Relative Bioavailability of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Administered With and Without a Spacer: Results of a Phase I,Randomized, Crossover Trial in Healthy Adults

PurposeThe triple combination therapy budesonide/glycopyrrolate/formoterol fumarate in a metered dose inhaler (BGF MDI), formulated by using innovative co-suspension delivery technology, is a new inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β₂-agonist fixed-dose combination for the maintenance treatment of COPD. For some patients, the use of an MDI may be optimized with a spacer. This Phase I study assessed the effect of a spacer on lung exposure, total systemic exposure, and safety of BGF MDI 320/36/9.6 μg in healthy subjects.Methods: This randomized, open-label, crossover study assessed the pharmacokinetic and safety profiles of BGF MDI in healthy adult subjects who received a single dose of BGF MDI 320/36/9.6 μg (administered as 2 inhalations with 160/18/4.8 μg per actuation) in 4 regimens: without spacer and no charcoal; with spacer and no charcoal; without spacer and with charcoal; and with spacer and with charcoal. Primary objectives were to assess total systemic exposure (without charcoal) and lung exposure (with charcoal) of budesonide, glycopyrronium, and formoterol administered as BGF MDI with and without a spacer. Safety was also assessed.FindingsIn total, 56 subjects were randomized (mean age, 29.9 years; 60.7% male, 17.9% former smokers). For systemic exposure (without charcoal), the spacer/without spacer ratio, expressed as a percentage (intrasubject %CV) of C_max and AUC_0–tlast, respectively, was 152.0 (47.5) and 132.8 (43.6) for budesonide, 240.6 (80.2) and 154.7 (73.4) for glycopyrronium, and 165.6 (50.7) and 98.6 (53.8) for formoterol. For lung exposure (with charcoal), the spacer/without spacer ratio percentage (%CV) of C_max and AUC_0–tlast, respectively, was 183.6 (65.9) and 198.4 (71.5) for budesonide, 262.0 (91.8) and 373.9 (120.7) for glycopyrronium, and 222.9 (56.3) and 385.2 (147.0) for formoterol. Subjects who were judged to have suboptimal inhalation technique without a spacer (those in the lowest drug exposure quartile based on AUC_0–tlast) had the greatest increase in both total systemic and lung exposure when a spacer was used versus no spacer. Subjects in the highest quartile had a minimal change in both total systemic and lung exposure when the spacer was used. Treatment-emergent adverse events (TEAEs) (all mild/moderate) reported by >1 subject per regimen were headache, cough, and dizziness. One subject withdrew because of TEAEs of headache and presyncope (neither considered treatment-related).ImplicationsDrug delivery can be improved for subjects with suboptimal MDI inhalation technique when using a spacer device with BGF MDI triple therapy. ClinicalTrials.gov identifier: NCT03311373.     

Ethnic Sensitivity Study of the Extrafine,Single-Inhaler,Triple Therapy Beclomethasone Dipropionate,Formoterol Fumarate,and Glycopyrronium Bromide Pressurized Metered Dose Inhaler in Japanese and Caucasian Healthy Individuals: A Randomized,Double-Blind,Single-Dose Crossover Study

PurposeA number of single-inhaler, fixed-dose, triple combinations are available for the management of chronic obstructive pulmonary disease and/or asthma. One of these is the extrafine formulation beclomethasone dipropionate, formoterol fumarate, glycopyrronium bromide (BDP/FF/GB). Given that differences in ethnicity can result in differences in systemic exposure, we evaluated the relative pharmacokinetic (PK) profiles of BDP/FF/GB in Japanese vs Caucasian healthy volunteers to assess the need for dose adjustment.MethodsThis randomized, double-blind, single-dose, 4-way crossover study recruited healthy men and women 20 to 55 years of age; for each Japanese person a Caucasian was enrolled who matched in terms of sex, age, and weight. Study treatments included BDP/FF/GB 200/12/25 and 400/12/25 μg (therapeutic), 800/48/100 μg (supratherapeutic), and placebo. PK blood samples were taken up to 24 hours for evaluation of BDP, beclomethasone 17-monopropionate (B17MP, an active metabolite of BDP), and formoterol and up to 48 h for GB. The primary objective was to characterize the PK profiles of BDP, FF, and GB after administration of a single dose of BDP/FF/GB in Caucasian and Japanese healthy volunteers in terms of the AUC_0–t and C_max of B17MP, formoterol, and GB.FindingsOf the 32 recruited participants (16 Japanese and 16 Caucasian ), 30 completed the study. A clear plasma exposure dose-response relationship was found for all 4 molecules. B17MP C_max geometric mean ratios for Japanese vs Caucasian participants for the 3 study treatments ranged from 1.17 to 1.26, and AUC_0–t ratios ranged from 1.16 to 1.22; thus, the findings were comparable between the ethnicities. Formoterol exposure was higher in Japanese than Caucasian participants (C_max, 1.22–1.53; AUC_0–t, 1.23–1.40). The GB C_max with BDP/FF/GB 400/12/25 μg (1.09) and AUC_0–t values for all three doses (0.98–1.17) were comparable in the 2 populations, but C_max with 200/12/25 and 800/48/100 μg were higher in Japanese participants (1.32 and 1.42, respectively). Pharmacodynamic (cortisol, potassium, glucose, blood pressure, heart rate, and QT interval with the Fridericia correction) and safety profile results were similar in the 2 ethnicities, with most patients not experiencing any adverse events.ImplicationsExposure to BDP/FF/GB pressurized metered dose inhaler at therapeutic and supratherapeutic doses was associated with higher plasma levels in Japanese versus Caucasian healthy volunteers. These PK differences did not translate into meaningful differences in the safety or pharmacodynamic parameters assessed in this study and were consistent with the results of other long-term (52-week) published studies. Dose adjustments in Japanese people are not deemed necessary.ClinicalTrials.gov identifierNCT03859414.     

A Randomized Comparison of the Pharmacokinetics and Bioavailability of Fluticasone Propionate Delivered via Xhance Exhalation Delivery System Versus Flonase Nasal Spray and Flovent HFA Inhalational Aerosol

PurposeThe exhalation delivery system with fluticasone propionate (Xhance®) has been shown to deliver drug substantially more broadly in the nasal cavity (particularly into superior/posterior regions), with less off-target loss of drug to drip-out and swallowing, than conventional nasal sprays. This open-label study evaluated the systemic bioavailability of Xhance® by comparing the pharmacokinetic (PK) properties of a single dose of fluticasone from 3 products administering the drug using 3 different devices: Xhance®, Flonase® (fluticasone propionate inhalational nasal spray), and Flovent® HFA (fluticasone propionate inhalational aerosol).MethodsThis open-label study was conducted in 2 parts. Study part 1 compared systemic exposure with a single dose of Xhance® 186 or 372 μg versus Flonase® 400 μg (3-way, 3-treatment, 3-sequence, randomized crossover in healthy subjects; n = 90). A separate study, part 2, under the same umbrella protocol, compared systemic exposure with Xhance® 372 μg versus Flovent® HFA 440 μg (2-way, 2-treatment, 2-sequence, randomized crossover in patients with mild to moderate asthma; n = 30).FindingsWith Xhance® 186 μg, the geometric least squares mean (LSM) C_max was higher than with Flonase® 400 μg (16.02 vs 11.66 pg/mL, respectively; geometric mean ratio [GMR], 137.42%) and the geometric LSM AUC_0–∞ values were similar (97.30 vs 99.61 pg · h/mL; GMR, 97.78%). With Xhance® 372 μg, the geometric LSM C_max and AUC_0–∞ were higher than with Flonase® 400 μg (C_max, 23.50 vs 11.66 pg/mL [GMR, 201.53%]; AUC_0–∞, 146.61 vs 99.61 pg · h/mL [GMR, 147.19%]). In part 2, the geometric LSM C_max and AUC_0–∞ values were lower with Xhance® 372 μg than with Flovent® HFA 440 μg (C_max, 25.28 vs 40.02 pg/mL [GMR, 63.18%]; AUC_0–∞, 205.78 vs 415.16 pg · h/mL [GMR, 49.57%]).ImplicationsSimilar intranasal doses of Xhance® (372 μg) and Flonase® (400 μg) are clearly not bioequivalent. Systemic exposure is very low with all products. Systemic exposure is higher with Xhance® than with Flonase® and substantially lower than with Flovent® HFA 440 μg and, based on dose normalization, Flovent® HFA 220 μg. ClincalTrials.gov identifier: NCT02266927.     

Celecoxib-tramadol co-crystal: A Randomized 4-Way Crossover Comparative Bioavailability Study

PurposeCelecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose pharmacokinetic (PK) parameters of CTC with those of the individual reference products from the United States, immediate-release celecoxib and tramadol, taken alone and simultaneously to determine their systemic exposure.MethodsThis was a single-center, randomized, single-dose, open-label, 4-period, 4-sequence, crossover study conducted in healthy subjects between October and December 2016. Study treatments included 200-mg CTC (equivalent to 112-mg celecoxib and 88-mg tramadol; Treatment-1); 100-mg tramadol (Treatment-2); 100-mg celecoxib (Treatment-3); and 100-mg celecoxib plus 100-mg tramadol (Treatment-4). The PK parameters of interest were C_max, AUC_0–T, and AUC_0–∞, which were also calculated normalized to the dose. T_max was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the two-sided 90% CI of the ratio of geometric mean values for the C_max, AUC_0–T, and AUC_0–∞ was based on ln-transformed data, and T_max was rank-transformed.FindingsThirty-six subjects aged 18 to 55 years (21 male subjects, 15 female subjects; mean age, 35 years) participated in the study. Celecoxib from CTC presented a lower C_max, reduced AUCs, and a faster T_max. The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC. For Treatment-1, -3, and -4, celecoxib PK parameters were 259, 318, and 165 ng/mL (C_max), respectively; 1930, 2348, and 1929 ng • h/mL (AUC_0–T); and 1.5, 3.0, and 2.5 hours (T_max). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower C_max and AUCs as well as a longer T_max. Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for C_max; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC_0–T; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for T_max. Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4.ImplicationsThe aim of this study was to compare the PK profile of the US-marketed tramadol and celecoxib products with CTC to determine their systemic exposure and to validate the dosing regimen for a subsequent pivotal factorial Phase 3study. PK parameters of each active component in CTC were favorably modified by co-crystallization and did not result in higher systemic exposure compared with US-marketed celecoxib, tramadol, and their concomitant administration. © 2021 Elsevier HS Journals, Inc.     

A single-dose,three-period,six-sequence crossover study comparing the bioavailability of solution,suspension, and enteric-coated tablets of magnesium valproate in healthy Mexican volunteers under fasting conditions

Background: Valproic acid has been associated with a highly variable intersubject absorptive phase; therefore, magnesium salt (magnesium valproate [MgV]) was developed to diminish variation during enteric absorption.Objectives: The aims of this study were to assess the pharmacokinetics of single oral doses of MgV 500-mg solution, suspension, and enteric-coated tablets in a healthy Mexican population, and to compare formulation-related differences.Methods: This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy Mexican volunteers aged 18 to 45 years. In each period, subjects received single oral doses of 500-mg MgV solution, suspension, and enteric-coated tablet formulations, with a 7-day washout period between each dosing period. Serial blood samples were collected at 0 hour (prior to MgV administration) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 24, 48, and 72 hours after dosing. Valproate was measured by a new method of ultraperformance liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters of interest were C_max, T_max, AUC_0–72, AUC_0?∞, t½, V_d/F, CL/F, and mean residence time (MRT). Formulation-related differences were assayed in accordance with the Mexican regulatory bioequivalence criteria. Log-transformed values of C_max and AUC were used to construct a classic 90% CI. Bioequivalence was established if the 90% CI for the mean test:reference ratio of log-transformed C_max and AUC were within the range of 0.80 to 1.25. Tolerability was assessed based on subject interview, vital sign monitoring, and clinical assessment.Results: A total of 24 healthy volunteers (12 women and 12 men; mean [SD] age, 28.79 [6.5] years; height, 164 [9.8] cm; weight, 65.42 [8.95] kg; and body mass index, 24.28 [2.11] kg/m²) were included. For the MgV solution, the mean (SD) pharmacokinetic parameters of C_max, T_max, AUC_0–72, AUC_0–∞, t½, V_d/F, CL/F, and MRT were 59.75 (8.24) μg/mL, 0.542 (0.14) hours, 1099.67 (241.70) μg · h/mL, 1156.30 (264.01) μg · h/mL, 16.19 (2.36) hours, 9633.68 (1892.70) mL, 418.35 (92.01) mL/h, and 18.36 (1.44) hours, respectively. For the MgV suspension, the mean (SD) pharmacokinetic parameters of C_max, T_max, AUC_0–72, AUC_0?∞, t½, V_d/F, CL/F, and MRT were 55.04 (7.72) μg/mL, 0.773 (0.51) hour, 1057.76 (223.37) μg · h/mL, 1111.09 (245.07) μg · h/mL, 16.32 (2.20) hours, 1069.05 (1775.64) mL, 435.43 (99.59) mL/h,\ and 18.41 (1.43) hours, respectively. For the MgV entericcoated tablets, the mean (SD) pharmacokinetic parameters of C_max, T_max, AUC_0–72, AUC_0?∞, t½, V_d/F, CL/F, and MRT were 54.88 (6.73) μg/mL, 2.79 (0.89) hours, 1100.79 (216.70) μg · h/mL, 1163.61 (238.36) μg · h/mL, 16.48 (2.10) hours, 9675.15 (1659.36) mL, 412.36 (85.24) mL/h, and 19.95 (1.53) hours, respectively. The 90% CIs for the tablets:solution ratio were 82.15 to 95.44, 94.60 to 105.39, and 95.43 to 105.95 for C_max, AUC_0–72, and AUC_0?∞, respectively. The 90% CIs for the suspension:solution ratio were 84.79 to 98.50, 88.89 to 99.02, and 89.15 to 98.97, respectively. The 90% CIs for the tablets:suspension ratio were 89.90 to 104.43, 100.84 to 112.34, and 101.60 to 112.80, respectively.Conclusion: This single-dose study found that the 3 formulations (solution, suspension, and enteric-coated tablets) of MgV met the regulatory criteria for bioequivalence in these healthy, fasting, Mexican volunteers.     

Pharmacokinetic and Pharmacodynamic Interactions Between Henagliflozin,a Novel Selective SGLT-2 Inhibitor,and Warfarin in Healthy Chinese Subjects

PurposeWhile controlling blood glucose, patients with diabetes and abnormal coagulation should be treated with positive anticoagulation because the hypercoagulable state of their blood is the primary cause of macroangiopathy. The goal of this study was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) interactions between henagliflozin, a novel selective sodium-glucose cotransporter 2 inhibitor, and warfarin in healthy subjects.MethodsThis single-center, open-label, single-arm clinical study was conducted in 16 healthy male Chinese subjects. According to the study protocol, the PK properties of henagliflozin 10 mg/d and warfarin 5 mg/d were collected and tabulated in accordance with sampling time. All study drugs were given with once-daily administration. Subjects were monitored for adverse reactions and their severity, outcomes, and relationship to study drug. This influences of warfarin on the PK properties of henagliflozin (C_max,ss and AUC_τ,ss), the effects of henagliflozin on the PK properties of warfarin (C_max, AUC_0–t, and AUC_0–∞), and the influences of henagliflozin on the PD properties of warfarin (PT_max, PT_AUC, INR_max, and INR_AUC) were evaluated.FindingsThe geometric mean ratios (GMRs; 90% CIs) of henagliflozin C_max,ss and AUC_τ,ss were 101.75% (96.11%–107.72%) and 102.21% (100.04%–104.42%), respectively. The GMRs (90% CIs) of S- and R-warfarin C_max, AUC_0–t, and AUC_0–∞ were as follows: C_max, 114.31% (106.30%–122.91%) and 115.09% (109.46%–121.01%), respectively; AUC_0–t, 120.15% (116.71%–123.69%) and 119.01% (116.32%–121.76%); and AUC_0–∞, 120.81% (117.17%–124.58%) and 121.94% (118.90%–125.05%). The GMRs (90% CIs) of warfarin PT_max and PT_AUC were 92.73% (91.25%–94.22%) and 97.42% (96.61%–98.24%). The GMRs (90% CIs) of warfarin INR_max and INR_AUC were 92.66% (91.17%–94.17%) and 97.36% (96.52%–98.21%). A total of 32 cases of mild adverse events were reported, and were recovered/resolved. There were no serious adverse events reported.ImplicationsNo significant clinically relevant effects on the PK/PD properties of henagliflozin or warfarin were found with coadministration of the two drugs in these healthy male Chinese subjects. Based on these findings, it is expected that henagliflozin and warfarin can be used in combination without dose adjustment. Chinadrugtrials.org.cn identifier: CTR20190240.     

Safety,Tolerability, and Pharmacokinetics of Single and Repeat Doses of Nemiralisib Administered via the Ellipta Dry Powder Inhaler to Healthy Subjects

Purpose

Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability.

Pharmacokinetics of duloxetine hydrochloride enteric-coated tablets in healthy Chinese volunteers: A randomized,open-label,single- and multiple-dose study

Background: Duloxetine hydrochloride is a balanced selective serotonin and norepinephrine reuptake inhibitor. Despite being widely used for the treatment of major depressive disorder in China, little information is available on the pharmacokinetic (PK) properties of duloxetine in Chinese subjects.Objectives: This study was designed to determine the concentration of duloxetine in human plasma and to compare the PK properties of duloxetine after administration of single and multiple doses of duloxetine in healthy Chinese volunteers.Methods: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining the concentration of duloxetine in human plasma was developed and applied to this single-center, open-label, single- and multiple-dose PK study. Subjects were randomized to receive a single dose of 30, 60, or 90 mg of duloxetine. Those who received the 30-mg dose continued on to the multiple-dose phase and received 30 mg twice daily for 7 days. In the single-dose phase, sequential blood samples were collected from 0 to 60 hours after drug administration. In the multiple-dose phase, samples were obtained before drug administration on days 4, 5, 6, and 7 to determine the Cssmin of duloxetine; on day 7, samples were collected from 0 to 60 hours after drug administration. The PK parameters that were calculated included C_max, T_max, t_1/2, AUC_0?t AUC_0?∞, CL, V_d, C_ssmax, C_ssmin, C_ssav, AUC_ss, AUC_ss(0?t), and C_max:C_min ratio. All values were expressed as mean (SD). Tolerability was assessed throughout the study.Results: The LC-MS/MS method was developed and validated. The standard calibration curve was linear in the concentration range from 0.89 to 106.8 ng/mL; the correlation coefficient was >0.995. The methodo-logic recovery and extraction recovery ranged from 87.22% to 113.75% and 72.81% to 89.96%, respectively. Both the intraday and interday relative SDs were <11%. Thirty Chinese subjects (3 groups of 10 subjects [5 men, 5 women] each) were enrolled in the single-dose phase of the PK study. The mean (SD) age of the subjects was 23.2 (1.8) years (range, 21–25 years); their mean (SD) weight was 61.0 (7.7) kg (range, 52–80 kg) and height was 169.0 (7.1) cm (range, 155–180 cm). The main PK parameters for duloxetine after administration of a single oral dose of 30, 60, and 90 mg were as follows: C_max = 22.46 (15.15), 44.40 (17.18), and 60.78 (27.84) ng/mL, respectively; AUC_0–60 = 328.64 (203.64), 696.04 (337.82), and 1219.33 (598.29) ng/mL · h^?1; AUC_0?∞) = 359.68 (201.01), 733.82 (343.40), and 1280.51 (644.81) ng/mL · h^?1; T_max = 6.83 (1.99), 6.10 (1.29), and 6.60 (1.58) hours; t1/2 = 12.95 (3.64), 12.81 (2.31), and 11.66 (2.06) hours; CL = 107.90 (53.05), 98.41 (41.98), and 109.58 (52.74) L/hour; and V_d = 2518.88 (1707.71), 1879.74 (999.09), and 1858.47 (1203.69) L. The 10 subjects who received the 30-mg dose in the single-dose phase continued on to the multiple-dose phase and received 30 mg of duloxetine twice daily for 7 days. Mean (SD) values for the main PK parameters for duloxetine after administration of multiple doses were as follows: C_ssmax = 47.33 (16.95) ng/mL; C_ssmm = 27.92 (9.46) ng/mL; AUC_ss(0?t) = 407.25 (125.94) ng/mL · h^?1; C_ssav = 33.94 (13.00) ng/mL; T_max = 6.36 (0.92) hours; t_1/2 = 11.19 (1.98) hours; CL = 83.12 (28.75) L/hour; and V_d = 1359.01 (590.06) L.Conclusions: In these healthy Chinese subjects, AUC and Cmax increased proportionally with the dose, whereas t_1/2 was independent of the dose. Linear PK properties were found at doses of 30 to 90 mg. No statistically significant differences were observed between the PK parameters for the subjects in the multiple-dose phase (t_1/2, CL, V_d) and those for subjects in the single-dose phase. The AUC and C_max were greater after administration of multiple doses than after administration of a single dose, suggesting du-loxetine accumulation with multiple-dose administration of 30 mg.     

A pharmacokinetic comparison of single doses of once-daily cyclobenzaprine extended-release 15 mg and 30 mg: A randomized,double-blind,two-period crossover study in healthy volunteers

Objective: The purpose of this study was to compare the pharmacokinetics and tolerability of single oral doses of cyclobenzaprine extended-release (CER) 15- and 30-mg capsules.Methods: This was a randomized, double-blind, 2-period crossover study in healthy adults aged 18 to 40 years. Subjects were assigned to receive a single dose of either CER 15 mg or 30 mg on days 1 and 15, separated by a 14-day washout. Study comparisons included the plasma cyclobenzaprine AUC to 168 hours after dosing (AUC_0–168), AUC_0–∞, and C_max. Plasma cyclobenzaprine T_max, terminal elimination t_1/2, and adverse events (AEs) were also assessed.Results: Sixteen subjects (9 women, 7 men) were randomized to receive cyclobenzaprine 15 mg or 30 mg; 13 (81.3%) were white and 3 (18.8%) were black. Mean age and weight were 30.2 years and 70.7 kg, respectively. The shapes of the pharmacokinetic profiles for CER 15 and 30 mg were parallel. Mean observed values for dose-dependent pharmacokinetic parameters of CER 15 and 30 mg were as follows: AUC_0–168, 318.3 and 736.6 ng · h/mL, respectively; AUC_0–∞), 354.1 and 779.9 ng · h/mL; and C_max, 8.3 and 19.9 ng/mL. Dose-independent parameters were comparable across doses. Median observed Tmax was 6.0 hours for both CER doses; mean t_1/2 was 33.4 hours for CER 15 mg and 32.0 hours for CER 30 mg. The bioavailability of the 2 doses, as indicated by the least squares mean AUC_0–∞, was 330.3 ng · h/mL for CER 15 mg and 755.1 ng · h/mL for CER 30 mg. During the CER 15-mg treatment sequence, 5 subjects experienced 5 AEs (headache, dizziness, musculoskeletal pain, dermatitis, and glossodynia); during the CER 30-mg treatment sequence, 2 subjects experienced 2 AEs (somnolence and dysmenorrhea). All AEs were mild in intensity. No serious AEs occurred during the study.Conclusions: Once-daily CER 15 and 30 mg exhibited similarly shaped pharmacokinetic profiles. AUC_0–168, AUC_0–∞), and C_max values for the 30-mg dose were approximately double those for the 15-mg dose, a result consistent with previously reported data on the dose proportionality of cyclobenzaprine immediate release.     

Pharmacokinetics of Efavirenz 600 mg Once Daily During Pregnancy and Post Partum in Ghanaian Women Living With HIV

PurposeThe updated World Health Organization guidelines recommend efavirenz (EFV) 400 mg as the preferred alternate first-line antiretroviral therapy to dolutegravir, with EFV 600 mg recommended only in special situations. We examined the pharmacokinetic (PK) properties of EFV 600 mg/d during pregnancy and post partum to inform EFV dosing decisions in pregnant women.MethodsGhanaian pregnant women with HIV infection initiating tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg/EFV 600 mg fixed-dose combination tablet once daily were enrolled. Efavirenz concentrations were measured at 4 weeks of antiretroviral therapy initiation during pregnancy and 6 weeks post partum using validated LC-MS/MS assays. Efavirenz PK parameters were calculated using noncompartmental analysis, and within-group parameters between the 2 periods were compared.FindingsOf 25 enrolled women, 19 completed PK sampling during pregnancy and post partum. The C_max, C_min, AUC_0–24h, and CL/F for EFV during pregnancy were similar to values at 6 weeks post partum. The pregnancy/postpartum geometric mean ratios for EFV C_max, C_min, AUC_0–24, and CL/F were 1.10 (95% CI, 0.93–1.31), 0.88 (95% CI, 0.67–1.17), 0.84 (95% CI, 0.71–0.98), and 1.20 (95% CI, 1.02–1.40), respectively. Viral load suppression (HIV RNA <200 copies/mL) was achieved in 16 of 17 participants (94%) by the time of delivery. There was 1 maternal-to-child transmission.ImplicationsWe found that the PK parameters of EFV 600 mg once daily during pregnancy were similar to those in the postpartum period. Our findings suggest that EFV dose adjustment during pregnancy is not necessary in our study population.     

Effects of Flibanserin on the Pharmacokinetics of a Combined Ethinylestradiol/Levonorgestrel Oral Contraceptive in Healthy Premenopausal Women: A Randomized Crossover Study

Purpose

This study aimed to investigate the effect of steady-state exposure to flibanserin, a 5-HT_1A agonist/5-HT_2A antagonist approved for the treatment of hypoactive sexual desire disorder in premenopausal women, on the single-dose pharmacokinetics of the contraceptive steroids ethinylestradiol and levonorgestrel in healthy premenopausal women.

A Phase I,Single- and Multiple-dose Study to Evaluate the Pharmacokinetics of Elbasvir and Grazoprevir in Healthy Chinese Participants

Purpose

This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals.

Safety,Tolerability, Pharmacokinetics,and Pharmacodynamics of SPH3127: A Phase I,Randomized, Double-Blind,Placebo-Controlled Trial

PurposeTo evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of single- and multiple-dose SPH3127 in healthy individuals.MethodsThis was a randomized, double-blind, placebo-controlled, Phase I dose-escalation study.FindingsSPH3127 exposure, expressed as C_max, AUC_0–t, and AUC_0–∞, was proportionally increased with dose for a range of 25–800 mg (single ascending dose [SAD]) and 100–400 mg daily (multiple ascending doses [MADs]). In an SAD, the C_max values with 25, 50, 100, 200, 400, and 800 mg of SPH3127 were 90.67, 344.50, 523.50, 1239.50, 2445.00, and 5753.33 ng/mL, respectively. The corresponding AUC_0–t values were 294.48, 843.62, 1109.33, 2858.56, 6697.50, and 13057.83 h × ng/mL. In MADs, after the first dose of SPH3127, the C_max values with 100, 200, and 400 mg of SPH3127 were 421.50, 969.00, and 2468.33 ng/mL, respectively. The corresponding AUC_0–t values were 1279.28, 2275.77, and 5934.26 h × ng/mL. At steady state, the C_max values with 100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL, respectively. The corresponding AUC_0–24 values were 1638.14, 3096.20, and 7577.70 h × ng/mL. The median T_max range from 0.33 to 1.0 h and the median t_1/2 from 3 to 4 h. In an SAD, when the dose was >100 mg, plasma renin activity inhibition of up to 90% lasted up to 24 h. In MADs, renin activity was continuously inhibited by up to 90% in each group for 24 h after the last administration. Treatment-emergent adverse events (AEs) were reported in 29.2% of individuals receiving the SAD and 33.3% of those receiving MADs. Only mild adverse events occurred.ImplicationsSPH3127 was well tolerated and had robust and sustained suppression of plasma renin activity.Clinicaltrials.gov identifiersNCT03128138 (SAD study) and NCT03255993 (MAD study).     

Differences in immunogenicity associated with non-product related variability: insights from two pharmacokinetic studies using GP2017, an adalimumab biosimilar

ABSTRACT

Introduction: Antidrug antibody (ADA) development is known to occur with adalimumab treatment and impacts adalimumab exposure. Here, we compare the impact of immunogenicity on pharmacokinetics (PK) across two randomized PK studies of GP2017, an approved biosimilar adalimumab, in healthy subjects.

Methods: Healthy male subjects (N= 107 in study GP17-104; N= 90 in study GP17-103) received a single 40 mg subcutaneous injection of the same GP2017 drug product batch. Cross-study PK comparison was performed for log-transformed C_max, AUC_0–360h, AUC_0–last, and AUC_0–inf, using an ANCOVA model.

Results: The proportion of ADA-positive subjects was higher in GP17-103 (in total 71.1%) vs. GP17-104 (57.9%). Comparison of GP2017 PK between studies showed that the exposure was lower in GP17-103 vs GP17-104, with 90% confidence intervals (CIs) for geometric mean ratios of AUC_0–last and AUC_0–inf being outside the range of 0.80–1.25. A subgroup analysis showed that in ADA-negative subjects 90% CIs for all PK parameters were within range, with geometric mean ratios close to 1.00.

Conclusion: The differences in GP2017 PK between the two groups are not considered to be product-related, but may be due to currently unknown factors related to differences between the two study populations.     

Open-label,Single-dose Studies of the Pharmacokinetics of Edaravone in Subjects with Mild,Moderate, or Severe Hepatic Impairment Compared to Subjects with Normal Hepatic Functioning

PurposeTwo studies were conducted to assess the pharmacokinetic (PK) properties and tolerability of edaravone in Japanese subjects with mild to moderate hepatic impairment or normal hepatic functioning (study 1), and in white subjects with severe hepatic impairment compared to subjects with normal hepatic functioning (study 2).MethodsStudies 1 and 2 were multicenter, open-label, single-dose studies that included subjects aged 18–75 years. In study 1, subjects were stratified into 3 different groups of hepatic functioning according to Child-Pugh score: mild hepatic impairment, score 5 or 6 (n = 8); moderate hepatic impairment, score 7–9 (n = 6); or normal hepatic functioning (n = 8). In study 2, subjects had severe hepatic impairment (Child-Pugh score 10–14; n = 6) or normal hepatic functioning (n = 6). In both studies, all subjects were given edaravone 30 mg IV infused over 60 min on the morning of day 1. Blood samples for use in PK analyses were collected from days 1–3. The PK properties (C_max, AUC_0–last, and AUC_0–∞) of edaravone and its sulfate conjugate metabolite were measured.FindingsIn study 1, the geometric least-squares mean (GLSM) C_max and AUC_0–∞ of unchanged edaravone were 1.203- and 1.065-fold greater, respectively, in subjects with mild hepatic impairment versus normal hepatic functioning, and were 1.235- and 1.142-fold greater, respectively, in subjects with moderate hepatic impairment versus normal hepatic functioning. In study 2, GLSM C_max and AUC_0–∞ of unchanged edaravone were 1.203- and 1.190-fold greater, respectively, in subjects with severe hepatic impairment versus normal hepatic functioning. In both studies the AUC_0–last, AUC_0–∞, unbound AUC from time zero to infinity, and C_max of unchanged edaravone were increased slightly with increases in Child-Pugh classification. No adverse events considered related to edaravone were reported, except for 1 case of sinus bradycardia in a subject with normal hepatic functioning in study 2. The event was moderate in severity, considered as possibly related to edaravone, and resolved during the study.ImplicationsMild to moderate and severe hepatic impairment had no apparent clinically significant effects on the PK profile of edaravone in Japanese and white subjects, respectively, relative to individuals with normal hepatic functioning, and there were no notable tolerability concerns. Thus, edaravone dosage adjustments are unlikely to be needed in edaravone-treated patients with mild to moderate and severe hepatic impairment. ClinicalTrials.gov identifiers: NCT03289234 (mild to moderate hepatic impairment) and NCT03664544 (severe hepatic impairment).     

Pharmacokinetics and Pharmacodynamics of Levornidazole in Patients With Intra-abdominal AnaerobicInfection

Purpose

The pharmacokinetic (PK) and pharmacodynamic characteristics of levornidazole were studied in patients with intra-abdominal anaerobic infection to provide the rationale of new clinical dosing regimen of levornidazole.

A single-dose,randomized, two-way crossover study comparing two olanzapine tablet products in healthy adult male volunteers under fasting conditions

Background: Olanzapine is a psychotropic agent that belongs to the thienobenzodiazepine class.Objective: The aim of this study was to assess the bioequivalence of 2 commercial 10-mg tablet formulations of olanzapine by statistical analysis of the pharmacokinetic parameters C_max, AUC from 0 to 72 hours after dosing (AUC_0-72), and AUC_0-∞ as required by the Egyptian health authority for the marketing of a generic product.Methods: This bioequivalence study was carried out in healthy male volunteers using a single-dose, randomized, 2-way crossover design under fasting conditions. Statistical analysis of the pharmacokinetic parameters C_max, AUC_0-72, and AUC_0-∞ was conducted to determine bioequivalence (after log-transformation of data using analysis of variance and 90% CIs) and to gain marketing approval in Egypt. The formulations were considered to be bioequivalent if the log-transformed ratios of the 3 pharmacokinetic parameters were within the predetermined bioequivalence range (ie, 80%–125%), as established by the US Food and Drug Administration (FDA). Both the test product (Trademark: Integrol^® [Global Napi Pharmaceuticals, Cairo, Egypt]) and the reference product (Trademark: Zyprexa^® [Eli Lilly and Company, Basingstoke, Hampshire, United Kingdom]) were administered as 10-mg tablets with 240 mL of water after an overnight fast on 2 treatment days, separated by a 2-week washout period. After dosing, serial blood samples were collected for 72 hours. Plasma samples were analyzed using a sensitive, reproducible, and accurate liquid chromatography-tandem mass spectrometry method capable of quantitating olanzapine in the range of 0.167 to 16.7 ng/mL, with a lower limit of quantitation of 0.167 ng/mL. Adverse events were reported by the volunteers as instructed or observed by the resident physician, and were recorded, tabulated, and evaluated.Results: Twenty-four healthy adult male volunteers participated in this study. Their mean (SD) age was 24.7 (6.2) years (range, 19–41 years), mean weight was 73.4 (6.7) kg (range, 64–89 kg), and mean height was 174.25 (4.6) cm (range, 168–186 cm). Values for C_max, AUC_0-72, AUC_0-∞, T_max, t_1/2, and the terminal disposition rate constant were found to be in agreement with previously reported values. The differences between the 2 products did not reach statistical significance at P ≤ 0.05 (90% CIs: C_max, 101.82–124.79; AUC_0-72, 93.36–102.04; and AUC_0-∞, 88.57–101.77). The test/reference ratio of these parameters was within the acceptance range of the FDA criterion for bioequivalence. Both formulations were apparently well absorbed from the gastrointestinal tract (ie, no specific gastrointestinal tract-related adverse events were reported).Conclusions: In this small study in healthy male volunteers, there were no statistically significant differences in any of the calculated pharmacokinetic parameters between the 10-mg test and reference tablets of olanzapine. The 90% CIs for the ratios of mean C_max, AUC_0-72, and AUC_0-∞ were within the range of 80% to 125% (using log-transformed data), meeting the FDA regulatory criterion for bioequivalence. Both formulations were well tolerated.     

Bioavailability and bioequivalence of two oral formulations of alendronate sodium 70 mg: An open-label,randomized, two-period crossover comparison in healthy Korean adult male volunteers

Background: Alendronate sodium is a Bisphosphonate drug used to treat and prevent osteoporosis and several other bone diseases. A new formulation has been developed and is currently awaiting regulatory approval, pending findings on bioequivalence.Objectives: The aims of the present study were to compare the bioavailability and pharmacokinetic (PK) properties, and to determine the bioequivalence, of a test and reference formulation of alendronate sodium 70 mg in a healthy Korean adult male population.Methods: This open-label, randomized, 2-sequence, 2-period crossover study was carried out at Hanyang University Medical Center (Seoul, Republic of Korea). Healthy Korean adult male volunteers were randomly assigned to receive a single 70-mg dose of the test or reference formulation of alendronate sodium, administered with 240 mL of water, followed by a 7-day washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Serial blood samples were collected and adverse events were monitored by a clinical investigator via observation, personal interview, and vital signs (blood pressure, heart rate, and body temperature) over a 7-hour period (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours) after drug administration. Plasma alendronate sodium concentrations were determined using a validated high-performance liquid chromatographic-postcolumn fluorescence derivatization method, with visible detection in the range of 2 to 100 ng/mL and lower limit of quantification set at 2 ng/mL. PK properties, including AUC_0?t, AUC_0?∞, C_max, T_max, t_1/2, and the elimination constant (k_e), were determined using noncompart-mental analysis. The formulations were considered bioequivalent if the 90% CI ratios for C_max and AUC were within the predetermined interval of 80% to 125%, the regulatory definition set by the US Food and Drug Administration (FDA).Results: Twenty-three healthy male volunteers (mean [SD] age, 23.5 [2.0] years [range, 19–28 years]; height, 175.9 [5.4] cm [range, 162.0–185.0 cm]; and weight, 71.2 [9.5] kg [range, 61–96 kg]) were included in the study. No period or sequence effects were detected. The 90% CIs for the corresponding ratios of AUC_0?t, AUC_0?∞ and C_max were 84.97 to 114.47, 86.09 to 115.59, and 82.37 to 110.71, respectively. Additionally, the mean (range) of T_max was 1.09 hours (0.5–2.0 hours), and the mean (SD) of t_1/2 and k_e were 2.04 (0.97) hours and 0.34 (0.71) hour, respectively. The values for the test and reference formulations were within the FDA bioequivalence definition interval of 80% to 125%. No adverse events were reported in this study.Conclusions: Single doses of these formulations of alendronate sodium 70 mg met the criteria for bio-equivalence. No statistically significant differences in AUC_0?t, AUC_0?∞, and C_max were found in this healthy Korean adult male population.     

Comparative Bioavailability Study of a New Orodispersible Formulation of Ibuprofen Versus Two Existing Oral Tablet Formulations in Healthy Male and Female Volunteers

PurposeThis study aimed to assess the comparative bioavailability between ibuprofen acid orodispersible tablets (Test product) and ibuprofen acid oral tablets (Reference product).MethodsThis was a randomized, single-dose, 3-way crossover, open-label, pharmacokinetic study in 36 healthy male and female volunteers. Blood samples were taken periodically over a 12-h period after dosing to derive total plasma ibuprofen and S(+)/R(−) ibuprofen enantiomer pharmacokinetic parameters; safety profile and tolerability were evaluated throughout the study.FindingsAfter a single-dose administration of ibuprofen acid oral tablets (2 × 200 mg), the total ibuprofen C_max and AUC_0–t (geometric least square [LS] mean) for the Test product was 29.4 μg/mL and 100.6 h/μg/mL, respectively, and for the Reference product it was 30.6 μg/mL and 98.7 h/μg/mL. The geometric LS mean Test/Reference ratio 90% CI for both total ibuprofen C_max (90.71–101.77) and AUC_0-t (98.72–105.23) was contained entirely within the predefined 80.00%–125.00% lower and upper limits; in addition, no statistically significant difference was found in T_max (P = 0.1819) after fasted administration of the Test and Reference products. There were 4 mild treatment emergent adverse events, considered unrelated to the study drug, reported by 2 volunteers during the study; no serious adverse events, no suspected unexpected serious adverse events. and no clinically significant changes in laboratory safety, vital signs, or 12-lead ECG measurements were reported. The enantiomer-specific analysis mirrored that of total ibuprofen, with the C_max and AUC_0–t LS mean Test/Reference ratio 90% CI for both ibuprofen S(+) and R(−) enantiomers contained entirely within the predetermined 80%–125.00% limits.ImplicationsThis study found that ibuprofen acid 200 mg orodispersible tablets and ibuprofen acid 200 mg tablets met the regulatory criteria for bioequivalence for AUC_0–t and C_max. Post hoc analysis of ibuprofen both S(+) and R(−) enantiomers mirrored the findings for total ibuprofen. All investigational products were found to be well tolerated. Clinicaltrials.gov identifier: NCT03180879.     

Bioequivalence and Food Effect of Dapagliflozin/Saxagliptin/Metformin Extended-release Fixed-combination Drug Products Compared With Coadministration of the Individual Components in Healthy Subjects

PurposeFixed-combination drug products (FCDPs) for patients with type 2 diabetes mellitus (T2DM) may show efficacy comparable to their individual components (ICs) while improving adherence to treatment. This study evaluated the bioequivalence and safety of 2 dapagliflozin/saxagliptin/metformin extended-release (XR) FCDPs relative to their ICs: saxagliptin and dapagliflozin/metformin XR.MethodsThis randomized, open-label, single-dose, single-center crossover study was conducted in 84 healthy subjects aged 18–55 years. The primary objective was to evaluate the fed-state bioequivalence of a dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP and a dapagliflozin 10-mg/saxagliptin 5-mg/metformin 1000-mg XR FCDP relative to the ICs. Secondary objectives included the evaluation of the effect of food on the pharmacokinetic (PK) parameters of saxagliptin, dapagliflozin, and metformin in both FCDPs and characterization of the PK parameters of the active metabolite of saxagliptin, 5-hydroxy saxagliptin, in healthy subjects. PK parameters (AUC_0–∞, AUC_0–t, and C_max) were used to assess the bioequivalence of the 2 FCDPs with their ICs. The C_max and AUC_0–t of the study drugs were compared between female and male subjects to assess sex differences in exposure. Safety and tolerability of both FCDPs and ICs were also assessed with adverse events, vital signs (systolic and diastolic blood pressures and pulse rate), 12-lead ECG, physical examinations, and laboratory assessments.FindingsBoth dapagliflozin/saxagliptin/metformin XR FCDPs were bioequivalent to their ICs. For the dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP, the 90% CI for the geometric mean ratio of dapagliflozin C_max was slightly above the 80%–125% bioequivalence limit, which is unlikely to be clinically relevant. Food delayed the absorption of the study drugs in both FCDPs, which is unlikely to have a clinically relevant impact on efficacy. In both cohorts, exposure was higher in female subjects compared with male subjects, potentially due to the lower body weight of the female subjects. The safety profile and tolerability of the FCDPs were similar to those of their ICs, and no deaths or serious adverse events were reported.ImplicationsThese data support the use of the dapagliflozin/saxagliptin/metformin XR FCDP in patients with T2DM. ClinicalTrials.gov identifier: NCT03169959.