases fingolimod blood levels in a drug interaction via CYP4F2 inhibition.

The sphingosine-1-phosphate receptor modulator fingolimod is predominantly hydroxylated by cytochrome CYP4F2. In vitro experiments showed that ketoconazole significantly inhibited the oxidative metabolism of fingolimod by human liver microsomes and by recombinant CYP4F2. The authors used ketoconazole as a putative CYP4F2 inhibitor to quantify its influence on fingolimod pharmacokinetics in healthy subjects. In a 2-period, single-sequence, crossover study, 22 healthy subjects received a single 5-mg dose of fingolimod in period 1. In period 2, subjects received ketoconazole 200 mg twice daily for 9 days and a single 5-mg dose of fingolimod coadministered on the 4th day of ketoconazole treatment. Ketoconazole did not affect fingolimod t(max) or half-life, but there was a weak average increase in C(max) of 1.22-fold (90% confidence interval, 1.15-1.30). The AUC over the 5 days of ketoconazole coadministration increased 1.40-fold (1.31-1.50), and the full AUC to infinity increased 1.71-fold (1.53-1.91). The AUC of the active metabolite fingolimod-phosphate was increased to a similar extent by 1.67-fold (1.50-1.85). Ketoconazole predose plasma levels were not altered by fingolimod. The magnitude of this interaction suggests that a proactive dose reduction of fingolimod is not necessary when adding ketoconazole to a fingolimod regimen. The clinician, however, should be aware of this interaction and bear in mind the possibility of a fingolimod dose reduction based on clinical monitoring.

Vildagliptin, a novel dipeptidyl peptidase IV inhibitor, has no pharmacokinetic interactions with the antihypertensive agents amlodipine, valsartan, and ramipril in healthy subjects.

We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC0-24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.

Evaluation of the potential for steady-state pharmacokinetic interaction between vildagliptin and simvastatin in healthy subjects.

BACKGROUND: Vildagliptin is an orally active, potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), the enzyme responsible for the degradation of incretin hormones. By enhancing prandial levels of incretin hormones, vildagliptin improves glycemic control in type 2 diabetes. Co-administration of vildagliptin and simva statin, an HMG-CoA-reductase inhibitor may be required to treat patients with diabetes and dyslipidemia. There fore, this study was conducted to determine the potential for pharmacokinetic drug-drug interaction between vildagliptin and simvastatin at steady-state. METHODS: An open label, single center, multiple dose, three period, crossover study was conducted in 24 healthy subjects. All subjects received once daily doses of either vildagliptin 100 mg or simvastatin 80 mg or the combination for 7 days with an inter-period washout of 7 days. Plasma levels of vildagliptin, simvastatin, and its active metabolite, simvastatin beta-hydroxy acid (major active metabolite of simvastatin) were determined using validated LC/MS/MS methods. Pharmacokinetic and statistical analyses were performed using WinNonlin and SAS, respectively. RESULTS: The 90% confidence intervals of C(max) and AUC(tau) of vildagliptin, simvastatin, and simvastatin beta-hydroxy acid were between 80 and 125% (bioequivalence range) when vildagliptin and simvastatin were admin istered alone and in combination. These data indicate that the rate and extent of absorption of vildagliptin and simvastatin were not affected when co-administered, nor was the metabolic conversion of simvastatin to its active metabolite. All treatments were safe and well tolerated in this study. CONCLUSIONS: The pharmacokinetics of vildagliptin, simvastatin, and its active metabolite were not altered when vildagliptin and simvastatin were co-administered.

Engraftment and tumorigenesis of HTLV-1 transformed T cell lines in SCID/bg and NOD/SCID mice.

Human T cell leukemia/lymphoma virus type-1 (HTLV-1) is recognized as the etiological agent of adult T cell leukemia (ATL). Although HTLV-1 can immortalize human lymphocytes in culture, identification of molecular events leading to tumorigenesis after HTLV-1 infection remain elusive. SCID/bg and NOD/SCID mice have reduced natural killer (NK) cell activity and were inoculated intraperitoneally with HTLV-1 transformed cells to refine and characterize the SCID mouse as a small animal model for investigation of HTLV-1 tumorigenesis. HTLV-1 transformed cell lines originally derived by cocultivation of uninfected peripheral blood mononuclear cells (PBMC) with lethally irradiated leukemic cells from patient samples (SLB-1, MT-2 and HT-1-RV) were lymphomagenic when inoculated into NOD/SCID mice. In contrast, immortalized cell lines generated by transfection PBMC with an infectious molecular clone of HTLV-1 (ACH or ACH.p12) were not tumorigenic. The differing behaviors of HTLV-1 infected cell lines in NOD/SCID mice indicates that viral infection and immortalization of human PBMC for growth in culture is not sufficient for induction of a tumorigenic phenotype. The higher level of engraftment of HTLV-1 transformed cell lines in NOD/SCID mice suggests that this is an effective animal model to investigate molecular determinants of HTLV-1 lymphomagenesis.