Ratio Of LS Means Research Articles

Single-Dose Crossover Comparative Bioavailability Study of Two Different Posaconazole 100 mg Gastro-Resistant Tablets Under Fasted and Fed Conditions in Healthy Volunteers.

This study aimed to compare the bioavailability of two different gastro-resistant oral tablet formulations of posaconazole under fasted and fed conditions and to evaluate a potential food effect on the bioavailability of each formulation. Healthy volunteers randomly assigned to receive a test product (Posagil® 100 mg gastro-resistant tablet) or reference product (Noxafil® 100 mg gastro-resistant tablet) were included in this single-center, randomized, four-period (days 1, 15, 29 and 43), four-sequence crossover comparative bioavailability study. Data on posaconazole plasma concentrations and related pharmacokinetic profile (the maximum observed plasma concentration [Cmax] from time 0 to the time of last observed quantifiable plasma concentration [AUC0-T] and from time zero to infinity [AUC0-∞]) were recorded to evaluate efficacy of the test product in relation to the reference product under both fasted and fed conditions, based on bioequivalence (T-fasted vs. R-fasted and T-fed vs. R-fed) and food effect (T-fasted vs. T-fed and R-fasted vs. R-fed) assessments. Safety was evaluated through assessment of adverse events (AEs), standard laboratory evaluations, and vital signs. The bioequivalence criteria were met under fed conditions (T-fed vs. R-fed: geometric LSMean ratios of Cmax, AUC0-T, and AUC0-∞ of posaconazole were 97.41%, 97.45%, and 97.08%, respectively; all within the range of 80% to 125%) but not under fasted conditions. There was a food effect on the reference product (R-fed vs. R-fasted: geometric LSMean ratios of Cmax, AUC0-T, and AUC0-∞ of posaconazole were 145.32%, 138.84%, and 138.46%, respectively) but not on the test product. No safety concerns were identified. Our findings suggest that the pharmacokinetic profile of Posagil® is similar to the pharmacokinetic profile of Noxafil®. The generic Posagil® seems to have similarly high bioavailability under fed and fasted conditions, offering a higher posaconazole exposure than the original Noxafil® in the fasted state. Hence, Posagil® may be considered a value-added generic product that offers adequate posaconazole exposure under fasted state and fed state, regardless of the concomitant high-fat meal intake.

The Comparative Bioavailability of Fluticasone and Azelastine Delivered as a Single Fixed Dose Combination (MP-AzeFlu) in Comparison to Two Different Formulations of Azelastine and Fluticasone Propionate Following Intranasal Administration in Healthy Chinese Volunteers.

Two studies (Study I and Study II) were conducted in healthy Chinese volunteers to confirm that there was no pharmacokinetic drug interaction between AZE and FLU in MP-AzeFlu. The secondary objective was to evaluate the pharmacokinetic parameters of MP-AzeFlu compared with the commercially available mono-components. Both studies were a randomized, open-label, three-period, six-sequence, single-dose cross-over trial (William's design) conducted at Beijing Hospital (Beijing, China) in September and October of 2019 in 30 healthy adult male and female volunteers. The natural log transformed parameters: AUC0-tlast, AUC0-∞ and Cmax were analyzed. The comparison of PK parameters between MP-AzeFlu and Aze (commercially available) showed that the LS mean ratios (90% CI) values for, AUC0-tlast, AUC 0-∞ and Cmax were 100.29% (94.31-106.66%), 100.76% (94.60-107.32%) and 93.14% (81.47-106.48%). The comparison of PK parameters between MP-AzeFlu and Flu (commercially available) for the bioavailability evaluation showed that the LS mean ratios (90% CI) values for, AUC0-tlast, AUC 0-∞ and Cmax were 83.48% (69.81-99.82%), 100.19% (87.34-114.94%) and 81.91% (68.50-97.95%). The study results confirm that neither the FLU or the AZE component in the combination product (MP-AzeFlu), nor the existing qualitative and quantitative differences in the formulation between the currently marketed AZE and FLU mono-product, display significant potential to impact the systemic exposure of AZE or FLU in Chinese subjects.

Sensitivity Analysis on the Primary Efficacy Results of SB12 (Eculizumab Biosimilar) Phase III Study in Paroxysmal Nocturnal Hemoglobinuria Patients

Background SB12 is a humanized monoclonal antibody that has developed as a proposed biosimilar to reference eculizumab (ECU) and its pharmacokinetics (PK) similarity compared with ECU in healthy subjects has demonstrated. Also, SB12 Phase III study has demonstrated equivalent clinical efficacy by evaluating lactate dehydrogenase (LDH) and comparable safety, PK, pharmacodynamics (PD), and immunogenicity between SB12 and ECU in paroxysmal nocturnal hemoglobinuria (PNH) patients (Jun Ho Jang et al., EHA 2022). Objective To explore the robustness of the primary efficacy results of SB12 Phase III clinical study (NCT04058158) by conducting sensitivity analysis. Methods This was a Phase III randomized, double-blind, multi-national, cross-over study in patients with PNH. A total of 50 patients who aged ≥ 18 years with a confirmed diagnosis of PNH and ≥ 1.5 upper limit of normal range (ULN) of LDH without previous exposure to a complement inhibitor were included. Patients were randomized in 1:1 ratio to either treatment sequences and received either SB12 or ECU by IV infusion every 7 days for the first 4 weeks (initial phase) and 900 mg for the fifth week, followed by 900 mg every 14 days (maintenance phase). The treatment was switched to ECU or SB12 at Week 26, and switched treatment was provided until Week 50. The primary endpoints of this study were LDH level at Week 26 (equivalence declared if the two-sided 95% confidence interval (CI) of the least squares means (LSMeans) difference in LDH level at Week 26 between SB12 and ECU lied within the pre-defined equivalence margin of [−1.2 × ULN, 1.2 × ULN] = [−337.2, 337.2], where ULN = 281 U/L) and time-adjusted area of under the effect curve (AUEC) of LDH from Week 14 to Week 26 and Week 40 to Week 52 (equivalence declared if the two-sided 90% CI of the ratio of geometric LSMeans in time-adjusted AUEC of LDH between SB12 and ECU lied within the pre-defined equivalence margin of [0.77, 1.29]). Sensitivity analysis was performed using complete case analysis or multiple imputation method in modified full analysis set (M-FAS). Complete case analysis is based on complete LDH data, without imputation on missing LDH data. With regard to multiple imputation that assumes missing at random (MAR), missing LDH data was imputed for patients who dropped out of the study prior to the primary analysis timepoint. Missing LDH data was imputed by fully conditional specification (FCS), with the non-missing LDH data at previous visits, treatment sequence, and gender as covariates. In case of sensitivity analysis of LDH level at Week 26, results of linear model based on loge-transformed LDH values were combined first using Rubin's rule and then delta method was used later to report mean difference and 95% CI in original scale. Results In the sensitivity analysis of LDH level at Week 26, for the complete case analysis in M-FAS, estimated LSMeans difference (SB12 − ECU) of LDH level at Week 26 between SB12 and ECU was 34.48 (95% CI [−47.66, 116.62]). In the multiple imputation analysis, estimated LSMeans difference (SB12 − ECU) of LDH level at Week 26 between SB12 and ECU was 26.91 (95% CI [−56.24, 110.05]). Sensitivity analysis results of LDH level at Week 26 provided consistent result with primary analysis (SB12 − ECU: estimated LSMeans difference 34.48, 95% CI [−47.66, 116.62]). Meanwhile, sensitivity analysis of time-adjusted AUEC of LDH from Week 14 to Week 26 and from Week 40 to Week 52, estimated ratio of geometric LSMeans in time-adjusted AUEC of LDH (SB12/ECU) between SB12 and ECU was 1.10 (90% CI [0.99, 1.21]) for the complete case analysis in M-FAS. In the multiple imputation analysis that assumed missing data were MAR, estimated ratio of geometric LSMeans in time-adjusted AUEC of LDH (SB12/ECU) between SB12 and ECU was 1.07 (90% CI [0.93, 1.22]). Sensitivity analysis results of time-adjusted AUEC of LDH from Week 14 to Week 26 and from Week 40 to Week 52 showed consistent result with primary analysis (SB12/ECU: estimated ratio of geometric LSMeans 1.08, 90% CI [0.95, 1.23]). Conclusion This sensitivity analysis results showed consistent results and validated robustness of the primary analysis and it supports the therapeutic equivalence between SB12 and ECU. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

RF23 | PSAT259 Comparable Bioavailability of a Novel Levothyroxine Solution when Administered with Coffee

Abstract Levothyroxine (LT4) is the treatment of choice for hypothyroidism and the second most prescribed medication in the United States. Despite its established efficacy and widespread availability, approximately 40% of patients treated with LT4 fail to achieve thyroid stimulating hormone (TSH) levels within the normal range. Current LT4 product guidelines recommend administration in the fasting state 30-60 minutes before breakfast to avoid a food interaction leading to reduced intestinal absorption of LT4. This recommendation may impact compliance, as over 50% of adult Americans drink coffee every day, 65% of which is consumed during breakfast.While the majority of patients receive LT4 tablets, there is evidence that liquid formulations that bypass the gastric dissolution phase may mitigate the interference with coffee. ThyquidityTM (levothyroxine sodium) oral solution has demonstrated bioequivalence to Synthroid® under fasting conditions and allows individualized dosing flexibility in a variety of clinical scenarios. A bioavailability study was conducted to assess the rate and extent of absorption of the oral LT4 solution (100 mcg /5 mL) administered with coffee compared to administration under fasting conditions in an open label, randomized, two-period, two-treatment, two-sequence, crossover, single dose bioavailability study in 40 healthy adults. A single 600 μg oral dose of LT4 solution (ThyquidityTM, 30 mL) was administered 5 minutes before drinking 8 ounces of American coffee (without milk or sweeteners) or under fasting conditions in each study period. Blood samples were collected for total (bound and free) T4 for 48 hours after drug administration. Treatment periods were separated by a 40-day wash-out period.The ratios of geometric LS means with corresponding 90% confidence intervals (CI) were calculated from the exponential of the difference between the LT4 solution administration 5 minutes prior to coffee and administration under fasting condition for AUC0-48 and Cmax. An absence of a food effect would be concluded if the baseline corrected 90% CIs of this ratio fell within 80.00% to 125.00% for Ln-transformed AUC0-48 and Cmax.Forty healthy adults participated in the trial. There were no serious adverse events (AE) or discontinuations due to AEs. The geometric LS mean ratio of AUC0-48 and Cmax for baseline-adjusted LT4 were 93.98% (90.06-98.07%) and 95.99% (92.64- 99.45%) respectively. The corresponding 90% CIs were included within the acceptance range for bioequivalence.This study demonstrated comparable bioavailability of a single oral 600 μg dose of Thyquidity oral solution administered, 5 minutes prior to coffee or under fasting conditions. These results are consistent with earlier evidence that liquid LT4 overcomes the interference from coffee seen with LT4 tablets and may offer additional flexibility for patients. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m.

RF23 | PSAT258 Comparable Bioavailability of a Novel Levothyroxine Solution taken 10 or 30 minutes prior to a High-Fat, High-Calorie Breakfast

Abstract Levothyroxine (LT4) is the recommended treatment for hypothyroidism and the second most prescribed medication in the US. Several formulations are available, however most patients take LT4 tablets. Evidence suggests that absorption of levothyroxine tablets is decreased when taken with food, especially those rich in soy, iodine, and fiber. In order to avoid erratic absorption of LT4, it is recommended that oral formulations are taken on an empty stomach, 30-60 minutes before breakfast. However, compliance with this recommendation is often difficult for patients with busy schedules or on multiple medications, yet important in patients with conditions that are sensitive to changes in TSH levels such as pregnancy and thyroid cancer.There is evidence that oral liquid LT4 formulations that bypass the gastric dissolution phase of absorption may mitigate this food effect. ThyquidityTM (levothyroxine sodium) oral solution has demonstrated bioequivalence to Synthroid® under fasting conditions and allows individualized dosing flexibility. A bioavailability study was conducted to assess the rate and extent of absorption of the oral LT4 solution (100 mcg /5 mL) administered either 10 or 30 minutes before a standardized high-calorie, high-fat breakfast in an open-label, randomized, single-dose, 2-period, 2-sequence, crossover study. A single 600 μg oral dose of LT4 solution (ThyquidityTM, 30 mL) was administered to healthy adults either 10 or 30 minutes before consuming a 950 kcal, high fat (56%) breakfast in each study period and blood was collected for total (bound and free) T4 for 48 hours after drug administration. Treatment periods were separated by a 40-day wash-out period.The ratios of geometric LS means with corresponding 90% confidence intervals were calculated from the exponential of the difference between the LT4 solution administration 10 and 30 minutes prior to the meal for AUC0-48 and Cmax. An absence of food effect (bioequivalence) would be concluded if the baseline corrected 90% confidence intervals of this ratio fell within 80.00% to 125.00% for Ln-transformed AUC0-48 and Cmax.Forty healthy volunteers participated in the trial, 38 were included in the data analysis. There were no serious adverse events or discontinuations due to AEs. The geometric LS mean ratios of AUC0-48 and Cmax for baseline-adjusted LT4 were 88.74% (84.71-92.95%) and 85.07% (81.1-89.33%) respectively. The corresponding 90% CIs were included within the acceptable range for bioequivalence, indicating the absence of a meaningful difference in LT4 absorption when administering at 10 or 30 minutes before a meal.Based on these results, it may be possible to decrease the interval between the administration of Thyquidity (levothyroxine sodium) oral solution to 10 minutes before breakfast, thus offering patients further dosing flexibility. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m.

A Randomized Pharmacokinetic Study in Healthy Male Subjects Comparing a High-concentration, Citrate-free SB5 Formulation (40mg/0.4ml) and Prior SB5 (Adalimumab Biosimilar).

IntroductionSB5 is an approved biosimilar of adalimumab, a monoclonal anti-tumor necrosis factor (anti-TNF) antibody. This study compared pharmacokinetics (PK), safety, tolerability, and immunogenicity between a new high-concentration, low-volume, and citrate-free formulation (40 mg/0.4 ml, SB5-HC) and the current low-concentration formulation with higher volume (40 mg/0.8 ml, SB5-LC) to evaluate the bioequivalence of the two formulations.MethodsThis study was a randomized, single-blind, two-arm, parallel-group, single-dose study in healthy male subjects. Subjects were randomized to receive either SB5-HC or SB5-LC via subcutaneous injection using a pre-filled syringe. Primary endpoints were the area under the curve of the concentration–time curve from zero to infinity (AUCinf) and maximum serum concentration (Cmax). Bioequivalence was achieved if the 90% confidence intervals (CIs) for the ratios of the geometric least squares mean (LSMean) of primary endpoints were within the pre-defined bioequivalence margins of 0.80–1.25. Secondary endpoints included safety, tolerability, and immunogenicity.ResultsSubjects (n = 188) were randomized to SB5-HC (n = 94) or SB5-LC (n = 94). Baseline characteristics were comparable between the two treatment groups. The mean values for AUCinf and Cmax were similar between the SB5-HC and SB5-LC groups. For the primary endpoints, the geometric LSMean ratios (90% CI) for AUCinf and Cmax were 0.920 (0.8262–1.0239) and 0.984 (0.9126–1.0604), respectively, placing the corresponding 90% CIs well within the pre-defined bioequivalence margin of 0.80–1.25. All treatment-emergent adverse events (TEAEs) were considered mild to moderate and were reported for 44.7% and 51.1% of subjects in the SB5-HC and SB5-LC groups, respectively. Immunogenicity assessed by frequency of occurrence of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) was comparable between groups.ConclusionsThis bridging study demonstrated PK equivalence and comparable safety and tolerability of subcutaneous injection of SB5 via SB5-HC or SB5-LC.Clinicaltrials.gov identifierhttps://clinicaltrials.gov/ct2/show/NCT04514796.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00471-8.

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.

Finerenone in Patients with CKD and T2D by SGLT-2i Treatment: An Analysis of the FIDELIO-DKD Study

IntroductionThe selective, nonsteroidal mineralocorticoid receptor antagonist finerenone was investigated in FIDELIO-DKD in patients with CKD and T2D (NCT02540993). Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are recommended for CKD in T2D to reduce risk of CKD progression. We report a predefined exploratory analysis of patients by SGLT-2i use. MethodsPatients (N=5674) with T2D, urine albumin-to-creatinine ratio (UACR) 30–5000 mg/g and estimated glomerular filtration rate (eGFR) 25–<75 mL/min/1.73 m2 receiving optimized RAS blockade were randomized to finerenone (10 mg daily increasing to 20 mg daily) or placebo. ResultsOf 5674 patients, 259 (4.6%) received SGLT-2i at baseline. Overall, finerenone significantly reduced the primary (time to kidney failure, sustained decrease in eGFR ≥40% from baseline, or renal death) and key secondary CV outcomes (time to CV death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure) vs placebo (p=0.001 and p=0.03, respectively) with no effect on A1C. Results were consistent irrespective of SGLT-2i use at baseline for the primary and key secondary CV outcomes (interaction p-value 0.21 and 0.46, respectively). Reduction in UACR with finerenone was seen without SGLT-2i use (ratio of LS-means 0.68, 0.65–0.71; p<0.0001) and on top of SGLT-2is at baseline (ratio of LS-means 0.75, 0.62–0.90; p=0.0024). Treatment-emergent hyperkalemia events were fewer with SGLT-2i vs no SGLT-2i (post hoc analysis). ConclusionThe benefits of finerenone on kidney and CV outcomes in patients with CKD and T2D appear consistent in the absence or presence of SGLT2i, with UACR improvement observed in patients already receiving SGLT-2i at baseline.

Efficacy and Safety of Finerenone in Patients with CKD and T2D by GLP-1RA Treatment

IntroductionFinerenone is a nonsteroidal mineralocorticoid receptor antagonist that significantly reduces risk of kidney and CV outcomes in patients with CKD and T2D. GLP-1RAs have also been shown to improve CV outcomes in patients with T2D. Mechanisms of action of finerenone and GLP-1RAs are largely independent but their combined effects are unknown. We report outcomes from the FIDELIO-DKD trial in patients by GLP-1RA treatment. MethodsFIDELIO-DKD (NCT02540993) randomized 5734 patients with T2D (UACR 30–5000mg/g; eGFR 25–<75mL/min/1.73 m2; treated with optimized RAS blockade) to finerenone or placebo. Primary outcome was time to kidney failure, sustained eGFR decline ≥40% from baseline, or renal death. Secondary outcomes included time to CV death, non-fatal MI, non-fatal stroke, or hospitalization for heart failure, and change in UACR from baseline to month 4. ResultsOf 5674 patients analyzed, 394 (6.9%) were treated with a GLP-1RA at baseline. There was no between-group interaction for primary kidney (HR 1.17, 95%CI 0.71–1.90 with GLP-1RA; HR 0.80, 95%CI 0.71–0.91 without GLP-1RA; P-interaction 0.15) or secondary CV outcomes (HR 1.02, 95%CI 0.60–1.74 with GLP-1RA; HR 0.85, 95%CI 0.73–0.98 without GLP-1RA; P-interaction 0.51). Reduction in UACR was independent of GLP-1RA use (ratio of LS-means 0.63, 95%CI 0.56–0.70 with GLP-1RA; 0.69, 95%CI 0.67–0.72 without GLP-1RA; P-interaction 0.20). Incidences of hyperkalemia events were similar in patients with and without GLP-1RA use. ConclusionEffects of finerenone on kidney and CV outcomes appear consistent irrespective of GLP-1RA use, with a potential additive benefit for UACR reduction.

14-LB: Finerenone in Patients with CKD and T2D by SGLT2i Treatment: An Analysis of the FIDELIO-DKD Study

Introduction: The selective, nonsteroidal mineralocorticoid receptor antagonist finerenone was investigated in FIDELIO-DKD in patients with CKD and T2D (NCT02540993). Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are recommended for CKD in T2D to reduce risk of CKD progression. We report a predefined exploratory analysis of patients by SGLT-2i use. Methods: Patients (N=5674) with T2D, urine albumin-to-creatinine ratio (UACR) 30-5000 mg/g and estimated glomerular filtration rate (eGFR) 25-&amp;lt;75 mL/min/1.73 m2 receiving optimized RAS blockade were randomized to finerenone (10 mg daily increasing to 20 mg daily) or placebo. Results: Of 5674 patients, 259 (4.6%) received SGLT-2i at baseline. Overall, finerenone significantly reduced the primary (time to kidney failure, sustained decrease in eGFR ≥40% from baseline, or renal death) and key secondary CV outcomes (time to CV death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure) vs. placebo (p=0.001 and p=0.03, respectively) with no effect on A1C. Results were consistent irrespective of SGLT-2i use at baseline for the primary and key secondary CV outcomes (interaction p-value 0.21 and 0.46, respectively). Reduction in UACR with finerenone was seen without SGLT-2i use (ratio of LS-means 0.68, 0.65-0.71; p&amp;lt;0.0001) and on top of SGLT-2is at baseline (ratio of LS-means 0.75, 0.62-0.90; p=0.0024). Treatment-emergent hyperkalemia events were fewer with SGLT-2i vs. no SGLT-2i (post hoc analysis). Conclusion: The benefits of finerenone on kidney and CV outcomes in patients with CKD and T2D appear consistent in the absence or presence of SGLT2i, with UACR improvement observed in patients already receiving SGLT-2i at baseline. Disclosure P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. G. Schernthaner: None. C. Wanner: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Speaker’s Bureau; Self; Eli Lilly and Company. A. Joseph: Employee; Self; Bayer AG. M. F. Scheerer: Employee; Self; AstraZeneca, Bayer AG, Stock/Shareholder; Self; Bayer AG, Eli Lilly and Company, Novo Nordisk A/S. C. Scott: Employee; Self; Bayer PLC. G. Bakris: Consultant; Self; Alnylam Pharmaceuticals, Inc., Bayer AG, Ionis Pharmaceuticals, Merck &amp; Co., Inc., Vascular Dynamics Inc. R. Agarwal: Advisory Panel; Self; Akebia Therapeutics, Inc., Bayer Healthcare Pharmaceuticals Inc., Diamedica, Relypsa Inc., Sanofi US, Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Reata Pharmaceuticals, Inc., Other Relationship; Self; AstraZeneca, Chinook. S. Anker: Consultant; Self; Abbott, Bayer AG, Boehringer Ingelheim International GmbH, Cardiac Dimensions Pty. Ltd., Impulse Dynamics, Novartis AG, Servier Laboratories, Vifor Pharma Management Ltd., Other Relationship; Self; Abbott, Vifor Pharma Management Ltd. G. Filippatos: Other Relationship; Self; Bayer AG, Boehringer Ingelheim International GmbH, Servier Laboratories. B. Pitt: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Consultant; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lexicon Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Sanofi. L. M. Ruilope: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. A. Kooy: Research Support; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Sanofi-Aventis. K. Mccafferty: Advisory Panel; Self; AstraZeneca, Bayer AG, Napp Pharmaceuticals, Pharmacosmos, Vifor Pharma Management Ltd., Research Support; Self; AstraZeneca.

406-P: Efficacy and Safety of Finerenone in Patients with CKD and T2D by GLP-1RA Treatment

Introduction: Finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist that significantly reduced the risk of kidney and CV outcomes in patients with CKD and T2D in the FIDELIO-DKD trial. GLP-1RAs have also been shown to improve CV outcomes in patients with T2D as well as lowering albuminuria. The mechanism of action of finerenone and GLP-1RAs are largely independent but their combined effects are unknown. This analysis will report outcomes from the FIDELIO-DKD trial in patients by GLP-1RA treatment. Methods: FIDELIO-DKD (NCT02540993) randomized 5734 patients to oral finerenone or placebo. Patients with T2D, UACR 30-5000mg/g and eGFR 25-&amp;lt;75mL/min/1.73 m2, and treated with optimized RAS blockade, were included. The primary kidney outcome was time to kidney failure, sustained eGFR decline ≥40% from baseline, or renal death. Secondary outcomes included time to CV death, non-fatal MI, non-fatal stroke, or hospitalization for heart failure, and change in UACR from baseline to month 4. Results: Of the 5674 patients analyzed, 394 (6.9%) were treated with a GLP-1RA at baseline. Patients treated with GLP-1RAs at baseline had a higher BMI and A1C, with higher diuretic and statin use, lower median UACR and less presence of CVD than those who were not. There was no between-group interaction for the primary kidney (HR 1.17, 95% CI 0.71-1.90 with GLP-1RA; HR 0.80, 95% CI 0.71-0.91 without GLP-1RA; P-interaction 0.15) or secondary CV outcomes (HR 1.02, 95% CI 0.60-1.74 with GLP-1RA; HR 0.85, 95% CI 0.73-0.98 without GLP-1RA; P-interaction 0.51). The reduction in UACR was independent of GLP-1RA use (ratio of LS-means 0.63, 95% CI 0.56-0.70 with GLP-1RA; 0.69, 95% CI 0.67-0.72 without GLP-1RA; P-interaction 0.20). Overall, incidences of hyperkalemia events were similar in patients with and without GLP-1RA use. Conclusion: The effects of finerenone on kidney and CV outcomes appear consistent irrespective of GLP-1RA use, with a potential additive benefit for UACR reduction. Disclosure P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. A. Z. Lage: Employee; Self; Bayer Healthcare Pharmaceuticals Inc. C. Scott: Employee; Self; Bayer PLC. G. Bakris: Consultant; Self; Alnylam Pharmaceuticals, Inc., Bayer AG, Ionis Pharmaceuticals, Merck &amp; Co., Inc., Vascular Dynamics Inc. R. Agarwal: Advisory Panel; Self; Akebia Therapeutics, Inc., Bayer Healthcare Pharmaceuticals Inc., Diamedica, Relypsa Inc., Sanofi US, Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Reata Pharmaceuticals, Inc., Other Relationship; Self; AstraZeneca, Chinook. S. Anker: Consultant; Self; Abbott, Bayer AG, Boehringer Ingelheim International GmbH, Cardiac Dimensions Pty. Ltd., Impulse Dynamics, Novartis AG, Servier Laboratories, Vifor Pharma Management Ltd., Other Relationship; Self; Abbott, Vifor Pharma Management Ltd. G. Filippatos: Other Relationship; Self; Bayer AG, Boehringer Ingelheim International GmbH, Servier Laboratories. B. Pitt: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Consultant; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lexicon Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Sanofi. L. M. Ruilope: None. A. Amod: Advisory Panel; Self; Aspen South Africa, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Servier Laboratories, Consultant; Self; Servier Laboratories, Other Relationship; Self; Bayer AG, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Servier Laboratories. M. Marre: Board Member; Self; Merck Sharp &amp; Dohme Corp., Consultant; Self; Novo Nordisk. A. Joseph: Employee; Self; Bayer AG. Funding Bayer AG

Computer-delivered brief alcohol intervention for patients with liver disease: a randomized controlled trial.

Reducing alcohol consumption by liver disease patients can reduce morbidity and mortality. This study compared a computer-delivered brief alcohol intervention (cBAI) with standard care in a sample of US military veterans with liver disease. Multi-site, randomized controlled trial of a cBAI plus standard care (n=67) versus standard care only (n=71). Participants were assessed at baseline and 3- and 6-month follow-up. US Veterans Health Administration liver clinics. Participants were mostly male and diagnosed with hepatitis C. A cBAI tailored to veterans with liver disease and consisting of assessment and personalized feedback. Standard care was brief education and advice about alcohol and liver disease. Primary outcomes were self-reported number of drinking days and unhealthy drinking days (defined as more than two drinks for men and more than one for women) in the past 30days at 6-month follow-up. Secondary outcomes were these two variables at 3-month follow-up, and drinks consumed per drinking day, depression and overall health at 3- and 6-month follow-ups. Missing data were imputed using multiple imputation. Compared with standard care, cBAI participants reported significantly fewer drinking days at 6-month follow-up and fewer unhealthy drinking days at both 3- and 6-month follow-ups. Least square means (LS-means) for number of drinking days were 3.78 for the cBAI condition and 6.89 for the standard care condition at 6months [LS-mean ratio=3.78/6.89=0.55, 95% confidence interval (CI)=0.34, 0.89]. LS-means for number of unhealthy drinking days were 1.04 for the cBAI condition and 2.57 for the standard care condition at 3-month follow-up (LS-mean ratio=1.04/2.57=0.41, 95% CI=0.19, 0.85). At 6-months follow-up, LS-means were 1.18 for the cBAI condition and 2.75 for the standard care condition (LS-mean ratio=1.18/2.75=0.43, 95% CI=0.20, 0.91). A computer-delivered brief alcohol intervention reduced drinking days and unhealthy drinking days at 6-month follow up in military veterans with liver disease compared with brief education and advice to reduce consumption.

Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin (U-500R) Administered via Continuous Subcutaneous Insulin Infusion (CSII) vs. Subcutaneous Injection (SCI) in Adults with Type 2 Diabetes and High Insulin Requirements

There have been no euglycemic clamp studies on U-500R in obese patients with type 2 diabetes mellitus (T2DM) and high insulin requirements. This open-label, randomized, 2-way crossover, euglycemic clamp study (NCT02588950) evaluated PK/PD of U-500R administered by CSII (using an investigational Omnipod® U-500 Insulin Management System) compared to SCI (using a U-100 syringe), in adults with T2DM requiring &amp;gt;150 U/day of insulin. Subjects (N=11, mean BMI: 39.6 kg/m2, mean A1C: 10.2%) each received a 100 U dose via CSII [primed with a 12-hour (hour) U-500R basal infusion] and a single SCI, both followed by a 24 hour clamp. Serum insulin concentrations were corrected for endogenous insulin using C-peptide for both administration methods. Basal infusion values in CSII were adjusted with baseline and model corrections. Following SCI, using model corrected method, time of maximum observed drug concentration (tmax) was about 1.5 hour longer compared to CSII [LSmean ratio (90% CI): 1.46 (1.08, 1.97)]. There was no statistically significant difference between CSII and SCI in median tmax, areas under the curve [AUC(0-24), AUC(0-tlast)], and maximum concentration. There was no statistically significant difference between CSII and SCI in median time to maximum glucose infusion rate (GIR) [CSII: 7.2 hour; SCI: 8 hour], median time of 50% of maximum GIR before Rmax (tRmax50) [CSII: 2.85 hour; SCI: 3.59 hour], and median time to last GIR [CSII: 18.9 hour; SCI: 14.6 hour]. No severe hypoglycemia was reported. U-500R was well tolerated whether given by syringe or CSII. The PK/PD profiles and time action parameters were similar with both methods of administration. Disclosure X. Ma: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R.P. Prescilla: None. S. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. L. Morrow: Stock/Shareholder; Self; ProSciento. Employee; Spouse/Partner; Eli Lilly and Company. J.A. Jackson: Other Relationship; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Johnson: Employee; Self; Eli Lilly and Company. D. Leishman: Employee; Self; Eli Lilly and Company.

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48-0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78-2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation. Patara Pharma.

A bioequivalence study of proposed bevacizumab biosimilar, MYL-1402O (A) vs EU-Avastin (B) and US-Avastin (C).

e14034 Background: MYL-1402O is a proposed bevacizumab biosimilar. The similarity of MYL-1402O to Avastin has been demonstrated in physicochemical analyses, and nonclinical studies. Methods: This single-center, randomized, double blind, three-arm, parallel-group, study was conducted in healthy adult male volunteers. The primary objective of this study was to establish PK similarity of A to B and C, and B to C. Subjects were randomized to receive either A, B or C 1 mg/kg over 90 minutes as an intravenous infusion. Dose was selected based on the lower dose in the linear range of PK and acceptable safety in healthy volunteers. Bioequivalence was to be concluded if the 90% CIs of the ratios (A/B, A/C and B/C) of LS means of the natural log transformed AUC0-inf were within 80% to 125%. AUC0-t, Cmax, tmax, kel and t½ were assessed as secondary PK parameters. Results: A total of 111 subjects (37/treatment) were enrolled and 110 [37 (A), 36 (B), 37(C)] were included in the analysis. Bioequivalence was demonstrated between A and B, A and C and between B and C. LS mean ratios were close to 1, and 90% CIs were within 0.80 to 1.25 for all of the comparisons. The secondary PK parameters were also comparable with the 90% CIs for ratios of AUC0-t and Cmax within 80%-125%. A total of 313 TEAEs were reported, 116 by 33 (89%) subjects who received A, 99 by 29 (78%) subjects who received B and 98 by 28 (76%) subjects who received C. Most TEAEs were consistent with the clinical data of bevacizumab (Avastin). No serious or unexpected TEAEs were reported. TEAEs were grade 1 or grade 2 in severity. The anti-drug antibodies are being evaluated (pending results). Conclusions: These results confirm bioequivalence of Myl-1402O vs. EU-Avastin and US-Avastin. All treatments were well tolerated and no significant safety issues emerged. Clinical trial information: NCT02469987 Clinical trial information: NCT02469987.

Impact of food, alcohol and pH on modified-release hydrocortisone developed to treat congenital adrenal hyperplasia.

BackgroundWe developed a modified-release hydrocortisone, Chronocort, to replace the cortisol rhythm in patients with congenital adrenal hyperplasia. Food, alcohol and pH affect drug absorption, and it is important to assess their impact when replicating a physiological rhythm.Subjects and methodsIn vitro dissolution to study impact of alcohol and pH on Chronocort. A phase 1, three-period, cross over study in 18 volunteers to assess the impact of food on Chronocort and to compare bioavailability to immediate-release hydrocortisone.ResultsIn vitro dissolution of Chronocort was not affected by gastrointestinal pH up to 6.0 nor by an alcohol content up to 20% v/v. Food delayed and reduced the rate of absorption of Chronocort as reflected by a longer Tmax (fed vs fasted: 6.75 h vs 4.5 h, P = 0005) and lower Cmax (549.49 nmol/L vs 708.46 nmol/L, ratio 77% with CI 71–85). Cortisol exposure was similar in fed and fasted state: Geo LSmean ratio (CI) AUC0t for fed/fasted was 108.33% (102.30–114.72%). Cortisol exposure was higher for Chronocort compared to immediate-release hydrocortisone: Geo LSmean ratios (CI) 118.83% (111.58–126.54%); however, derived free cortisol showed cortisol exposure CIs were within 80.0–125.0%: Geo LSmean ratio (CI) for AUC0t 112.73% (105.33–120.65%).ConclusionsGastric pH ≤6.0 and alcohol do not affect hydrocortisone release from Chronocort. Food delays Chronocort absorption, but cortisol exposure is similar in the fasted and fed state and exposure as assessed by free cortisol is similar between Chronocort and immediate-release hydrocortisone.

Pharmacokinetic and Safety of CT-P10, a Biosimilar Candidate to the Rituximab Reference Product, in Patients with Newly Diagnosed Advanced Stage Follicular Lymphoma (AFL)

Background: CT-P10 is a biosimilar candidate to the reference rituximab product, EU-approved MabThera® and US-licensed Rituxan®. CT-P10 has an identical amino acid sequence and highly similar physicochemical and in vitro functional properties to its reference drug. In patients with rheumatoid arthritis, CT-P10 has demonstrated compelling similarity in pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety and immunogenicity (Yoo DH, et al. Arthritis Rheum. 2013;65(10):1736).Objective: The goal of this study was to demonstrate PK similarity of CT-P10 to rituximab, each administered in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed Advanced Follicular Lymphoma (AFL) (NCT02162771) (Kim WS et al. Blood. 2015;126(23): 5111). The results of PK, PD, safety and immunogenicity up to Core Cycle 4 (12 weeks) are presented here from this ongoing study.Methods: Patients with AFL were randomized 1:1 to receive infusion (375mg/m2) of either CT-P10 or rituximab, at a 3-week interval, in combination with CVP. PK analysis was conducted in terms of AUCtau and Cmax at steady state, Core Cycle 4, as primary PK endpoints. PK parameter values considered as outliers determined by robust regression outlier testing were excluded from the pharmacokinetic primary analysis.Results: In total, 121 patients were randomly assigned to receive either CT-P10 (n=59) or rituximab (n=62) in combination with CVP. Result of CT-P10 PK at Core Cycle 4 was similar to that of rituximab. The ratios (90% CI) of geometric least square means (CT-P10 to rituximab treatment group) were 102.3% (94.1%-111.2%) for AUCtau and 100.7% (93.8%-108.0%) for CmaxSS at Core Cycle 4. The 90% CIs of ratio of geometric LS means for both AUCtau and CmaxSS were entirely contained within the equivalence margin of 80% to 125% (Table 1 and Figure 1). Mean serum concentrations of the study drug were highly similar for the 2 treatment groups at each time point (Core Cycle 1 to 4).The B-cell kinetics was similar up to Core Cycle 4 in the 2 treatment groups. Median number of B-cells decreased to below the lower limit of quantification (LLoQ) (20 cells/μL) 1 hour after the end of infusion at Core Cycle 1 and remained below the LLoQ at each subsequent cycle, up to and including Core Cycle 4.The proportion of patients with a positive anti-drug antibody up to Core Cycle 4 at post-treatment visits was similar between the 2 treatment groups; 3/59 (5.1%) patients and 2/62 (3.2%) patients in the CT-P10 and rituximab groups, respectively.In addition, CT-P10 was well tolerated and the safety profile of CT-P10 up to Core Cycle 4 was similar to that of rituximab. The number of patients who experienced at least 1 treatment emergent adverse event (TEAE) was 43 (72.9%) patients and 41 (66.1%) patients in CT-P10 and rituximab treatment groups, respectively. The proportion of patients who experienced at least 1 treatment emergent serious adverse event considered by the investigator to be related to the study treatment was similar between the 2 treatment groups; 2/59 (3.4%) patients and 2/62 (3.2%) patients in the CT-P10 and rituximab groups, respectively. The frequencies of adverse events special interest (AESI) were similar between the 2 treatment groups (Table 2).Conclusion: This study demonstrated similarity of PK in terms of AUCtau and CmaxSS between CT-P10 and rituximab in AFL patients. The B-cell kinetics and immunogenicity were comparable between the two treatment groups. CT-P10 was well tolerated with a safety profile comparable to that of rituximab up to and including Core Cycle 4 (12 weeks). [Display omitted] [Display omitted] [Display omitted] DisclosuresCoiffier:Celltrion, Inc.: Consultancy, Honoraria. Sancho:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jurczak:Celltrion, Inc: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; Bayer: Research Funding; Janssen: Research Funding. Kim:Celltrion, Inc.: Research Funding. Nagarkar:Celltrion, Inc.: Research Funding. Zhavrid:Celltrion, Inc.: Research Funding. Hernandez Rivas:Celltrion, Inc.: Research Funding. Prokharau:Celltrion, Inc.: Research Funding. Zodelava:Celltrion, Inc.: Research Funding. Osmanov:Celltrion, Inc.: Research Funding. Ogura:SymBio Pharmaceuticals: Consultancy, Honoraria; Celltrion, Inc.: Consultancy, Honoraria. Buske:Celltrion, Inc.: Consultancy, Honoraria. Kwak:Celltrion, Inc.: Consultancy. Kim:Celltrion, Inc.: Consultancy, Honoraria.

Pharmacokinetic Comparison and Bioequivalence of a New Generic Formulation of Lenalidomide 25 mg Capsules versus Revlimid in Healthy Volunteers under Fasting Conditions

Lenalidomide is an immunomodulatory agent with direct antiproliferative, proapoptotic, and antiangiogenic effects, combined with long-term immunostimulatory effects which improve both cellular and humoral immune function. Lenalidomide is indicated for the treatment of patients with multiple myeloma, who are previously untreated and not eligible for transplant. Lenalidomide has dual effects, involving both direct tumoricidal properties and immunomodulatory activity. A single centre, open-label, single-dose, randomized, two-period, two-treatment, two sequence, crossover, comparative bioavailability study was conducted in 24 healthy volunteers to compare pharmacokinetics profile of a new lenalidomide generic formulation (lenalidomide capsules 25 mg, Hikma Pharmaceuticals) with those of the reference product (Revlimid, Celgene Gmbh, United Kingdom). The study was conducted at Pharma Medical Research Inc. (Canada) in accordance with Good Clinical Practices and the applicable regulatory requirements. One capsule of each formulation was administered with 240 mL of water after a 10 hr overnight fast. In each study period, eighteen (18) blood samples were collected by venepuncture in pre-cooled Vacutainers containing EDTA. First blood sample (2 × 6 mL) was collected prior to drug administration while the others (1 × 6 mL each) were collected at 0.167, 0.333, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12 and 14 h after drug administration. The drug product administrations were separated by a washout period of 7 calendar days. Plasma samples were analyzed for lenalidomide by a validated LC/MS/MS method. For a 25 mg dose of lenalidomide, the analytical range was approximately 2 ng/mL to 1000 ng/mL. Descriptive statistics were used to summarize adverse events (AE), safety results and demographic variables (age, height, weight and BMI) The main pharmacokinetic parameters of interest for this study were Cmax, AUC0-T and AUC0-∞. Other parameters such as Tmax, AUCT/∞, Kel and T1/2el were provided for information purposes only. The natural logarithmic transformation of Cmax, AUC0-T and AUC0-∞ was used for all statistical inference. The mean (CV %) of Cmax, AUC0-T and AUC0-∞ (for lenalidomide were 467.1 ng/mL (21%), 1395.4 ng.h/mL (12%) and 1448.7 ng.h/mL (13%) versus 454.3 ng/mL (27%), 1396.3 ng.h/mL (13%) and 1448.1 ng.h/mL (13%) for Revlimid. The 90% confidence intervals of Cmax, AUC0-T and AUC0-∞ for lenalidomide were (93.7%-116.3%), (97.8%-102.3%) and (97.9%-102.4%) respectively. The ratio of the geometric LS means for the test to reference Cmax, AUC0-T and AUC0-∞ were 104.4%, 100.0% and 100.1% respectively. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range for bioequivalence. Based on these statistical outcomes it was concluded that the two formulations of lenalidomide exhibited comparable pharmacokinetic profiles.

Abstract B153: Effect of food and gastric pH modifiers on the pharmacokinetics of AZD9291

Abstract Background AZD9291 is a potent, oral, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for sensitizing (EGFRm) and T790M resistance mutations. Clinical activity has been demonstrated in patients with advanced EGFR T790M positive non-small cell lung cancer (NSCLC). We report results from two Phase I clinical studies, one investigating the effect of food, and another on the impact of increased gastric pH, on the pharmacokinetics (PK) of AZD9291. Design The studies were conducted in accordance with ICH/GCP guidance; protocols were reviewed and approved by IEC and IRB prior to implementation. The likely commercial formulation of AZD9291 80 mg film-coated tablet was used. The Food effect study (NCT02163733) had two parts: A and B. Part A was an open-label randomized two-period crossover design where the primary objective was to evaluate the effect of food on AZD9291 PK following oral dosing of 80 mg tablet in patients with EGFRm+ NSCLC, whose disease had progressed following treatment with a prior EGFR-TKI. Part B is an ongoing extension phase where patients may receive continuous AZD9291 80 mg dosing, if they continue to derive benefit, with safety monitoring conducted for up to 1 year. The Gastric pH interaction study (NCT02224053) was an open-label, two-fixed-period study with primary objective to evaluate the effect of omeprazole 40 mg on AZD9291 exposure in healthy, male volunteers. In Period 1, subjects received omeprazole on Days 1-4 and on Day 5 they received AZD9291 and omeprazole after a 10-hour fast. In Period 2, after a washout of at least 21 days, subjects received AZD9291 alone after a 10-hour fast. After Period 1 the AZD9291 AUC0-72 exposure was assessed and subjects with exposures exceeding set limits were withdrawn and replaced. In both studies, blood samples were taken serially post dose in each treatment period to determine concentrations of AZD9291 and its active metabolites (AZ5104 and AZ7550). The safety and tolerability of AZD9291 was a secondary objective in the Food effect (fed and fasted state) and Gastric pH interaction studies (AZD9291±omeprazole). Results Food effect study (Part A only): 38 patients were assigned to treatment. Geometric LS mean ratios comparing fed to fasted treatments for AZD9291 Cmax and AUC0-72 were 92.75% (81.40, 105.68) and 106.05% (94.82, 118.60), respectively and 90% confidence intervals were contained within the predefined equivalence limits of 70% to 143%. Gastric pH interaction study: 68 subjects were assigned to treatment and 47 subjects completed both study periods. The geometric LS mean ratios comparing AZD9291 Cmax and AUC when given with omeprazole compared to administration of AZD9291 alone were 101.65% (94.65, 109.16) and 106.66% (100.26, 113.46), respectively and 90% confidence intervals were within the equivalence limits of 80% to 125%. In addition, neither food nor co-administration of AZD9291 with omeprazole had a clinically relevant effect on exposure (Cmax and AUC) for the AZD9291 metabolites AZ5104 and AZ7550. Oral administration of 80 mg AZD9291 was well tolerated, with no deaths or discontinuations due to AE in either study. Conclusions These studies suggest that AZD9291 can be administered without regard to food and no restrictions are necessary when administered with gastric pH modifying agents. AZD9291 was well tolerated under fed or fasted conditions, and when co-dosed with omeprazole. Citation Format: Karthick Vishwanathan, Paul A. Dickinson, Khanh Bui, Doris K. Weilert, Karen So, Karen Thomas, Eleanor A. Lisbon, Ruth Plummer. Effect of food and gastric pH modifiers on the pharmacokinetics of AZD9291. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B153.

Safety and pharmacokinetics of oxycodone DETERx administered intranasally in recreational opioid users

s / Drug and Alcohol Dependence 146 (2015) e118–e201 e163 middle school students described parental disapproval as a deterrent, high school students also cited friend disapproval as deterring use. Across all groups, thosewhohad not tried e-cigs described lack of “coolness” as an additional deterrent. Conclusions: This qualitative study indicated several reasons why youth initiated, abstained from and discontinued e-cigarettes. While there were some common themes across groups, different themes also emerged across the age groups. Understanding these factors may inform e-cig prevention messages. Financial Support: This work was supported by the National Institute on Drug Abuse grant P50DA009241. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.359 Safety and pharmacokinetics of oxycodone DETERx administered intranasally in recreational opioid users A. Kopecky1, Alison B. Fleming1, Patrick K. Noonan2 1 Collegium Pharmaceutical, Inc., Canton, MA, United States 2 PK Noonan Pharmaceutical Consulting, LLC, Williamsburg, VA, United States Aims: Oxycodone DETERx is a multi-particulate, abusedeterrent formulation designed to retain ER properties following common methods of tampering. The purpose of this study was to assess the safety and the pharmacokinetics (PK) of crushed DETERx capsule contents administered IN (DETERx IN) compared with 2 control treatments: immediate-release (IR) oxycodone powder administered IN (Oxy IN) and intact DETERx capsules administered orally (DETERx PO). Methods: Open-label, randomized, naltrexone-blocked, 3treatment, 3-period, crossover comparison study. Safety and PK of 40mg doses of DETERx IN, Oxy IN, and DETERx PO were compared innondependent, recreational opioid users experiencedwith IN administration (n=13). DETERx capsule contents were crushed using themost aggressive crushingmethod identified in previously conducted studies. Plasma samples were collected at pre-specified time points and analyzed using a LC–MS/MS method. PK parameters Cmax, AUCINF, TmaxandAbuseQuotient (AQ)were calculated. Safety assessments included treatment-emergent adverse events, vital signs, oxygen saturation and nasal cavity assessments. Results: Cmax LSMean ratio for DETERx IN relative to Oxy IN was 59.0%. Cmax LSMean ratio for DETERx IN relative to DETERx PO was 79.6%. DETERx IN and DETERx PO both had a median Tmax of 5.0h, longer than Oxy IN (3.0h). Oxy IN had the highest AQ value (42.5ng/ml/h); AQ values for DETERx IN and DETERx POwere similar (8.5 and 8.4ng/ml/h, respectively). AUCINF values were similar for all treatments. There weremore spontaneously reported nasalrelated AEs and a greater number of episodes of need to blow nose post insulation of crushed DETERx compared with Oxy. Conclusions: Crushing and snorting DETERx capsule contents produces relatively lower plasma concentrations of oxycodone compared with intact DETERx PO and Oxy IN, indicating that a concentration driven euphoric effect sought by drug abusers may not be achieved. Due to the higher number of nasal-related AEs, abusers may find DETERx less desirable. Financial Support: Collegium Pharmaceutical. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.360 A novel behavioral activation intervention for smoking cessation; mechanisms of change Catalina Kopetz1, Laura MacPherson2, Avery Mitchell 2, Alexandra HoustonLudlam2, Reinout W. Wiers3, Helle Larsen3 1 Psychology, Wayne State University, Detroit, MI, United States 2 Psychology, University of Maryland, College Park, MD, United States 3 Psychology, University of Amsterdam, Amsterdam,