Doses In Healthy Subjects Research Articles

Population Pharmacokinetic Model for Ertugliflozin in Healthy Subjects and Patients With Type 2 Diabetes Mellitus.

Ertugliflozin is a selective sodium‐glucose cotransporter 2 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). A population pharmacokinetic (popPK) model was developed to characterize the pharmacokinetics (PK) of ertugliflozin and quantify the influence of intrinsic (eg, body weight, age, sex, race, estimated glomerular filtration rate [eGFR], T2DM) and extrinsic (eg, food) covariates on the PK parameters of ertugliflozin. The analysis was conducted using data from 15 clinical studies (phases 1‐3) enrolling healthy subjects and patients with T2DM, which included 13,691 PK observations from 2276 subjects and was performed using nonlinear mixed‐effects modeling. A 2‐compartment popPK model with first‐order absorption and a lag time and first‐order elimination, described the plasma concentration–time profile of ertugliflozin after single and multiple dosing in healthy subjects and in patients with T2DM. Apparent clearance increased with increasing body weight and eGFR, was slightly lower in patients with T2DM and females, and was slightly higher in Asians. Apparent central volume of distribution increased with increasing body weight and was higher in females and Asians. Administration of ertugliflozin with food decreased the absorption rate constant (ka) and relative bioavailability (F1) compared with fasted. When ertugliflozin was administered without regard to food, estimates of ka and F1 were similar to those for administration with food. The popPK model successfully characterized ertugliflozin exposure in healthy subjects and patients with T2DM. None of the covariates evaluated had a clinically relevant effect on ertugliflozin PK.

Pharmacokinetic and Glucodynamic Responses of Ultra Rapid Lispro vs Lispro Across a Clinically Relevant Range of Subcutaneous Doses in Healthy Subjects

PurposeUltra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic and glucodynamic parameters of URLi and Lispro (Humalog®) at 3 dose levels in healthy subjects. MethodsThis randomized, 6-period, subject- and investigator-blind, crossover study included 42 healthy subjects. At each period, subjects received a single subcutaneous dose of 7, 15, or 30 U of URLi or Lispro followed by a 10-h automated euglycemic clamp. Insulin lispro and blood glucose concentrations were measured. FindingsAcross all 3 doses, insulin lispro appeared in the serum 2–5 min faster, and exposure was 6- to 8-fold greater in the first 15 min, with URLi versus Lispro. Exposure beyond 3 h postdose was 45%–52% lower, and duration of exposure was 67–86 min shorter with URLi versus Lispro for all dose levels. Onset of insulin action was 7–9 min faster and insulin action was ~3-fold greater in the first 30 min with URLi versus Lispro across the dose levels. Insulin action beyond 4 h was reduced by 32%–45%, and duration of action was reduced by 47–67 min, with URLi versus Lispro for all 3 dose levels. Overall exposure and total glucose infused were similar between URLi and Lispro at each dose level. Dose proportionality was observed for maximum and overall exposure after URLi. Less than dose-proportional increases in maximum and total glucose infused were observed and were similar for both URLi and Lispro. ImplicationsURLi exhibited ultra-rapid pharmacokinetic and glucodynamic parameters across all 3 dose levels studied and exhibited dose-proportional increases in exposure in healthy subjects. ClinicalTrials.gov identifier: NCT03286751.

In Vitro Activity of KBP-7072, a Novel Third-Generation Tetracycline, against 531 Recent Geographically Diverse and Molecularly Characterized Acinetobacter baumannii Species Complex Isolates.

KBP-7072 is a novel third-generation tetracycline (aminomethylcycline) antibacterial that overcomes common efflux and ribosomal protection resistance mechanisms that cause resistance in older-generation tetracyclines. KBP-7072 completed phase 1 clinical development studies for safety, tolerability, and pharmacokinetics (ClinicalTrials.gov identifier NCT02454361) and multiple ascending doses in healthy subjects (ClinicalTrials.gov identifier NCT02654626) in December 2015. Both oral and intravenous formulations of KBP-7072 are being developed. In this study, we evaluated the in vitro activities of KBP-7072 and comparator agents by CLSI document M07 (2018) broth microdilution against 531 recent geographically diverse and/or molecularly characterized Acinetobacter baumannii-A. calcoaceticus species complex (A. baumannii) isolates from the United States, Europe, Asia-Pacific (excluding China), and Latin America. A. baumannii isolates included carbapenem-resistant, colistin-resistant, tetracycline-resistant, and extended-spectrum-β-lactamase (ESBL)- and metallo-β-lactamase (MBL)-producing isolates. Overall, KBP-7072 (MIC50/90, 0.25/1 mg/liter) was comparable in activity to colistin (92.8%/92.8% susceptible [S] [CLSI/EUCAST]) against A. baumannii isolates, inhibiting 99.2% of isolates at ≤2 mg/liter and 97.6% of isolates at ≤1 mg/liter. KBP-7072 was equally active against A. baumannii isolates, including carbapenem-resistant, colistin-resistant, and tetracycline-resistant isolates, regardless of geographic location, and maintained activity against ESBL- and MBL-producing isolates. KBP-7072 outperformed comparator agents, including ceftazidime (40.3% S [CLSI]), gentamicin (48.2%/48.2% S [CLSI/EUCAST]), levofloxacin (39.5%/37.9% S [CLSI/EUCAST]), meropenem (42.0%/42.0% S [CLSI/EUCAST]), piperacillin-tazobactam (33.3% S [CLSI]), and all tetracycline-class comparator agents, which include doxycycline (67.3% S [CLSI]), minocycline (73.8% S [CLSI]), tetracycline (37.2% S [CLSI]), and tigecycline (79.5% inhibited by ≤2 mg/liter). The potent in vitro activity of KBP-7072 against recent geographically diverse, molecularly characterized, and drug-resistant A. baumannii isolates supports continued clinical development for the treatment of serious infections, including those caused by A. baumannii.

Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 cytolytic antibody TAK-079 in healthy subjects.

AimsThis investigation characterised tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 antibody TAK‐079.MethodsA randomised, double‐blind, placebo‐controlled trial of a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection of TAK‐079 at escalating doses in healthy subjects (n = 74), who were followed for 92 days postexposure.ResultsTAK‐079 was well tolerated. All adverse events were mild or moderate. There were no withdrawals, infusion, or injection site reactions over the tested i.v. and s.c. doses up to 0.06 and 0.6 mg kg−1, respectively. At higher doses, transient cytokine level increases, following i.v. administration, coincided with reduction in CD38‐expressing cells; clinical symptoms included mild pyrexia, headache, and postural hypotension. Following an i.v. infusion of 0.06 mg kg−1 TAK‐079, maximum observed serum concentration (C max) was 100.4 (%CV: 52) ng mL−1, time to C max was the end of infusion and natural killer (NK_ cells were reduced 93.8 (±8.5) % from baseline levels. Following a s.c. injection of 0.6 mg kg−1 TAK‐079, C max was 23.0 (%CV: 67) ng mL−1 with time to C max of 24 (range 7.98–96.02) hours, and plasmablasts were subsequently reduced 93.4 (±8.8) % from predose levels. Serum immunoglobulin (Ig)M, IgA and IgG levels were reduced by 15–60% and had not returned to baseline levels within 78 days after administration at ≥0.3 mg kg−1 s.c. Reductions in NK cells at 0.6 mg kg−1 s.c. were approximately 2–3 times more durable than at 0.06 mg kg−1 i.v.ConclusionsTAK‐079 was well tolerated and s.c. administration elicited more durable reductions in plasmablasts and NK cells. This plasmacytolytic profile could be useful for treating disorders caused by plasma or NK cells, malignant counterparts, and/or pathogenic antibodies.

Safety, tolerability and pharmacokinetics of a potent and selective histamine h3 receptor inverse agonist, SUVN-G3031 following single and multiple ascending doses in healthy subjects

Safety, tolerability and pharmacokinetics of a potent and selective histamine h3 receptor inverse agonist, SUVN-G3031 following single and multiple ascending doses in healthy subjects

ONCE DAILY ORAL DOSING OF RODATRISTAT ETHYL (RVT-1201) ACHIEVES REDUCTIONS IN SEROTONIN BIOSYNTHESIS COMPARABLE TO THOSE ASSOCIATED WITH REVERSAL OF VASCULAR REMODELING IN PAH ANIMAL MODELS

SESSION TITLE: Tuesday Electronic Posters 5 SESSION TYPE: Original Inv Poster Discussion PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM PURPOSE: RVT-1201, a pro-drug for the tryptophan hydroxylase (TPH) inhibitor KAR5417, is being developed for PAH. TPH1 is the rate-limiting enzyme for peripheral biosynthesis of serotonin (5HT), which has been implicated as a causative factor in PAH. RVT-1201 decreased pulmonary vessel wall thickness in 2 PAH rodent models indicating potential to halt/reverse pulmonary remodeling in humans. The median effective dose (100 mg/kg QD) in PAH rat models yielded a ∼35% reduction in 5-HT biosynthesis (based on reduction in urinary 5-HIAA, a metabolite of 5HT). Divided-dose pharmacodynamic (PD) studies in healthy rats (QD vs BID vs TID) demonstrated KAR5417 AUC, rather than Cmax or Cmin, best correlated with lowering of 5-HT, indicating QD dosing was as effective as more frequent dosing. The purpose of this study was to compare reductions in 5-HIAA levels following QD and BID dosing in healthy subjects. METHODS: 24 healthy subjects received 800 mg total daily oral doses of RVT-1201 or placebo (PBO), either as single (800mg QD) or divided (400mg BID) doses for 14 days across two cohorts (9 active: 3 PBO per cohort). KAR5417 plasma levels and change from Baseline (BSL) PD biomarker data (plasma and urine 5-HIAA) were compared between QD and BID cohorts at Day 14. Safety and tolerability were assessed via adverse event (AE) monitoring and laboratory, vital signs and ECG assessments. RESULTS: At Day 14, KAR5417 mean (±SD) AUC0-24 at 800 mg QD (9180 ng*h/mL, ± 4280) was comparable to the mean pAUC0-24 for 400 mg BID (10400 ng*h/mL, ± 3260). 5-HT lowering was similar across both dose regimens, with 800 mg QD achieving mean (± SD) 40.0 (6.32) % and 45.8 (6.59) % reductions in plasma and urinary 5-HIAA at D14, respectively, compared to 49.9 (9.52) % and 55.5 (10.3) % reductions, respectively, with the 400 mg BID regimen. Plasma and urinary 5-HIAA levels were not reduced from BSL in the PBO arms. 5-HIAA reductions in both regimens exceeded those associated with efficacy in the rodent models. Both dose regimens were generally well-tolerated. The overall incidence of GI-related AEs was greater in the QD group (78%) compared to the divided dose group (33%); however, most AEs were mild in intensity and there were no treatment-related withdrawals in either cohort. CONCLUSIONS: Repeated QD dosing of RVT-1201, an investigational treatment for PAH, reduced 5-HT biosynthesis similarly to divided (BID) daily dosing. Reductions in 5-HIAA levels were comparable to those associated with reversal of vascular remodeling in animal PAH models. RVT-1201 was generally well-tolerated in both dose regimens. CLINICAL IMPLICATIONS: RVT-1201 has the potential to reduce serotonin production and impact vascular remodeling in PAH patients. If ultimately proven effective, the potential to dose RVT-1201 once-daily may help improve overall treatment adherence in a disease like PAH in which patients often take more than one drug in combination chronically. DISCLOSURES: Employee relationship with Altavant Sciences Please note: >$100000 Added 02/05/2019 by David Carpenter, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: >$100000 Added 03/15/2019 by Katelyn Crizer, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: >$100000 Added 03/20/2019 by Laurence Keller, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: $1-$1000 Added 03/20/2019 by Laurence Keller, source=Web Response, value=Ownership interest Removed 03/20/2019 by Laurence Keller, source=Web Response Employee relationship with Altavant Sciences Please note: $20001 - $100000 Added 03/15/2019 by Thomas Pack, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: $20001 - $100000 Added 03/15/2019 by Michelle Palacios, source=Web Response, value=Salary No relevant relationships by Julie Rurka, source=Web Response No relevant relationships by Michele Snyder, source=Web Response Employee relationship with Altavant Sciences Inc Please note: >$100000 Added 03/18/2019 by Stephen Wring, source=Web Response, value=Salary

1179-P: Pharmacokinetics, Pharmacodynamics, and Safety of HD-6277, a Selective Agonist of G-Protein-Coupled Receptor 40, in Healthy Subjects as a First-in-Human Study

HD-6277 is a potent and selective G-protein-coupled receptor 40 agonist for the treatment of type 2 diabetes mellitus. Previous studies with HD-6277 showed enhanced glucose-stimulated insulin secretion and improved glycemic control in type 2 diabetic rodent models. To evaluate the potential benefits of HD-6277 on safety, tolerability, pharmacokinetics and pharmacodynamics, HD-6277 was investigated with six and four sequential cohorts in single and multiple ascending doses in healthy subjects as randomized, double-blind, placebo-controlled study, respectively. HD-6277 was well absorbed over all doses under fasting conditions and systemic exposure was increased in dose-dependent manner both in single and multiple ascending dose study. There was no severe or serious adverse events showing generally mild and transient profile, which suggested no safety concerns with the doses administered. Therefore, this study showed HD-6277 was safe and well tolerated in healthy subjects. Its exploratory efficacy on type 2 diabetes mellitus patients is currently under evaluation. Disclosure K. Kim: Employee; Self; Hyundai Pharmaceutical Co., Ltd. P. Kim: Employee; Self; Hyundai Pharmaceutical Co., Ltd. H. Yang: Employee; Self; Hyundai Pharmaceutical Co., Ltd. Funding Korean Ministry of Health and Welfare (HI17C2529)

0053 SUVN-G3031: Safety, Tolerability and Pharmacokinetics of a Potent and Selective Histamine H3 Receptor Inverse Agonist - Single and Multiple Ascending Doses in Healthy Subjects

0053 SUVN-G3031: Safety, Tolerability and Pharmacokinetics of a Potent and Selective Histamine H3 Receptor Inverse Agonist - Single and Multiple Ascending Doses in Healthy Subjects

Effect of food on the pharmacokinetics of YH4808, a potassium-competitive acid blocker, after single- and multiple-oral dosing in healthy subjects.

YH4808 is a potassium-competitive acid blocker, developed for the treatment of acid-related disorders. Two clinical studies in healthy male subjects were conducted to evaluate the effect of food on the pharmacokinetics of YH4808. The first study, a randomized, three-treatment, three-period, crossover study, compared pharmacokinetics of YH4808 (300mg) after a single dose at fed state with a standard or a high-fat meal to those at fasted state. The second study, a randomized, two-treatment, two-period, crossover study, investigated pharmacokinetics at fasted or fed state with a standard meal after twice daily dose of YH4808 (100mg) for 7days. Bloods for pharmacokinetic evaluation were sampled up to 48h post-dose and 24h post-dose at steady state, respectively. The pharmacokinetic parameters were estimated by non-compartmental method. After single dosing, the geometric means of maximum plasma concentration increased by 1.2 and 2.1 times in the fed states with a standard meal and a high-fat meal, respectively, of that in fasted state. Corresponding values of area under the plasma concentration-time curve (AUC) from time 0 to the last measurable time point increased by 1.8 and 2.8 times, respectively. After multiple dosing, the geometric mean for 24-h AUC at steady state slightly increased in fed state by 1.1 times of that in fasted state. As fat content of the food increased, the systemic exposure of YH4808 after single dosing increased. However, systemic exposures at steady state after multiple dosing between fasted and fed states were similar. ClinicalTrials.gov registry no.: NCT01520012.

Application of physiologically based pharmacokinetic modeling to the prediction of drug-drug and drug-disease interactions for rivaroxaban

Rivaroxaban is a direct oral anticoagulant with a large inter-individual variability. The present study is to develop a physiologically based pharmacokinetic (PBPK) model to predict several scenarios in clinical practice. A whole-body PBPK model for rivaroxaban, which is metabolized by the cytochrome P450 (CYP) 3A4/5, 2J2 pathways and excreted via kidneys, was developed to predict the pharmacokinetics at different doses in healthy subjects and patients with hepatic or renal dysfunction. Hepatic clearance and drug-drug interactions (DDI) were estimated by in vitro in vivo extrapolation (IVIVE) based on parameters obtained from in vitro experiments. To validate the model, observed concentrations were compared with predicted concentrations, and the impact of special scenarios was investigated. The PBPK model successfully predicted the pharmacokinetics for healthy subjects and patients as well as DDIs. Sensitivity analysis shows that age, renal, and hepatic clearance are important factors affecting rivaroxaban pharmacokinetics. The predicted fold increase of rivaroxaban AUC values when combined administered with the inhibitors such as ketoconazole, ritonavir, and clarithromycin were 2.3, 2.2, and 1.3, respectively. When DDIs and hepatic dysfunction coexist, the fold increase of rivaroxaban exposure would increase significantly compared with one factor alone. Our study using PBPK modeling provided a reasonable approach to evaluate exposure levels in special patients under special scenarios. Although further clinical study or real-life experience would certainly merit the current work, the modeling work so far would at least suggest caution of using rivaroxaban in complicated clinical settings.

A first-in-human, randomized, double-blind, placebo-controlled, single and multiple ascending oral dose study to assess the safety, tolerability, and pharmacokinetics of BZF961 with and without ritonavir in healthy adult volunteers

Objective: Infection with hepatitis C virus is the leading indication for liver transplantation and most common cause of infectious disease-related mortality in the United States. BZF961 is a novel inhibitor of the hepatitis C virus NS3-4A protease.Methods: This sequential, three part exploratory first-in-human study investigated the safety and pharmacokinetics of single and multiple ascending oral doses of BZF961 in healthy subjects. The first two parts were randomized, double-blind, placebo-controlled, time-lagged, single and multiple ascending oral dose segments. The third part analyzed the effect of ritonavir on BZF961 pharmacokinetics.Results: BZF961 was generally safe and well-tolerated in single and multiple oral doses in healthy subjects. There were no deaths and no serious adverse events. The most common adverse events were nausea and other gastrointestinal symptoms. Co-administration of ritonavir with BZF961 was well tolerated and increased BZF961 exposure by up to 60-fold, as well as reduced the overall exposure variability.Conclusions: BZF961 was generally safe and well-tolerated and its exposure was boosted by the co-administration of ritonavir.

Concizumab, an anti-tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay.

Concizumab, a humanized monoclonal antibody against tissue factor pathway inhibitor (TFPI), is being developed as a subcutaneously (s.c.) administered treatment for haemophilia. It demonstrated a concentration-dependent procoagulant effect in functional TFPI assays; however, global haemostatic assays, such as the thrombin generation assay (TGA), offer a more complete picture of coagulation. We investigated how concizumab affects thrombin generation following ex vivo spiking in plasma from haemophilia patients using the TGA, and if the assay can detect the effect of multiple s.c. concizumab doses in healthy subjects. For the ex vivo spiking study, platelet-poor plasma (PPP) from 18 patients with severe haemophilia was spiked with 0.001-500 nm concizumab. For the multiple-dosing study, four healthy males received concizumab 250 μg kg-1 s.c. every other day for eight doses; blood was collected before and after dosing and processed into PPP. In both studies, thrombin generation was measured using a Calibrated Automated Thrombogram® system with 1 pm tissue factor. In spiked samples from haemophilia patients, peak thrombin and endogenous thrombin potential (ETP) increased concentration dependently, reaching near-normal levels at concizumab concentrations >10 nm. Repeated s.c. doses of concizumab in healthy subjects increased both peak thrombin and ETP; these effects were sustained throughout the dosing interval. Thrombin generation assay demonstrated increased thrombin generation with concizumab after ex vivo spiking of haemophilia plasma and multiple s.c. doses in healthy subjects, supporting both the utility of the TGA in evaluating concizumab treatment and the potential of s.c. concizumab as a novel haemophilia therapy.

A phase I study to evaluate the pharmacokinetics of a new oncology nce, apatinib mesylate tablets, with and without food following single and multiple doses in healthy subjects.

e14049 Background: Apatinib Mesylate (YN968D1) is a selective inhibitor of VEGFR-2 being developed for the treatment of advanced gastric cancer. Objectives: 1. Evaluate single- and multiple-dose PKs 2. Evaluate food effect on bioavailability 3. Evaluate dose-proportionality 4. Determine CYP3A4 and 2C19 metabolic effects on the PKs Methods: Single ascending-dose (SAD), open-label, crossover of 2 oral doses of apatinib mesylate tablets (100 mg and 250 mg, [81 mg and 201 mg apatinib]) in healthy male and female volunteers with a minimum 3-day washout between dosing, plus a multiple ascending-dose (MAD), open-label, crossover study of the same doses. Both doses were administered with and without food in a crossover for the SAD and MAD parts. PK blood samples were collected for each dosing period. Subjects were genotyped for CYP3A4 and CYP2C19. WinNonlin 6.4 used for analysis. Results: 24 male and female subjects completed the SAD study section. They were extensive or intermediate metabolizers of CYP2C19, and 23/24 were normal metabolizers of CYP3A4. 22 male and female subjects completed the MAD study section. Most were extensive, intermediate or ultra-rapid metabolizers of CYP2C19; 21/22 subjects were normal metabolizers of CYP3A4. Conclusions: For the 100 mg dose in the SAD and MAD parts of the study, there was no significant food effect. For the 250 mg dose in SAD and MAD parts, food appeared to increase bioavailability by 20–30% in the SAD part, and 30–40% in the MAD part. Noncompartmental PK analysis of the SAD and MAD showed medium tmaxvalue delayed at 2 doses when apatinib was administered with food. Compartmental PK analysis showed food delayed initiation in absorption and reduced first order absorption rate constant. Dose proportionality was confirmed only for the AUC0-∞ value from the SAD-fasted cohort but inconclusive for Cmax and AUC parameters under other dosing regimens. Visual inspection of the effect of CYP2C19 genotype on the clearance of apatinib did not show correlation. Inspection of CYP3A4 genotype on the calculated clearance values was tenuous given the intermediate metabolizers (N = 1), compared to extensive metabolizers.

P469 Safety, tolerability, and pharmacokinetics of the intestine-restricted oral pan-Janus kinase inhibitor TD-1473 after single and multiple oral doses in healthy subjects

P469 Safety, tolerability, and pharmacokinetics of the intestine-restricted oral pan-Janus kinase inhibitor TD-1473 after single and multiple oral doses in healthy subjects

A Physiologically-Based Pharmacokinetic Modeling Approach To Predict Drug-Drug Interactions of Sonidegib (LDE225) with Perpetrators of CYP3A in Cancer Patients.

Sonidegib (Odomzo) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro. The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed. These data were used to verify a physiologically-based pharmacokinetic (PBPK) model developed to 1) bridge the clinical drug-drug interaction (DDI) study of sonidegib with KTZ and RIF in healthy subjects to the marketed dose (200 mg) in patients 2) predict acute (14 days) versus long-term dosing of the perpetrators with sonidegib at steady state and 3) predict the effect of moderate CYP3A perpetrators on sonidegib exposure in patients. Treatment of healthy subjects with KTZ resulted in an increased sonidegib exposure of 2.25- and 1.49-fold (area under the curve0-240h and maximal concentration respectively), and RIF decreased exposure by 72% and 54%, respectively. The model simulated the single- and/or multiple-dose PK of sonidegib (healthy subjects and patients) within ∼50% of observed values. The effect of KTZ and RIF on sonidegib in healthy subjects was also simulated well, and the predicted DDI in patients was slightly less and independent of sonidegib dose. At steady state, sonidegib was predicted to have a higher DDI magnitude with strong or moderate CYP3A perpetrators compared with a single dose. Different dosing regimens of sondigeb with the perpetrators were also simulated and provided guidance to the current dosing recommendations incorporated in the product label.

CYP2C9 Genotype-Dependent Warfarin Pharmacokinetics: Impact of CYP2C9 Genotype on R- and S-Warfarin and Their Oxidative Metabolites.

Multiple factors can impact warfarin therapy, including genetic variations in the drug-metabolizing enzyme cytochrome P450 2C9 (CYP2C9). Compared with individuals with the wild-type allele, CYP2C9*1, carriers of the common *3 variant have significantly impaired CYP2C9 metabolism. Genetic variations in CYP2C9, the primary enzyme governing the metabolic clearance of the more potent S-enantiomer of the racemic anticoagulant warfarin, may impact warfarin-drug interactions. To establish a baseline for such studies, plasma and urine concentrations of R- and S-warfarin and 10 warfarin metabolites were monitored for up to 360 hours following a 10-mg warfarin dose in healthy subjects with 4 different CYP2C9 genotypes: CYP2C9*1/*1 (n = 8), CYP2C9*1/*3 (n = 9), CYP2C9*2/*3 (n = 3), and CYP2C9*3/*3 (n = 4). Plasma clearance of S-warfarin, but not R-warfarin, decreased multiexponentially and in a CYP2C9 gene-dependent manner: 56%, 70%, and 75% for CYP2C9*1/*3, CYP2C9*2/*3, and CYP2C9*3/*3 genotypes, respectively, compared with CYP2C9*1/*1, resulting in pronounced differences in the S:R ratio that identified warfarin-sensitive genotypes. CYP2C9 was the primary P450 enzyme contributing to S-warfarin metabolism and a minor contributor to R-warfarin metabolism. In the presence of a defective CYP2C9 allele, switching of warfarin metabolism to other oxidative pathways and P450 enzymes for the metabolic elimination of S-warfarin was not observed. The 10-hydroxywarfarin metabolites, whose detailed pharmacokinetics are reported for the first time, exhibited a prolonged half-life with no evidence of renal excretion and displayed elimination rate-limited kinetics. Understanding the impact of CYP2C9 genetics on warfarin pharmacokinetics lays the foundation for future genotype-dependent warfarin-drug interaction studies.

Abstract CT153: Pharmacokinetic drug interactions between abemaciclib and CYP3A inducers and inhibitors

Abstract Abemaciclib is a selective and potent small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) being investigated for treatment of refractory hormone-receptor positive (HR+) advanced or metastatic breast cancer. In vitro, CYP3A is responsible for >99% of the CYP-mediated microsomal metabolism of abemaciclib and its active metabolites. Three clinical studies evaluated the disposition and metabolism and drug interaction potential of abemaciclib in the presence of a strong CYP3A-inducer, rifampin, or a strong CYP3A-inhibitor, clarithromycin. Abemaciclib disposition and metabolism were determined following a single oral 150 mg dose of [14C]-abemaciclib in healthy subjects (N = 6). In the rifampin interaction study, abemaciclib was administered as a single oral 200 mg dose in healthy subjects (N = 24) on 2 occasions: alone on Day 1 of Period 1 and in combination with 600 mg rifampin on Day 7 of Period 2, after 6 days of rifampin once daily (QD) dosing; rifampin continued QD for 7 days after abemaciclib. In the clarithromycin interaction study, abemaciclib was administered as a single oral 50 mg dose in patients with advanced cancer (N = 26) on 2 occasions: alone in Period 1 and on Day 5 of clarithromycin dosing (500 mg BID) in Period 2 followed by an additional 7 days of clarithromycin. Abemaciclib was extensively metabolized, with less than 10% of parent drug recovered unchanged in feces. Parent drug and 3 active metabolites; (LSN2839567 [M2], LSN3106729 [M18], and LSN3106726 [M20]) were detected in plasma. The mean t1/2 in healthy subjects was 29.0, 104.0, 55.9, and 43.1 hours for abemaciclib, M2, M18, and M20, respectively. Coadministration with rifampin compared to abemaciclib alone decreased abemaciclib AUC(0-?) and Cmax by 95% and 92%, respectively, and decreased AUC(0-?) and Cmax of total active species (abemaciclib + M2 + M18+ M20) by 77% and 45%, respectively. Coadministration with clarithromycin compared to abemaciclib alone increased abemaciclib AUC(0-?) and Cmax by 237% and 30%, respectively; and increased the total active species AUC(0-?) by 119% and decreased Cmax by 7%. The mean abemaciclib t1/2 was prolonged from 28.8 to 63.6 hours. No clinically significant safety concerns were observed following single doses of abemaciclib in healthy subjects or in patients with advanced cancer based on vital signs, clinical laboratory evaluations, and electrocardiogram data. The human absorption, distribution, metabolism and excretion study indicated that abemaciclib was cleared primarily by hepatic metabolism, and the clinical drug-drug interaction studies with strong CYP3A inducer and inhibitor substantiated the major role of CYP3A in the metabolism of abemaciclib. Due to significant changes in abemaciclib and active-metabolite exposure in the presence of strong CYP3A inducers and inhibitors, concomitant use with abemaciclib should be avoided, or abemaciclib dose may require adjustment. Citation Format: Palaniappan Kulanthaivel, Daruka Mahadevan, P. Kellie Turner, Jane Royalty, Wee Teck Ng, Ping Yi, Jessica Rehmel, Kenneth Cassidy, Jill Chappell. Pharmacokinetic drug interactions between abemaciclib and CYP3A inducers and inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT153.

Pharmacokinetics, pharmacodynamics and safety of CEP-26401, a high-affinity histamine-3 receptor antagonist, following single and multiple dosing in healthy subjects.

CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3 receptor (H3R) antagonist, with potential therapeutic utility in cognition enhancement. Two randomized, double-blind, placebo-controlled dose escalation studies with single (0.02 to 5 mg) or multiple administration (0.02 to 0.5 mg once daily) of CEP-26401 were conducted in healthy subjects. Plasma and urine samples were collected to investigate CEP-26401 pharmacokinetics. Pharmacodynamic endpoints included a subset of tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and nocturnal polysomnography. Population pharmacokinetic-pharmacodynamic modeling was conducted on one CANTAB and one polysomnography parameter of interest. CEP-26401 was slowly absorbed (median tmax range 3-6 hours) and the mean terminal elimination half-life ranged from 24-60 hours. Steady-state plasma concentrations were achieved within six days of dosing. CEP-26401 exhibits dose- and time-independent pharmacokinetics, and renal excretion is a major elimination pathway. CEP-26401 had a dose-dependent negative effect on sleep, with some positive effects on certain CANTAB cognitive parameters seen at lower concentrations. The derived three compartment population pharmacokinetic model, with first-order absorption and elimination, accurately described the available pharmacokinetic data. CEP-26401 was generally well tolerated up to 0.5 mg/day with most common treatment related adverse events being headache and insomnia. Further clinical studies are required to establish the potential of low-dose CEP-26401 in cognition enhancement.

Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, After Single and Multiple Doses in Healthy Subjects.

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once‐weekly DPP‐4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single‐dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP‐4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once‐weekly doses over the dose range studied. Omarigliptin resulted in ∼2‐fold increases in weighted average postprandial active GLP‐1. Omarigliptin acts by stabilizing active GLP‐1, which is consistent with its mechanism of action as a DPP‐4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once‐weekly dosing. A model‐based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.

Pharmacokinetics and bioavailability in healthy Chinese volunteers of a novel rabeprazole sterile powder formulation for injection.

Rabeprazole sterile powder for injection (RSPI) is a new formulation, compared with rabeprazole enteric coated tablets. The aim of this study was to evaluate the pharmacokinetic properties and bioavailability of RSPI in healthy Chinese volunteers. Pharmacokinetic studies included an ascending single dose of 10, 20, 40 mg, and a multiple doses of 20 mg. A bioavailability study was evaluated following a single dose of 20 mg between RSPI and Pariet® Pharmacokinetic parameters of rabeprazole given in each treatment period were calculated using non-compartmental analysis. In the PK study, after a single intravenous dose of 10, 20, and 40 mg, the main pharmacokinetic parameters for rabeprazole were as follows: Cmax 566.88, 897.23, 2,171.6 ng/mL; AUClast/794.31, 1,122.76, 2,446.85 ng×h/mL, respectively. After multiple doses of 20 mg, the main pharmacokinetic parameters for rabeprazole were Cmax 991.90 ng/mL, AUClast 1,261.08 ng×h/mL. In the BA study, after a single oral dose of Pariet® 20 mg, the main pharmacokinetic parameters for rabeprazole were Cmax 582.74 ng/mL, AUClast 1,135.5 ng×h/mL. RSPI produced a less-than-proportional increase in exposure with increasing dose in healthy subjects. The accumulation ratio was 1.0, suggesting RSPI displayed no accumulation after repeated administration. The bioavailability of RSPI was increased by ~ 11% as measured by AUClast compared with Pariet® after a single oral administration.