Kenneth Kulmatycki

Pharmacokinetic and pharmacodynamic interaction of vildagliptin and voglibose in Japanese patients with Type 2 diabetes.

OBJECTIVE To assess the extent of pharmacokinetic and pharmacodynamic interaction between vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4) enzyme, and voglibose, an α-glucosidase inhibitor widely prescribed in Japan, when coadministered in Japanese patients with Type 2 diabetes. METHODS In this open-label, randomized, 3-treatment, 3-period and 6-way crossover study, 24 Japanese patients with Type 2 diabetes received 50 mg vildagliptin twice daily; 50 mg vildagliptin twice daily co-administered with 0.2 mg voglibose three times daily; or 0.2 mg voglibose three times daily for 3 days in each period. Plasma concentrations of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin, and glucagon were determined from blood samples collected at steady state. RESULTS Exposure to vildagliptin 50 mg (area under the concentration-time curve from 0 to 12 hours (AUCτ,ss)) and maximum plasma concentration at steady state (Cmax,ss) was reduced by 23% and 34% respectively with co-administration of voglibose. The percentage of DPP-4 inhibition by vildagliptin remained unchanged when vildagliptin was given alone or co-administered with voglibose; maximum inhibition was 98.3 ± 1.4% (mean ± SD) for vildagliptin alone and 97.4 ± 1.1% with co-administration. Coadministration of vildagliptin and voglibose led to a greater increase in the active GLP-1 plasma concentration than did vildagliptin alone (geometric mean ratio 1.63 (90% CI, 1.30, 2.03), p = 0.0007). The combination of vildagliptin and voglibose also led to a significantly lower plasma glucose levels (p < 0.0001). CONCLUSIONS Plasma vildagliptin levels were decreased when voglibose was co-administered, although DPP- 4 inhibition remained unchanged. Co-administration led to significantly better pharmacodynamic response compared with each treatment alone, including higher active GLP-1 and lower glucose levels. The results indicate that this coadministration may be beneficial in the clinical situation. Vildagliptin and voglibose treatments, alone or when co-administered, were well tolerated in Japanese patients with Type 2 diabetes.

TORC1 inhibition enhances immune function and reduces infections in the elderly

Treating elderly subjects with two low-dose mTOR inhibitors that selectively block TORC1 led to a decrease in infection rates. Dialing down TORC1 dials up immunity Aging may be regulated by a discrete set of intracellular proteins including the mechanistic target of rapamycin (mTOR) kinase. mTOR functions within two multiprotein complexes called TORC1 and TORC2. Inhibition of TORC1 has extended life span in every species studied to date and ameliorated multiple aging-related pathologies including declining immune function. Mannick et al. now show that low-dose TORC1 inhibitor therapy in elderly humans decreased the incidence of all infections, improved influenza vaccination responses, and up-regulated antiviral immunity. Thus, targeting the TORC1 pathway that regulates aging may have clinical benefits for elderly humans including improvement in immune function and decreased infection rates. Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant (P = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly.

Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor.

OBJECTIVE An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. METHODS The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. RESULTS Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC(50) value of 5 μM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17β glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC(50) values of 1.66 ± 0.95 μM, 3.34 ± 0.64 μM, and 0.973 ± 0.11 μM, respectively. In the presence of steady state pradigastat concentrations, AUC(τ, ss) of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC(τ, ss) and C(max, ss) were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. CONCLUSION These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin.

Pradigastat disposition in humans: in vivo and in vitro investigations

Abstract 1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients. 2. Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans. 3. In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma. 4. In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigastat was completely bioavailable in the radiolabeled AME study and therefore completely absorbed. 5. Pradigastat is eliminated very slowly into the feces, presumably via the bile. Renal excretion is negligible. Oxidative metabolism is minimal. The extent to which pradigastat is eliminated via metabolism to M18.4 could not be established from these studies due to the inherent instability of glucuronides in the gastrointestinal tract.

Effect of Pradigastat, a Diacylglycerol Acyltransferase 1 Inhibitor, on the QTcF Interval in Humans

Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supratherapeutic concentrations of pradigastat on the QTc interval, 2 studies were conducted. The first study assessed the safety, tolerability, and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100, and 115 mg over 60 minutes) in healthy adults. Single intravenous doses were safe, well tolerated, and at the higher doses resulted in supratherapeutic pradigastat exposure. The second was a parallel, 3‐arm thorough QTc study in which healthy male subjects were randomized to pradigastat (115 mg intravenously), moxifloxacin (400 mg oral, positive control), or placebo. Following intravenous administration, pradigastat exposure peaked at 4 times the therapeutic concentration and did not prolong the baseline‐adjusted and placebo‐corrected QTc intervals. During the 60‐minute pradigastat infusion, a number of infusion reactions and a small mean decrease in QTc were observed. Both effects disappeared when the infusion was stopped, suggesting that an infusate excipient may have been responsible. As expected, moxifloxacin significantly increased the QTc interval at multiple points, confirming the studys sensitivity to detect a true positive effect. Pradigastat is therefore unlikely to increase the risk of dysrhythmias associated with QTc prolongation in humans.

TORC1 inhibition as an immunotherapy to reduce infections in the elderly

mTOR inhibition extends lifespan and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this Phase 2a clinical trial was to determine if low dose mTOR inhibitor therapy enhanced immune function and thereby decreased infection rates in elderly subjects. The results indicate that 6 weeks of treatment with a low dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor (that selectively inhibits TORC1 downstream of mTOR) was safe, significantly decreased the rate of infections reported by elderly subjects for a year following study drug initiation, upregulated antiviral gene expression, and significantly improved influenza vaccination response. Thus selective TORC1 inhibition with a combination of BEZ235 and RAD001 may be efficacious as immunotherapy to reduce infections, a leading cause of death in the elderly. One Sentence Summary Treatment of elderly subjects with a low dose mTOR inhibitor regimen that selectively inhibits TORC1 significantly decreased infection rates

Bioequivalence and food effect assessment for vildagliptin/metformin fixed-dose combination tablets relative to free combination of vildagliptin and metformin in Japanese healthy subjects.

OBJECTIVE To assess the bioequivalence of vildagliptin/metformin fixeddose combination (FDC) tablets (50/250 mg and 50/500 mg) to free combinations of vildagliptin and metformin and the effect of food on the pharmacokinetics (PK) of vildagliptin and metformin following administration of 50/500 mg FDC tablets. METHODS Two openlabel, randomized, single-center, singledose, 2-period crossover studies were conducted in Japanese healthy male volunteers. Participants were administered vildagliptin/ metformin FDC tablets (study I: 50/250 mg, study II: 50/500 mg) or their free combinations under fasted condition. Food effect (standard Japanese breakfast: fat, 20 - 30% with ~ 600 kcal in total) was assessed during an additional period in study II (50/500 mg). PK parameters (AUC, C(max), t(max), t(1/2)) were calculated for vildagliptin and metformin. RESULTS In both studies, vildagliptin/metformin FDC tablets were bioequivalent to their respective free combinations. Administration of FDC tablets after meals had no effect on vildagliptin PK parameters. The rate of absorption of metformin decreased when administered under fed condition, as reflected by a prolonged t(max) (3 hours in fasted state vs. 4 hours in fed state) and decrease in C(max) by 26%, however, the extent of absorption (AUC(last)) was similar to that in the fasted state. CONCLUSIONS Vildagliptin/metformin FDC tablets were bioequivalent to their free combinations. Food decreased the C(max) of metformin by 26%, while AUC(last) was unchanged, consistent with previous reports. No food effect was observed on the C(max) or AUC(last) of vildagliptin. Thus, food had no clinically relevant effects on the PK of metformin or vildagliptin.