Single-dose Study In Healthy Subjects Research Articles

Pharmacodynamics of CT-P39, a Proposed Biosimilar of Omalizumab, Comparing with EU-Xolair and US-Xolair; Result of a Phase 1, Randomized, Double-blind, Parallel Group, Single-dose Study in Healthy Subjects

CT-P39, a proposed biosimilar to omalizumab, demonstrated pharmacokinetic (PK) equivalence to reference omalizumab by all primary PK parameters. In line with PK results, CT-P39 is expected to have similar pharmacodynamic (PD) response on IgE to the reference omalizumab.

1120. Absorption, Metabolism, and Excretion of [14C]-Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) Following a Single Oral Dose in Healthy Male Subjects

BackgroundTebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug that is converted to tebipenem (TBP), the active moiety, with activity against multidrug-resistant gram-negative pathogens, including extended-spectrum-β-lactamase (ESBL)-producing Enterobacterales. TBP-PI-HBr is the first oral carbapenem intended for treating complicated urinary tract infections and acute pyelonephritis. This study evaluated the absorption, metabolism, and excretion (AME) of TBP-PI-HBr following a single oral dose of [14C]-TBP-PI-HBr to healthy males and characterized metabolites in plasma, urine, and feces.MethodsThis was a Phase 1, open-label, single-dose study in healthy subjects. Study drug was provided as radiolabeled and non-radiolabeled active pharmaceutical ingredient containing approximately 150 μCi of [14C]-TBP-PI-HBr. On Day 1, each subject received a 600 mg dose of TBP-PI-HBr. administered with 240 mL of water and fasted overnight for at least 10 hours. Blood samples were collected to determine TBP concentrations (whole blood), total radioactivity (whole blood and plasma), and metabolite profiling and identification were determined from plasma, urine, and feces. For mass balance, total radioactivity derived from urine and feces collections were determined. PK parameters were calculated using noncompartmental methods.ResultsTotal radioactivity in plasma and whole blood decreased rapidly with geometric mean t½ values of 6.0 hours and 3.5 hours, respectively and Tmax of 1 hour. The cumulative mean recovery of radioactivity was 38.7% in urine and 44.6% in feces. Most of the administered radioactivity was recovered in the first 144 hours post dose in urine and feces (80.0%). Six of 8 subjects achieved a mass balance recovery ranging from 80.1% to 85.0%. The TBP plasma to total radioactivity ratio of 0.536 indicated that other metabolites contribute to the total radioactivity AUC in plasma. Metabolite profiling and identification results indicated that TBP was the major component in plasma and urine. The inactive ring open metabolite of TBP (LJC 11,562) was also found in plasma ( >10%), urine (5.27%), and feces ( >10%) as a secondary metabolite.ConclusionThis study adequately characterized the AME of TBP-PI-HBr in humans.Disclosures Vipul K. Gupta, Ph.D., Spero Therapeutics (Employee, Shareholder) Gary Maier, PhD, Spero Therapeutics, Inc. (Consultant) Leanne Gasink, MD, Spero Therapeutics, Inc. (Consultant) Amanda Ek, MS, Spero Therapeutics, Inc. (Employee) Mary Fudeman, BA, MBA, Spero Therapeutics, Inc. (Employee) Praveen Srivastava, MS, BS, Spero Therapeutics, Inc. (Employee) Angela Talley, MD, Spero Therapeutics, Inc. (Employee)

A Randomized, Double-Blind, Single-Dose Phase 1 Comparative Pharmacokinetic Study Comparing SB12 (Eculizumab Biosimilar) with Reference Eculizumab in Healthy Volunteers

Background: SB12 has been developed as a biosimilar of the reference product (RP) eculizumab. Eculizumab is a humanized monoclonal antibody (IgG2/4 kappa immunoglobulin) that binds to the human C5 complement protein with high affinity. Binding to this protein blocks its cleavage into C5a and C5b, thereby inhibiting terminal complement-mediated intravascular haemolysis. It is currently indicated for the treatment of patients with paroxysmal nocturnal haemoglobinuria, atypical haemolytic uremic syndrome (aHUS), refractory generalized Myasthenia Gravis (gMG) and Neuromyelitis Optica Spectrum Disorder (NMOSD).Objectives: To demonstrate pharmacokinetic (PK) equivalence and evaluate pharmacodynamic (PD), safety, tolerability, and immunogenicity profiles between SB12 and the RP eculizumab.Methods: This was a double-blind, three-arm, parallel group, and single-dose study in healthy subjects, between 18-55 years of age, randomized in a ratio of 1:1:1 to receive a single 300 mg dose of either SB12, European Union (EU) sourced eculizumab, or United States of America (US) sourced eculizumab via intravenous (IV) infusion for 35 minutes. Blood samples for PK and PD analysis were collected over 64 days. The primary objective of this study was to demonstrate PK similarity between the investigational products (IPs), as assessed by area under the concentration-time curve from time zero to infinity (AUC inf). Secondary PK endpoints included area under the concentration-time curve from time zero to the last quantifiable concentration (AUC last) and maximum observed concentration (C max). Equivalence for the primary endpoint (AUC inf) was determined if 90% confidence intervals (CIs) for the ratio of geometric least squared means (LSMeans) of SB12 to EU sourced eculizumab, SB12 to US sourced eculizumab, and EU sourced eculizumab to US sourced eculizumab was within the equivalence margin of 80.00% to 125.00%, respectively. Other objectives for the study were to evaluate safety, tolerability, immunogenicity, and PD profiles for the IPs.Results: A total of 240 subjects (80 in each treatment group) were enrolled. Back transformation provided the geometric LSMean ratio for the comparison of SB12/EU sourced eculizumab, SB12/US sourced eculizumab and EU sourced eculizumab/US sourced eculizumab for AUC inf were 99.1 % (95.41,102.85), 95.1 % (91.40, 99.04), and 96.0 % (92.16, 100.10), respectively. The corresponding 90% CI was within the pre-defined equivalence margin of 80.00-125.00%, indicating that the each of two treatments are bioequivalent.The profiles of mean terminal complement activity and mean change from baseline of complement activity were superimposable following administration of SB12, EU sourced eculizumab, and US sourced eculizumab. There was a rapid decrease in the complement activity at the end of infusion and then a slow restoration. There was no non-responder in the aspect of the measured complement activity after treatment.There were no deaths or discontinuation of IP due to treatment-emergent adverse events (TEAEs) during the study. Two serious adverse events (SAEs) (renal colic in the SB12 treatment group and back pain in the US eculizumab treatment group) were reported, in 2 subjects. Both events were considered not related to the IP. The proportion of subjects who experienced TEAEs were similar between the SB12, EU sourced eculizumab, and US sourced eculizumab treatment groups (70.0%, 65.0%, and 71.3% of subjects, respectively). The overall incidence of subjects with post-dose anti-drug antibodies (ADA) to eculizumab was 2 (2.5%), 1 (1.3%), and 0 (0.0%) subjects in the SB12, EU sourced eculizumab, and US sourced eculizumab treatment groups, respectively. There was no significant difference between treatment groups. None of the subjects with post-dose ADA to eculizumab had a positive result for neutralizing antibodies.Conclusion: The Phase I study demonstrated PK bioequivalence and showed comparable PD, safety, immunogenicity between SB12 and the RP eculizumab. DisclosuresLee: Samsung Bioepis, Co., Ltd.: Current Employment. Jang: Samsung Bioepis, Co., Ltd.: Current Employment. Kim: Samsung Bioepis, Co., Ltd.: Current Employment. Jeong: Samsung Bioepis, Co., Ltd.: Current Employment. Lee: Samsung Bioepis, Co., Ltd.: Current Employment. Jung: Samsung Bioepis, Co., Ltd.: Current Employment. Demichelis: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol/Celgene: Consultancy, Speakers Bureau; AMGEN: Consultancy, Speakers Bureau; ASH: Research Funding; Jazz: Consultancy; Gilead: Consultancy; Astellas: Consultancy; Abbvie: Consultancy, Speakers Bureau.

High-Fat Breakfast Increases Bioavailability of Albendazole Compared to Low-Fat Breakfast: Single-Dose Study in Healthy Subjects.

Purpose: Albendazole is a benzimidazole carbamate drug with anthelmintic and antiprotozoal activity against intestinal and tissue parasites. It has been described that the administration with meals increases albendazole absorption. Our aim was to compare the systemic exposure in healthy volunteers of two albendazole formulations after a single oral dose under fed conditions and to evaluate the effect of breakfast composition on albendazole and albendazole sulfoxide bioavailability. Methods: 12 healthy volunteers were included in a 4-period, 4-sequence, crossover, open, randomized, bioequivalence clinical trial, including two stages to compare two formulations of albendazole. Single oral doses of 400 mg albendazole were administered under fed conditions (a low-fat breakfast in first stage and a high-fat breakfast in the second) separated by 7-day washout periods. Plasma albendazole and albendazole sulfoxide concentrations were measured by HPLC-MS/MS. Findings: Albendazole absorption was clearly influenced by the meal composition. A high-fat breakfast increased albendazole and albendazole sulfoxide area under the concentration–time curve (AUC) and maximum concentration (Cmax) by double, compared to a low-fat breakfast. The bioavailability of the two formulations was very similar, although the sample size was not sufficient to demonstrate bioequivalence because the intraindividual variability of albendazole was approximately 60%. Implications: The higher albendazole and albendazole sulfoxide levels when administered with a high-fat meal could be of importance in clinical practice. Since albendazole labeling recommends its administration with meals, it is necessary to insist on taking it with a fatty meal so that the effectiveness of albendazole is not compromised.

Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma

Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma

Bioequivalence and Dose Proportionality of Inhaled Fluticasone Furoate

Fluticasone furoate (FF), a new inhaled corticosteroid delivered via the ELLIPTA dry powder inhaler, is being developed as a once-daily inhaled treatment for asthma. Study 1 was a part-randomised, open-label, four-way crossover, single- and repeat-dose study in healthy subjects (n=36) to assess whether the systemic exposure of FF increased proportionately across different strengths of FF (50 μg, 100 μg and 200 μg) and to determine the absolute bioavailability of FF inhalation powder. Study 2 was a randomised, open-label, replicate, six-way crossover, single-dose study in healthy subjects (n=30) to determine the bioequivalence of FF inhalation powder (single-strip configuration) compared with FF inhalation powder (two-strip configuration) and with fluticasone furoate/vilanterol (FF/VI) inhalation powder. A population pharmacokinetic analysis was also conducted on sparse samples collected from asthma patients in five Phase III studies conducted with FF/ VI or FF. Overall, FF systemic exposure, as measured by single-dose AUC(0-∞), was dose proportional whilst Cmax showed a less than proportional increase. Inhaled absolute bioavailability of FF was 14%. Bioequivalence was not demonstrated for FF single-strip compared with either FF two-strip or FF/VI since the estimated 90% confidence interval for the ratio of adjusted geometric means for AUC and Cmax did not fall completely between 0.8000-1.2500. However, this difference was in line with the higher respirable mass delivered by the batch of single-strip product used in this study. Although the formal bioequivalence study showed higher exposure with FF single-strip ELLIPTA compared with FF two-strip or FF/VI, the results of the population PK analysis of data in asthmatics show that there is no notable difference in systemic exposure between the FF configurations (single-strip, two-strip or FF/VI). In healthy subjects all treatments were generally safe and no new safety issues were apparent at these supra-therapeutic inhaled doses of FF (up to 1200 μg) and high intravenous FF dose (250 μg).

Absolute Bioavailability and Effect of Formulation Change, Food, or Elevated pH with Rabeprazole on Cobimetinib Absorption in Healthy Subjects

Cobimetinib is a potent and highly selective inhibitor of MEK1/2. Since cobimetinib exhibited absorption variability in cancer patients, a series of single-dose studies in healthy subjects were conducted to determine absolute bioavailability and elucidate potential effects of formulation, food, and elevated gastric pH on cobimetinib bioavailability. Three crossover trials were performed with a 20 mg cobimetinib oral dose: absolute bioavailability using a 2 mg intravenous infusion (n = 13), relative bioavailability of tablets versus capsules and food effect (n = 20), and drug interaction with a proton pump inhibitor (20 mg of rabeprazole daily for 5 days prior to cobimetinib administration; n = 20). Absolute bioavailability of cobimetinib was 46.2% (24.2, CV %), likely due to metabolism rather than incomplete absorption. The mean systemic clearance of cobimetinib was low (11.7 L/h [28.2, CV %]). Administration of cobimetinib tablets with a high-fat meal delayed drug absorption (prolonged tmax) but had no statistically significant effect on cobimetinib exposure (Cmax and AUC0-∞). Tablet and capsule formulations of cobimetinib showed comparable exposures. Cobimetinib exhibited delayed absorption (tmax) in the presence of rabeprazole, with no statistically significant effects on drug exposure (Cmax and AUC0-∞) in the fasted state. In conclusion, cobimetinib oral absorption was not affected by change in formulation, food, or elevated gastric pH.

The Pharmacokinetics of Fluticasone Furoate and Vilanterol Following Single Inhaled Administration in Combination and Intravenous Administration of Individual Components in Healthy Subjects

Fluticasone furoate (FF)/vilanterol (VI), a novel inhaled corticosteroid/long-acting β 2 -agonist combination, is being developed as a once-daily inhaled treatment for asthma and chronic obstructive pulmonary disease. The two studies described here assess FF dose proportionality and VI equivalence across the clinical strengths of FF/ VI and the absolute bioavailability of the components administered as FF/VI in combination via the dry powder inhaler (DPI) intended for commercial use. Study 1 (NCT01213849) was a randomized, open-label, three-way crossover, single- dose study in healthy subjects designed to assess whether the systemic exposure of FF increased proportionately and VI systemic exposure was constant across different strength combinations of FF/VI (four inhalations of FF/ VI; 50/25 μg, 100/25 μg and 200/25 μg). Study 2 (NCT01299558) was an open-label, non-randomized, three- way crossover, single-dose study in healthy subjects conducted to determine the absolute bioavailability of FF/VI inhalation powder. Both FF and VI have high plasma clearance and extensive distribution into tissues. Overall, FF systemic exposure, as measured by AUC (0–t’) , was dose proportional over the 200-800 μg FF dose range. The less than dose proportional increase seen for FF C max is likely due to rate limited absorption from the lung. FF acts topically in the lung, whilst systemic exposure is related to safety. Consequently, the lack of dose proportionality for FF C max would be considered not to impact efficacy. Equivalence of VI exposure across the three FF/VI dosage strengths was demonstrated for AUC (0–t’) and C max . Following a single inhaled dose of FF/VI administered via DPI the absolute bioavailabilities of FF and VI were estimated to be 15% (90% confidence interval [CI]: 13%, 18%) and 27% (90% CI: 22%, 35%), respectively. FF showed longer retention in the lung than VI following inhaled administration, with the time for 90% of the total to be absorbed from the lung being on average 35.2 hours and 3.8 hours, respectively.

Effects of formulation on the bioavailability of lutein and zeaxanthin: a randomized, double-blind, cross-over, comparative, single-dose study in healthy subjects

PurposeLutein and zeaxanthin are macular pigments with a protective function in the retina. These xanthophylls must be obtained from the diet or added to foods or supplements via easy-to-use, stable formulations. The technique employed to produce these formulations may affect the bioavailability of the xanthophylls.MethodsForty-eight healthy volunteers were randomized into this double-blind, cross-over study investigating the plasma kinetics of lutein provided as two different beadlet formulations. Subjects (n = 48) received a single dose of 20 mg of lutein as either a starch-matrix (“SMB”, FloraGLO® Lutein 5 %) or as a cross-linked alginate-matrix beadlet (“AMB”, Lyc-O-Lutein 20 %) formulation. Plasma concentrations of lutein and zeaxanthin were measured at 0, 1, 3, 6, 9, 12, 14, 24, 26, 28, 32, 36, 48, 72, 168, and 672 h.ResultsThe mean plasma AUC(0–72h), AUC(0–672h), and C max for total lutein and zeaxanthin and their all-E-isomers were significantly increased (p < 0.001) from pre-dose concentrations in response to SMB and AMB. There was no difference in lutein T max between the two test articles. However, by 14 h post-dose, total plasma lutein increased by 7 % with AMB and by 126 % with SMB. Total lutein AUC(0–72h) and AUC(0–672h) were 1.8-fold and 1.3-fold higher, respectively, for SMB compared to AMB. Both formulations were well tolerated by subjects in this study.ConclusionThese findings confirm that the bioavailability of lutein and zeaxanthin critically depends on the formulation used and document a superiority of the starch-based over the alginate-based product in this study.

Single oral doses of netazepide (YF476), a gastrin receptor antagonist, cause dose‐dependent, sustained increases in gastric pH compared with placebo and ranitidine in healthy subjects

Nonclinical studies have shown netazepide (YF476) to be a potent, selective, competitive and orally active gastrin receptor antagonist. To administer to humans for the first time single oral doses of netazepide, to assess their tolerability, safety, pharmacokinetics and effect on 24-h gastric pH. We did two randomised double-blind single-dose studies in healthy subjects. The first (n = 12) was a six-way incomplete crossover pilot study of rising doses of netazepide (range 0.5-100 mg) and placebo. The second (n = 20) was a five-way complete crossover study of netazepide 5, 25 and 100 mg, ranitidine 150 mg and placebo. In both trials we collected frequent blood samples, measured plasma netazepide and calculated pharmacokinetic parameters. In the comparative trial we measured gastric pH continuously for 24 h and compared treatments by percentage time gastric pH ≥4. Netazepide was well tolerated. Median t (max) and t (½) for the 100 mg dose were about 1 and 7 h, respectively, and the pharmacokinetics were dose-proportional. Netazepide and ranitidine each increased gastric pH. Onset of activity was similarly rapid for both. All netazepide doses were more effective than placebo (P ≤ 0.023). Compared with ranitidine, netazepide 5 mg was as effective, and netazepide 25 and 100 mg were much more effective (P ≤ 0.010), over the 24 h after dosing. Activity of ranitidine lasted about 12 h, whereas that of netazepide exceeded 24 h. In human: netazepide is an orally active gastrin antagonist, and gastrin has a major role in controlling gastric acidity. Repeated-dose studies are justified. NCT01538784 and NCT01538797.

Effect of Cyclosporine on the Pharmacokinetics of Aliskiren in Healthy Subjects

To explore the clinical relevance of inhibition of multidrug resistance transporter 1 and organic anion transporting polypeptide transporter, a drug-drug interaction study was conducted using aliskiren and cyclosporine. This was an open-label, single-sequence, parallel-group, single-dose study in healthy subjects. Subjects (n = 14) first received aliskiren 75 mg orally (period 1), followed by aliskiren 75 mg + cyclosporine 200 mg (period 2) after a 7-day washout period, and aliskiren 75 mg + cyclosporine 600 mg (period 3) after a 14-day washout period. Safety and pharmacokinetics were analyzed during each period. The primary objective was to characterize pharmacokinetics of aliskiren (single-dose and combination with cyclosporine). The increases in area under the time-concentration curve from time 0 to infinity and maximum concentration associated with cyclosporine 200 mg or 600 mg were 4- to 5-fold and 2.5-fold, respectively. Mean half-life increased from 25 to 45 hours. Based on comparison to literature, a single-dose of aliskiren 75 mg did not alter the pharmacokinetics of cyclosporine. Aliskiren 75 mg was well tolerated. Combination with cyclosporine increased the number of adverse events, mainly hot flush and gastrointestinal symptoms, with no serious adverse events. Two adverse events led to withdrawal (ligament rupture, not suspected to be study-drug related; and vomiting, suspected to be study-drug related). Laboratory parameters, vital signs, and electrocardiographs showed no time- or treatment-related changes. As cyclosporine significantly altered the pharmacokinetics of aliskiren in humans, its use with aliskiren is not recommended.

Prophylactic use of anti‐emetic medications reduced nausea and vomiting associated with exenatide treatment: a retrospective analysis of an open‐label, parallel‐group, single‐dose study in healthy subjects

AimsTransient nausea and, to a lesser extent, vomiting are common adverse effects of exenatide that can be mitigated by dose titration and usually do not result in treatment discontinuation. This retrospective analysis of data from a phase 1, open-label, parallel-group, single-dose study in healthy subjects evaluated the effect of oral anti-emetics on exenatide-associated nausea and vomiting and on the pharmacokinetics of exenatide.MethodsA single subcutaneous dose (10 μg) of exenatide was administered to 120 healthy subjects (19–65 years, BMI 23–35 kg/m2). Incidences of nausea and vomiting were compared between 60 subjects premedicated with two oral anti-emetics 30 min before the exenatide dose and 60 non-premedicated subjects. Similarly, the area under the concentration-time curve (AUC) and the maximum observed concentration (Cmax) of plasma exenatide concentrations over 8 h post-dose were compared.ResultsAmong all subjects [61% male, 32 ± 12 years, body mass index (BMI) 29.1 ± 3.4 kg/m2 (mean ± sd)], mild to moderate nausea was the most frequent adverse event after exenatide dosing. Vomiting was also observed. Subjects premedicated with anti-emetics experienced significantly less nausea and vomiting (16.7 and 6.7%, respectively) vs. non-premedicated subjects (61.7 and 38.3%, respectively; P-value < 0.0001 for both nausea and vomiting). The mean area under the concentration-time curve and the maximum observed concentration AUC and Cmax of plasma exenatide concentrations during 8 h post-dose were not significantly different between groups.ConclusionAdministration of oral anti-emetics before a single 10-μg exenatide dose was associated with significant reductions in treatment-emergent nausea and vomiting, with no discernible effect on the pharmacokinetics of exenatide. Use of anti-emetic therapy may provide a short-term strategy to minimize the nausea and vomiting associated with exenatide treatment.

Pharmacokinetic and Pharmacodynamic Interactions Between the Immunosuppressant Sirolimus and the Lipid-Lowering Drug Ezetimibe in Healthy Volunteers

Organ transplant recipients who have dyslipidemia related to immunosuppression may benefit from cholesterol-lowering therapy with ezetimibe, a substrate of ABCB1, ABCC2, and OATP1B1. Adverse pharmacokinetic interactions are hypothesized with sirolimus, which is a substrate of OATP1B1 and OATP1B3 and an inhibitor of ABCB1, OATP1B1, and OATP1B3 but not of ABCC2. However, competition between sirolimus and ezetimibe for ABCB1 and OATP1B1 is not of major clinical relevance, as confirmed in our randomized, controlled, single-dose study in healthy subjects.

561 Safety and pharmacokinetics of the now nucleoside polymerase inhibitor, HCV-796: Results of a randomized, double-blind, placebo-controlled, ascending single-dose study in healthy subjects

561 Safety and pharmacokinetics of the now nucleoside polymerase inhibitor, HCV-796: Results of a randomized, double-blind, placebo-controlled, ascending single-dose study in healthy subjects

Drug-antacid interactions: assessment of clinical importance.

Antacids and adsorbents are commonly used preparations that are generally considered to be pharmacologically inert and free from adverse effects. They may, however, interact with a diverse range of primary drugs and the sequelae can be disadvantageous to the efficacy of the primary medication. Many such reports in the literature are based on animal experiments, or on single-dose studies in healthy subjects. Some reports are anecdotal and are unconfirmed; others are based solely on in vitro evidence. Potentially important interactions have been suggested for a relatively small group of drugs: tetracyclines, phenytoin, digoxin, chloroquine, cimetidine, quinidine, nonsteroidal antiinflammatory drugs, and beta-blocking agents. The evidence for these has been critically evaluated, as well as for antacid-anticoagulant and antacid-nitrofurantoin interactions that have been wrongly emphasized in the literature. The majority of literature reports on interactions with antacids have been overemphasized; only ferrous sulfate-, isoniazid-, and tetracycline-antacid interactions fall into a category I importance (scale I-III of descending importance). This category is for those interactions with good evidence of actual or potential importance in patients or in relevant studies on normal subjects.