Introduction VLX-1005 is a novel small molecule inhibitor of platelet-type 12-lipoxygenase (12-LOX) intended for the prevention or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). Argatroban, a direct thrombin inhibitor, is currently the only agent approved in the U.S. for use in HIT. Its use is associated with a substantial risk of major bleeding in HIT patients, and a stubbornly high rate of thrombosis. As VLX-1005 and argatroban are co-administered in the ongoing VLX-1005-003 ALATHEA (A study of VLX-1005 to evaLuAte Thrombocyte change in HEpArin Induced Thrombocytopenia) clinical trial in HIT patients, the present study was designed to characterize the safety and tolerability of these agents alone and in combination, and the pharmacokinetics and pharmacodynamics and potential interaction of both agents in a population of healthy subjects. Methods This was a 3-period, open-label, Phase I, drug-drug interaction (DDI) study of VLX-1005 and argatroban, each administered intravenously via PICC line to healthy volunteers. Treatment A was argatroban (5 mcg/kg/min constant IV infusion for 6 hours without a loading dose). Treatment B was VLX-1005 (400 mg IV over 1 hour). Treatment C was argatroban at 5 mcg/kg/min constant IV infusion for 6 hours, VLX-1005 dosed at 400 mg IV over 60 minutes from 180 minutes to 240 minutes from the start of the argatroban infusion. Twelve (12) healthy male or female (non-lactating and not of childbearing potential) subjects aged 19 to 55 inclusive, were randomized to 1 of 3 treatment sequences: A-B-C or B-C-A, or C-A-B with a 1-week washout period between each period to avoid carryover effects. During each treatment period, monitoring of vital signs, laboratory tests (hematology, clinical biochemistry, and coagulation studies with monitoring of aPTT), and 12-lead ECG was conducted by appropriately trained personnel. Telemetry was performed for 24-hour time periods postdose in each treatment. PK samples were obtained in each treatment period, analyzed and PK parameters calculated. Results A total of 12 participants received study treatments, and 11 participants completed the full dosing period. One participant (Treatment Sequence A-B-C) was discontinued by the investigator on Day 3 of Period 2 due to behavioral issues and noncompliance with clinic rules. There were no discontinuations or study disruptions because of treatment. There were 12 participants included in the safety analyses and 11 participants included in the PK analyses. There were no deaths, SAEs, or participant discontinuations due to AEs in this study. The incidence of AE reporting was minimal and was observed to be similar across the 3 treatments. The most common event reported overall was vessel puncture site pain, reported by 3 [25%] participants, followed by vessel puncture site bruise and rhinorrhea (2 [17%] participants each). The investigator considered 18 of the 28 TEAEs to be mild (grade 1) and 10 to be moderate (grade 2); all events resolved. Coadministration of argatroban and VLX-1005 had no effect on the PK of either drug and no impact on the effect of argatroban on activated partial thromboplastin time (aPTT) in healthy human adult participants. Conclusions All treatment regimens appeared to be safe and well tolerated by the male and female healthy human subjects in this study; no evidence of increased bleeding was noted across treatment groups. Coadministration of argatroban and VLX-1005 had no effect on the PK of either drug. The administration of VLX-1005 had no effect on aPTT in healthy human adult subjects. The coadministration of VLX-1005 with argatroban had no impact on the effect of argatroban on aPTT in healthy human adult subjects. The Phase 2 ALATHEA (A study of VLX-1005 to evaLuAte Thrombocyte change in HEpArin Induced Thrombocytopenia) study of VLX-1005 in HIT is currently ongoing.

ABSTRACT Immunocompromised patients are susceptible to fungal infections, and drug-drug interactions with antifungals may occur due to concomitant medications. Fosmanogepix [FMGX; active moiety manogepix (MGX)] targets glycosylphosphatidylinositol-anchored mannoprotein synthesis and maturation, essential for fungal virulence. This phase 1, fixed-sequence study in healthy participants evaluated the effect of strong CYP3A4 inhibitor itraconazole [Cohort 1 ( n = 18); FMGX 500 mg intravenous (IV) twice a day (BID )+ itraconazole 200 mg oral once a day (QD)] and pan-CYP inducer rifampin [Cohort 2 ( n = 18); FMGX 1,000 mg IV BID + rifampin 600 mg oral QD] on the pharmacokinetics of FMGX and MGX. In cohort 1, geometric mean (GM) MGX C max , AUC 0-t , and AUC inf were almost similar with and without itraconazole administration. In Cohort 2, GM MGX C max was slightly lower and AUC 0-t and AUC inf were significantly lower after rifampin administration, with the least squares GM ratio associated 90% confidence intervals (CIs) below 80 – 125% (no effect window). No deaths, serious adverse events (SAEs), or FMGX-related withdrawals were reported. In both cohorts, a total of 188 AEs ( n = 30; 186 mild; two moderate) were reported. In all, 37 of 188 AEs ( n = 12) were considered FMGX related (most frequent: headache, nausea, and hot flush). Administration of FMGX alone and with itraconazole or rifampin was safe and well tolerated. A strong CYP3A4 inhibitor had no effect on FMGX or MGX exposure. A strong pan-CYP inducer had no effect on FMGX exposure but demonstrated ~45% decrease in MGX exposure. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT04166669 and with EudraCT as number 2019-003586-17.

ABSTRACT Fosmanogepix [FMGX, APX001; active form: manogepix (MGX), APX001A] is a first-in-class, intravenous (IV)/oral antifungal currently being evaluated for invasive fungal disease treatment. Data from two phase 1, placebo-controlled studies [IV–oral switch (study 1) and multiple IV doses (study 2)] evaluating FMGX tolerability, and pharmacokinetics (PK) are presented. Healthy adults (study 1: 18–65 years; study 2: 18–55 years) were eligible (randomized 3:1 to FMGX: placebo). Eleven participants completed study 1. In study 2, 51 participants (48 planned + 3 replacement) were enrolled in six cohorts (8 participants each; 34 completed the study). In study 1, overall MGX systemic exposures were comparable from day 1 to day 42 of dosing; steady-state plasma concentrations were achieved in ≤24 h following two IV loading doses (1,000 mg) and exposures maintained after switching [IV (600 mg) to daily oral doses (800 mg)]. FMGX was safe and well-tolerated. In study 2, FMGX IV doses (loading doses twice daily/maintenance doses once daily; 3-h infusion) of 1,500/900 mg (cohort A), 900/900 mg (cohort B), and 1,000/900 mg (cohort C: with ondansetron) were not well-tolerated; most participants reported nausea and infrequent vomiting. FMGX IV doses of 1,000/750 mg (cohort D), 1,000/850 mg (cohort E), and 1,000/900 mg (cohort F: ondansetron prn) were relatively better tolerated. Steady-state systemic exposures were achieved between days 2 and 4. All cohorts had similar geometric mean (GM) concentrations during maintenance dosing and similar GM PK parameters. Dosing regimen evaluated in study 1 was safe, well-tolerated, and may be used for future clinical evaluations.

Fosmanogepix (FMGX, APX001), a first-in-class, intravenous (i.v.) and oral (p.o.) antifungal prodrug candidate is currently in clinical development for the treatment of invasive fungal infections. Manogepix (MGX, APX001A), the active moiety of FMGX, interferes with cell wall synthesis by targeting fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, thereby causing loss of cell viability.

OBJECTIVES:Fosmanogepix (APX001), a first-in-class, intravenous (IV) and oral (PO) antifungal prodrug, is being developed to treat invasive fungal diseases (IFDs). Manogepix (APX001A; active moiety) targets fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, inhibiting cell wall synthesis causing loss of viability. This open-label, multicentre, Phase 1b study in patients with AML and neutropenia (absolute neutrophil count <500 cells/μL; >10 days) undergoing chemotherapy aimed to assess tolerability, safety and pharmacokinetics (PK) of IV and PO fosmanogepix. METHODS:Of 21 adult AML patients undergoing remission induction chemotherapy, 10 received IV fosmanogepix (600 mg; q24h) and 11 received oral fosmanogepix (500 mg; q24h) over 14 days, with a 28 day follow-up. Patients also received remission induction chemotherapy [sequential high-dose cytarabine and mitoxantrone (S-HAM) or 7 + 3 regimen] for AML and IFD prophylaxis (posaconazole). A two-compartmental PK model from previous studies in healthy volunteers was fitted to manogepix plasma data. RESULTS:Of 26 fosmanogepix-related adverse events (AEs; IV: 14; PO: 12) in 9 (42.9%) patients [IV: 5 (50%); PO: 4 (36.4%)], none were serious or resulted in fosmanogepix discontinuation. Most frequently occurring fosmanogepix-related AEs were Grade 1/2 nausea [four events in three patients (14.3%)]; vomiting, ALT increase, and delirium [two events; two patients (9.5%) each]. One patient experienced fosmanogepix-related Grade 3 hypertension. Dose-corrected geometric mean ratio of AUC (PO-to-IV) was 95%. Elimination half-lives (∼2 days) were consistent with prior studies in healthy volunteers. CONCLUSIONS:Fosmanogepix was safe and well tolerated in AML patients with neutropenia receiving remission induction chemotherapy. Safety and PK profiles were comparable to healthy volunteers.

Abstract Background Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is an oral potassium binder for the treatment of hyperkalemia in adults. SZC acts in the gastrointestinal tract and additionally binds hydrogen ions in acidic environments like the stomach, potentially transiently increasing gastric pH and leading to drug interactions with pH-sensitive drugs. This study assessed potential pharmacokinetic (PK) interactions between SZC and nine pH-sensitive drugs. Methods In this single-dose, open-label, single-sequence cross-over study in healthy adults, amlodipine, atorvastatin, clopidogrel, dabigatran, furosemide, glipizide, levothyroxine, losartan or warfarin were each administered alone and, following a washout interval, with SZC 10 g. Maximum plasma concentration (Cmax), area under the plasma concentration–time curve from 0 to the last time point (AUC0–t) and AUC extrapolated to infinity (AUCinf) were evaluated. No interaction was concluded if the 90% confidence interval for the geometric mean ratio (SZC coadministration versus alone) of the PK parameters was within 80–125%. Results During SZC coadministration, all PK parameters for amlodipine, glipizide, levothyroxine and losartan showed no interaction, while reductions in clopidogrel and dabigatran Cmax, AUC0–t and AUCinf (basic drugs) were <50% and increases in atorvastatin, furosemide and warfarin Cmax (acidic drugs) exceeded the no-interaction range by ˂2-fold. Conclusions SZC coadministration was associated with small changes in plasma concentration and exposure of five of the nine drugs evaluated in this study. These PK drug interactions are consistent with transient increases in gastric pH with SZC and are unlikely to be clinically meaningful.

Purpose: To evaluate the ocular safety of OTX-101 0.09% - a novel, nanomicellar, clear, aqueous solution of cyclosporine (CsA) - and to determine the systemic exposure to CsA following ophthalmic administration. Patients and methods: Healthy volunteers >= 18 years of age were recruited for participation in this phase 1, open-label, single-center, single-arm, study. Subjects received one drop of OTX-101 0.09% in each eye every 12 hours for 7 days, and once on day 8. Blood samples were collected predose, and 0.25, 0.5, 1, 2, 4, 8, and 12 hours post-first dose on day 1 and day 8. CsA levels in whole blood samples were analyzed using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters (maximal whole blood concentration [C-max, ng/mL], time to C-max [T-max, hours]), and area under the concentration-time curve from 0 to the last measurement [AUC((0- t)), h.ng/mL]) were calculated using noncompartmental analysis. Safety assessments included subject-reported adverse events (AEs), vital signs, visual acuity, intraocular pressure measurement, biomicroscopy, and direct ophthalmoscopy. Results: A total of 16 subjects were enrolled; 15 subjects completed the study. Blood sample analysis indicated limited systemic exposure to CsA; three subjects had a CsA concentration greater than or equal to the lower limit of quantitation (LLOQ) on day 1; only four subjects had three consecutive CsA concentration measurements >LLOQ on day 8; the mean +/- SD for C-max was 0.17 +/- 0.02 ng/mL, T-max was 1.5 +/- 0.58 hours, and AUC((0- t)) was 0.53 +/- 0.06 h.ng/mL. Three subjects reported three AEs (eye pain, eye pruritis, and eye irritation) during the study. No clinically significant changes in the safety assessments were noted. Conclusion: The OTX-101 formulation was well tolerated. Systemic exposure to CsA was negligible in healthy volunteers after twice-daily ocular administration. No evidence for systemic accumulation of CsA was observed.

Purpose: Evaluate the ocular distribution, tolerability, and systemic exposure of cyclosporine (CsA) in New Zealand white rabbits following topical administration of OTX-101, a novel, clear aqueous nanomicellar solution developed for the treatment of dry eye disease (DED). Methods: The study design included single- and repeat-dose phases. In the single-dose phase, rabbits received a single instillation of OTX-101 0.05% or CsA ophthalmic emulsion 0.05% (Restasis (R); Allergan, Irvine, CA) as a comparator. In the repeat-dosing phase, OTX-101 (0.01%, 0.05%, or 0.1% CsA) or comparator was instilled 4 times per day for 7 days. Samples collected included whole blood, tears, and ocular tissues/fluids (aqueous humor, choroid-retina, conjunctiva, cornea, superior eyelid, third eyelid, iris/ciliary body, lacrimal gland, lens, sclera, and vitreous humor). CsA concentrations were analyzed using liquid chromatography-tandem mass spectrometry. Results: Analysis included samples from 112 rabbits. The highest concentration of CsA following a single OTX-101 0.05% instillation occurred in the third eyelid (C-max = 1,200 ng/g). Concentrations of CsA in the cornea and superior bulbar conjunctiva increased in a dose-related manner following repeated administration of OTX-101 formulations; C-max [T-max (h)] for cornea was 1,543 ng/g (6.50), 5,410 ng/g (7.0), and 8,123 ng/g (6.50), for 0.01%, 0.05%, and 0.1% CsA concentrations, respectively; for superior bulbar conjunctiva was 726 ng/g (6.50), 1,468 ng/g (6.50), and 2,080 ng/g (6.25), respectively. Conclusions: OTX-101 topical ophthalmic instillation resulted in extensive distribution of CsA in ocular tissues, particularly in target tissues for DED (cornea and conjunctiva), while systemic exposure was negligible.

Background: Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. Purpose: Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties. Pre-clinical data in multiple mouse models of inflammation showed retention of anti-inflammatory efficacy, but loss of most or all side effects. Experimental approach: We report first-in-human Phase 1 clinical trials (86 healthy adult males), with single ascending doses (0.1-20.0 mg/kg), and multiple ascending doses (1.0-20 mg/kg/day; 14 days treatment). Key results: Vamorolone was well-tolerated at all dose levels. Vamorolone showed pharmacokinetic and metabolism profiles similar to prednisone. Biomarker studies showed loss of side effects of traditional glucocorticoid drugs (bone fragility, metabolic disturbance, immune suppression). Suppression of the adrenal axis was 10-fold less than prednisone. The crystallographic structure of vamorolone was solved, and compared to prednisone and dexamethasone. There was overlap in structure, but differences in conformation at the C-ring where glucocorticoids interact with Asn564 of the glucocorticoid receptor. The predicted loss of Asn564 binding to vamorolone may underlie the loss of gene transcriptional activity. Conclusions and interpretations: Vamorolone is a dissociative steroid that retains high affinity binding and nuclear translocation of both glucocorticoid (agonist) and mineralocorticoid (antagonist) receptors, but does not show pharmacodynamic safety concerns of existing glucocorticoid drugs at up to 20 mg/kg/day.

Abstract Background APX001 is a novel antifungal agent which is rapidly converted to the active metabolite APX001A. APX001A exhibits in vitro activity against many clinically important yeast and fungi, including echinocandin- and azole-resistant Candida species. Given this activity, intravenous (IV) and oral (PO) formulations of APX001 are being developed for the treatment of patients with candidemia or invasive candidiasis. Phase 1 data were used to develop a population PK (PPK) model to describe the time-course of APX001A in plasma. Methods The PPK model was developed using 3,736 plasma PK samples collected from 128 healthy subjects who received APX001 single and multiple IV and PO doses ranging from 10 to 1,000 mg. Instantaneous conversion was assumed by scaling input doses by the molecular weight ratio of APX001A to APX001. After development of the structural PK model, stepwise forward and backward selection procedures were used to identify significant covariate relationships. Model qualification included standard goodness-of-fit metrics and prediction-corrected visual predictive check (PC-VPC) plots. Results A two-compartment model with zero-order IV input, or first-order PO absorption with lag time to account for the apparent delay in oral absorption, best described APX001A plasma PK. Exponential error models were used to estimate interindividual variability (IIV) for all parameters. Interoccasion variability was estimated for the absorption rate constant, bioavailability, and lag time. Body weight was identified as a statistically significant predictor of the IIV on the volume of the central and peripheral compartments. The PPK model provided an accurate and unbiased fit to the plasma data based on individual- and population-predicted concentrations (r2 = 0.977 and 0.873, respectively). The PC-VPC plots for the final PPK model (Figure 1) demonstrated good alignment between observed concentrations and the model predicted 5th, 50th, and 95th percentiles. Conclusion A PPK model describing APX001A plasma PK following IV or PO doses was successfully developed. This model will be useful for generating simulated APX001A exposures for use in pharmacokinetic–pharmacodynamic target attainment analyses to support APX001 dose selection. Disclosures M. Trang, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. J. C. Bader, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. E. A. Ople, Amplyx Pharmaceuticals, Inc.: Employee, Salary. W. G. Kramer, Amplyx Pharmaceuticals, Inc.: Scientific Advisor, Consulting fee. M. R. Hodges, Amplyx Pharmaceuticals, Inc.: Employee, Salary. S. M. Bhavnani, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. C. M. Rubino, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support.

Given their established analgesic properties, nonsteroidal anti‐inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl‐β‐cyclodextrin (HPβCD) following administration of the injectable NSAID HPβCD‐diclofenac; and (2) the PK of HPβCD following administration of HPβCD‐diclofenac and intravenous itraconazole formulated with HPβCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (V z ) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between V z (but not CL or elimination half‐life, t ½ ) and renal function. HPβCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t ½ . There were no significant differences in diclofenac or HPβCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPβCD in healthy subjects following HPβCD‐diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (<5% without adjustment). With respect to PK properties, these results suggest that HPβCD‐diclofenac might be administered to patients with mild or moderate renal insufficiency or mild hepatic impairment without dose adjustment (NCT00805090).

Daily injections of growth hormone (GH) as replacement therapy in GH-deficient (GHD) patients may cause poor compliance and inconvenience. C-terminal peptide-modified human GH (MOD-4023) has been developed for once-weekly administration in GHD adults and children. In the present study, the pharmacokinetics (PK) and pharmacodynamics (PD) of a single subcutaneous dose of MOD-4023 were evaluated in healthy Caucasian and Japanese adults, using a phase 1 double-blind, vehicle-controlled, randomized study design. The study was conducted in 42 healthy Japanese (n = 21) and Caucasian (n = 21) men receiving either MOD-4023 at a dose of 2.5, 7.5, or 15 mg or vehicle. In the 2.5- and 7.5-mg cohorts, no differences in mean MOD-4023 serum concentration were found between Japanese and Caucasian subjects. A comparison of PK parameters in the 15-mg group suggests a slower absorption rate of MOD-4023 in Japanese subjects. PD analysis showed no apparent differences in IGF- 1 and IGFBP-3 plasma concentrations between the Japanese and Caucasian subjects and indicated that a dose of 15 mg achieved the maximal effect in both ethnic groups. MOD-4023 demonstrated a favorable safety profile and local tolerance following single-dose subcutaneous administration. This study provides additional support for the development of MOD-4023 as a long-acting human growth hormone formulation for once-weekly administration.

BackgroundAPX001 is a first-in-class, intravenous (IV) and oral (PO) broad-spectrum antifungal agent in clinical development for the treatment of invasive fungal infections (IFIs) due to Candida, Aspergillus and rare molds. The active moiety APX001A inhibits Gwt1, an early step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Excellent in vivo efficacy has been demonstrated in murine models of IFIs with APX001A AUC0-24 target exposures ~ 80 µg.hours/mL.

APX001 is a first-in-class, intravenous (IV) and oral (PO) broad-spectrum antifungal agent in clinical development for the treatment of invasive fungal infections (IFIs) due to Candida, Aspergillus and rare molds. The active moiety APX001A inhibits Gwt1, an early step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Excellent in vivo efficacy has been demonstrated in murine models of IFIs with APX001A AUC0–24 target exposures ranging from 2 to 80 µg hours/mL. There were six single ascending dose (SAD) and four multiple ascending dose (MAD) cohorts, eight subjects/cohort. Subjects were randomized in a 6:2 ratio to receive 3-hour IV infusions of APX001 or placebo. SAD Cohorts 1–6 received single doses of 10, 30, 100, 200, 275, and 350 mg, respectively. MAD Cohorts 7–10 received doses of 50, 150, 300, and 600 mg, respectively, once daily for 14 days. Pharmacokinetic (PK) parameters for APX001A in plasma were calculated using non-compartmental analysis. Safety monitoring and intense PK sampling occurred throughout the trial. A safety committee reviewed the PK and safety data to determine dose escalation steps. Plasma exposure to APX001A was linear, dose proportional, with low intersubject variability and a half-life of ~2.5 days. As expected from the half-life and dosing frequency, accumulation of APX001A was observed in the MAD cohorts. A single APX001 dose of 350 mg maintained drug levels above the minimum inhibitory concentration (MIC) of Candida and Aspergillus for one week. The 600 mg/day AUC0–24on Day 14 was 245 μg.hours/mL. APX001 was well tolerated across all doses with no clinically significant adverse events observed. One subject discontinued due to the adverse event (AE) of flu. There were no dose limiting toxicities. Most of the AEs were mild, transient and required no treatment. The most common AE was headache. Target exposures of APX001A for efficacy against Candida and Aspergillus as well as the high MIC rare mold pathogens were exceeded at doses that are safe and well tolerated. M. R. Hodges, Amplyx Pharmaceuticals: Employee, Salary; E. Ople, Amplyx Pharmaceuticals Inc.: Employee, Salary. K. J. Shaw, Amplyx Pharmaceuticals Inc.: Employee, Salary; R. Mansbach, Amplyx Pharmaceuticals Inc.: Consultant, Consulting fee; S. J. Van Marle, PRA Health Sciences: Employee, Salary. E. J. Van Hoogdalem, PRA Health Sciences: Employee, Salary. P. Wedel, Amplyx Pharmaceuticals Inc.: Employee, Salary. W. Kramer, Amplyx Pharmaceuticals Inc.: Consultant, Consulting fee.

Purpose: The purpose of this study was to evaluate the bioavailability of hydroxyprogesterone caproate (HPC) administered as a subcutaneous injection in the back of the upper arm using a prefilled autoinjector syringe with a 27-gauge needle compared with standard intramuscular injection in the gluteus maximus using a 21-gauge needle. Methods: Healthy postmenopausal women 50 to 75 years old were randomized in a parallel group design to receive a single SC injection of 1.1 mL (275-mg total dose) of preservative-free HPC administered using an autoinjector in the back of the upper arm or a single IM injection of 1 ml, (250-mg total dose) of preservative-free HPC administered in the gluteus maximus. Blood samples were collected through 1008 hours (42 days) after injection. The primary measures were the C-max, AUC(0-t), and AUC(0-infinity). Secondary measures were T-max, k(e), t(1/2), and injection site reactions captured as a treatment-emergent adverse event. Findings: The pharmacokinetic population consisted of 90 individuals; 45 received subcutaneous administration and 45 received intramuscular administration. Geometric mean whole blood concentrations of HPC were comparable between administration regimens. Subcutaneous administration resulted in a higher geometric mean C-max than intramuscular administration (7.88 vs 6.91 ng/mL), but median T-max values were comparable (48.1 vs 49.7 hours). The least square geometric mean ratios for AUC(0-168)), AUC(0-t), and AUC(0-infinity) a were 102.89%, 110.25%, and 113.51%, respectively, with all 90% CIs within the 80.0% to 125.0% window that defined bioequivalence. The ratio for C-max was 113.95% with a 90% CI of 91.94% to 141.23% but with substantial overlap of individual values between administration regimens. The geometric mean t(1/2) of HPC was 212 hours for the subcutaneous administration and 188 hours for the intramuscular administration. The most common treatment-emergent adverse event was injection site pain (subcutaneous, 37.3%; intramuscular, 8.2%), described as mild (85%) to moderate (15%). Implications: Administration of HPC by SC injection of 1.1 mL (275 mg) via autoinjector is bioequivalent to IM injection of 1.0 mL (250 mg). (C) 2017 The Authors. Published by Elsevier HS Journals, Inc.

In bioequivalence (BE) testing, it is the convention to identify tlast separately for each concentration-vs-time profile. Within-subject differences in tlast between treatments can arise when assay sensitivity is reached during washout, causing profiles to fall below the limit of quantitation (LOQ) at different sampling times. The resulting tlast difference may be systematic, due to true differences in exposure, and/or random, due to measurement noise. The conventional profile-specific tlast approach assumes that concentrations in the terminal phase are sufficiently low that use of different tlast values between treatments within a subject causes negligible bias in the AUC0-t geometric mean ratio (GMR). Here we investigate the validity of this assumption. Using concentration-vs-time data following oral inhalation of 50 μg salmeterol as an example data set, we conducted simulations to evaluate whether use of different test/reference AUC timeframes arising from a systematic difference in exposure causes sufficient AUC0-t GMR bias to influence the determination of BE. To ensure that results would be relevant to BE testing, we considered only test/reference relative systemic exposures within the BE window (80.00%-125.00%). We show that use of conventional profile-specific tlast exaggerates true differences in systemic exposure; the resulting AUC0-t ratios are biased from true relative exposure by an amount large enough to impact the conclusion of BE. Thus, drugs whose concentrations fall below LOQ during washout may fail BE inappropriately using conventional methods. AUC0-t calculated over a common timeframe within each subject (tlast [common]) minimizes this bias and harmonizes the statistical analysis of BE.

198 Background: The capsule formulation of dronabinol, a pharmaceutical tetrahydrocannabinol (THC), is approved for anorexia associated with weight loss in patients with AIDS and for cancer chemotherapy-associated nausea/vomiting in patients with inadequate response to conventional antiemetics. A new oral formulation (i.e., dronabinol solution) was evaluated in a bioequivalence study versus currently marketed dronabinol capsules. Methods: In an open-label, 2-treatment, 2-sequence, 4-period, single-dose crossover study, healthy volunteers were randomized to receive 1 of 2 treatment sequences (T-R-T-R or R-T-R-T; T = dronabinol 4.25 mg oral solution and R = dronabinol 5 mg capsules). Dosing occurred after an overnight fast, with a minimum 7-day washout period between treatment periods. A validated liquid chromatography-tandem mass spectrometry method was used to determine plasma concentrations of dronabinol and the primary metabolite 11-OH-Δ9-THC. Results: Fifty-one of 52 enrollees had pharmacokinetic data for analysis. Mean pharmacokinetics were (oral solution vs capsule): Cmax (2.0 vs 2.4 ng/mL), median Tmax (1.0 vs 1.5 h), AUC0-∞ (3.8 vs 4.1 h∙ng/mL), and t1/2 (5.6 vs 3.1 h). The 2 formulations were bioequivalent with respect to maximum plasma concentration (Cmax; reference-scaled criteria) and area under the plasma concentration-time curve (from time zero to last measurable concentration and from time zero to infinity [AUC0-∞]; average bioequivalence) of dronabinol. The data for the 11-OH-Δ9-THC metabolite provide further support for the bioequivalence of the 2 products. Post hoc analysis demonstrated that all volunteers (100%) had detectable plasma dronabinol concentrations at 15 min with the oral solution compared with < 25% of volunteers for the capsules. Intra-individual variability was lower with oral solution versus capsules (for AUC0-∞, 13.5% vs 36.8%, respectively). Conclusions: Dronabinol oral solution 4.25 mg was bioequivalent to dronabinol capsules 5 mg, and exhibited quicker onset of detectable levels and lower intra-individual variability in comparison with dronabinol capsules 5 mg. Clinical trial information: NCT01448772.

Purpose: The analgesic and opioid-sparing effects of nonsteroidal anti-inflammatory drugs can be beneficial in postoperative populations. Hydroxypropyl-beta-cyclodextrin (HP beta CD)-diclofenac is an injectable formulation of diclofenac solubilized with HP beta CD that is administered as a low-volume intravenous bolus. This open-label, single-dose study examined the effects of age and weight on the pharmacokinetic (PK) profile of HP beta CD-diclofenac.Methods: Eighty-eight adult volunteers were enrolled. An age-based cohort included 34 subjects 55-82 years old stratified into three groups and receiving HP beta CD-diclofenac 18.75 mg. A weight-based cohort included 54 subjects stratified into five groups based on body weight and body mass index and receiving HP beta CD-diclofenac 37.5 mg. PK analysis was performed on blood samples collected predosing and at predefined intervals (5, 10, 20, 30, and 45 minutes; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 18 hours) postdosing. Diclofenac PK parameters were examined in the individual cohorts, and regression analyses of the relationship between age, weight, and PK parameters were performed on pooled data from all enrolled subjects.Results: Examination of the age-based cohort revealed similar diclofenac PK parameters across age groups. PK parameters were likewise similar across weight groups in the weight-based cohort. Regression analysis on pooled data from the age-and weight-based cohorts revealed that increasing body weight was associated with a significant increase in diclofenac clearance (CL), suggesting decreased exposure in high-weight patients. Analysis of the pooled population also demonstrated an inverse relationship between age and elimination half-life (t(1/2)), likely due to a decrease in the volume of distribution (V-z) with increased age, not a change in CL. There were no deaths, serious adverse events, or adverse events that led to discontinuation.Conclusion: This study suggests that the CL of diclofenac is not dependent on age in elderly subjects receiving HP beta CD-diclofenac but indicates that diclofenac CL increases with increasing body weight.

Background: Selectins, among other adhesion-mediated functions, facilitate and augment thrombosis; standard anticoagulants address thrombosis but also increase bleeding risk. Previous work in animal models showed inhibiting E-selectin decreases venous thrombosis (VTE) and vein wall inflammation without adverse bleeding events, making E-selectin inhibition a favorable therapeutic candidate for VTE. GMI-1271 is a potent, specific E-selectin antagonist. Here we report final analysis of safety, PK, biomarker and bleeding risk profile for GMI-1271 in 2 phase 1 studies of healthy subjects.