Geometric Least Squares Mean Research Articles

Pharmacokinetics and Bioequivalence of Mirogabalin Orally Disintegrating Tablets and Conventional Tablets in Healthy Japanese Participants.

This single-center, randomized, open-label, single-dose, 2-group, 2-stage crossover trial evaluated the bioequivalence of 15mg of mirogabalin as orally disintegrating tablets (ODTs) with conventional mirogabalin tablets in healthy Japanese men. The trial involved two studies: in Study 1, the ODT formulation was taken without water, and in Study 2, the ODT formulation was taken with water. The conventional tablet was taken with water in both studies. We investigated the pharmacokinetic parameters and bioequivalence of the 2 formulations, including the maximum plasma concentration and the area under the plasma concentration-time curve up to the last quantifiable time. The plasma concentrations of mirogabalin were determined by a validated liquid chromatography with tandem mass spectrometry method. A total of 72 participants were enrolled and completed the trial. The geometric least-squares mean ratios of maximum plasma concentration of the ODT formulation to the conventional formulation were within the prespecified bioequivalence range of 0.80-1.25 (Study 1, 0.995; Study 2, 1.009), as was the area under the plasma concentration-time curve up to the last quantifiable time (Study 1, 1.023; Study 2, 1.035). No serious adverse events were observed. In conclusion, mirogabalin 15-mg ODTs, either with or without water, were bioequivalent to conventional 15-mg tablets.

Effect of the P-glycoprotein inhibitor tamoxifen on edoxaban plasma levels in women with breast cancer

BackgroundConcomitant use of P-glycoprotein inhibitors can reduce clearance of edoxaban and increase its plasma concentration. Caution is advised with simultaneous use of edoxaban and the frequently used P-glycoprotein inhibitor tamoxifen. However, pharmacokinetic data are lacking. ObjectivesThis study aimed to assess the effect of tamoxifen on edoxaban clearance. MethodsThis was a prospective, self-controlled, pharmacokinetic study in breast cancer participants starting tamoxifen. Edoxaban was given at a dose of 60 mg once daily for 4 consecutive days, first without tamoxifen and later with concomitant tamoxifen in steady-state. On day 4 of both edoxaban sequences, serial blood samples were taken. A population pharmacokinetic model was developed using nonlinear mixed effects modelling in which the effect of tamoxifen on edoxaban clearance was assessed. Additionally, mean area under the curves (AUC) were estimated. Geometric least square means (GLM) ratios were calculated and no interaction was concluded if the 90 % CI was within the 80–125 % no-effect boundaries. ResultsTwenty-four women with breast cancer scheduled for tamoxifen were included. The median age was 56 years (IQR 51–63). The average edoxaban clearance was 32.0 L/h (95 % CI, 11.1–35.0 L/h). There was no effect of tamoxifen on edoxaban clearance, with a fraction of 100 % (95 % CI 92–108) compared to clearance without tamoxifen. The mean AUCs were 1923 ng*h/ml (SD 695) without tamoxifen and 1947 ng*h/ml (SD 595) with tamoxifen (GLM-ratio 100.4; 90 % CI 98.6–102.2). ConclusionsConcomitant use of the P-glycoprotein inhibitor tamoxifen does not lead to reduced clearance of edoxaban in patients with breast cancer.

Pharmacokinetics and safety of candidate tocilizumab biosimilar CT-P47 versus reference tocilizumab: a randomized, double-blind, single-dose phase I study

ABSTRACT Background CT-P47 is a candidate tocilizumab biosimilar. This study assessed the pharmacokinetic (PK) equivalence of CT-P47 and European Union-approved reference tocilizumab (EU-tocilizumab) in healthy Asian adults. Research design and methods This double-blind, multicenter, parallel-group trial randomized healthy adults (1:1) to receive a single (162 mg/0.9 mL) subcutaneous dose of CT-P47 or EU-tocilizumab. The primary endpoint (Part 2) was PK equivalence by area under the concentration – time curve (AUC) from time zero to last quantifiable concentration (AUC0–last), AUC from time zero to infinity (AUC0–inf), and maximum serum concentration (Cmax). PK equivalence was concluded if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the 80–125% equivalence margin. Additional PK endpoints, immunogenicity, and safety were evaluated. Results In Part 2, 289 participants were randomized (146 CT-P47; 143 EU-tocilizumab); 284 received study drug. AUC0–last, AUC0–inf, and Cmax were equivalent between CT-P47 and EU-tocilizumab: 90% CIs for the ratios of gLSMs were within the 80–125% equivalence margin. Secondary PK endpoints, immunogenicity, and safety were comparable between groups. Conclusions CT-P47 demonstrated PK equivalence with EU-tocilizumab and was well tolerated, following a single dose in healthy adults. Clinical trial registration www.clinicaltrials.gov identifier is NCT05188378.

Brigatinib pharmacokinetics in patients with chronic hepatic impairment

SummaryBrigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. This open-label, parallel-group study investigated the effect of chronic hepatic impairment on the pharmacokinetics (PK) of brigatinib to inform dosing recommendations for these patients. Participants with hepatic impairment classified according to Child-Pugh categories of mild (A), moderate (B), or severe (C) and matched-healthy participants with normal hepatic function received a single oral dose of 90-mg brigatinib. Plasma samples were collected for the determination of brigatinib plasma protein binding and estimation of plasma PK parameters. Twenty-seven participants were enrolled (Child-Pugh A–C, n = 6 each; matched-healthy participants, n = 9). The mean fraction of free plasma brigatinib was comparable for the Child-Pugh A (11.1%), Child-Pugh B (10.8%), and healthy participant groups (8.5%); free brigatinib was higher in the Child-Pugh C group (23.1%). There were no clinically meaningful effects of mild or moderate hepatic impairment on unbound systemic exposures (area under the plasma concentration-time curve [AUC]) of brigatinib (geometric least-squares mean ratios [90% CI] of 89.32% [69.79%–114.31%] and 99.55% [77.78%–127.41%], respectively). In the severe hepatic impairment group, brigatinib unbound AUC was approximately 37% higher (geometric least-squares mean ratio [90% CI] of 137.41% [107.37%–175.86%]) compared with healthy participants with normal hepatic function. Brigatinib was well tolerated in healthy participants and in participants with hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment. The brigatinib dose should be reduced by approximately 40% for patients with severe hepatic impairment.

Open-label, drug-drug interaction study between the HIV-1 maturation inhibitor GSK3640254 and a metabolic probe cocktail in healthy participants.

GSK3640254 (GSK'254) is an HIV-1 maturation inhibitor with pharmacokinetics (PK) supporting once-daily dosing. GSK'254 will be co-administered with cytochrome P450 enzyme substrates and drug transporters, including other antiretrovirals, in people living with HIV-1 (PLWH). In this open-label study, healthy participants received a single dose of a cocktail of eight cytochrome P450 and transporter probe substrates on Day 1, followed by a 10-day washout before receiving GSK'254 200 mg once daily from Days 11 to 20 and a single dose of cocktail + GSK'254 200 mg on Day 21. Geometric least-squares mean ratios and 90% confidence intervals were obtained using linear mixed-effects models. Adverse events (AEs) were monitored. Of 20 participants enrolled, 19 completed the study. Plasma concentrations of all cocktail substrates were generally similar with or without GSK'254 co-administration. All 90% confidence intervals around geometric least-squares mean ratios for cocktail substrate PK parameters indicated no to weak interactions. Steady-state plasma GSK'254 concentrations were achieved by Day 17 and maintained through Day 21. Nine participants (45%) reported 17 AEs; most (88%) were grade 1. Two grade 2 treatment-related AEs (maculopapular rash [leading to withdrawal] and papular rash) were reported during GSK'254 administration alone. Co-administration of GSK'254 with a metabolic probe cocktail in healthy participants indicated very low risk of clinically relevant effect on PK of any substrates or associated metabolites. No new safety/tolerability concerns were identified. These results support ongoing phase IIb and planned phase III studies of GSK'254 in people living with HIV-1.

Pharmacokinetics and safety of CT-P17 (40mg/0.4ml) versus reference adalimumab: randomized study in healthy Japanese adults.

Aim: Comparing pharmacokinetics and safety of CT-P17 and EU-approved reference adalimumab (EU-adalimumab) in Japan. Materials & methods: Double-blind, parallel-group phase I trial at three hospitals. Healthy Japanese adults were randomized (1:1) to CT-P17 or EU-adalimumab (single 40-mg subcutaneous dose). The primary end point was pharmacokinetic equivalence for area under the concentration-time curve from time zero to infinity and maximum serumconcentration. Results: Of the 205 randomized subjects (102 CT-P17, 103 EU-adalimumab), 204 received study drug. CT-P17 and EU-adalimumab were pharmacokinetically equivalent: 90% CIs for geometric least-squares mean ratios were within predefined 80-125% equivalence margins. Secondary pharmacokinetic end points, safety and immunogenicity were similar between the groups. Conclusion: CT-P17 had pharmacokinetics, safety and immunogenicity comparable to EU-adalimumab in healthy Japanese adults.

Effect of Food (Low and High Fat) on Pharmacokinetics of FCN-159, a Selective MEK Inhibitor, in Healthy Chinese Males.

FCN-159 is a novel, oral, potent, selective MEK1/2 inhibitor in clinical development for the treatment of NRAS-mutant advanced melanoma and neurofibromatosis type 1. We investigated the effect of food on the pharmacokinetics (PK), safety, and tolerability of FCN-159. In this single-center, open-label, phase 1 study with a three-period, three-sequence, crossover design, healthy Chinese male subjects (n = 24) were randomized (1:1:1) to receive a single, oral 8mg dose of FCN-159 in the fasted state (overnight, > 10h), and with a low-fat and a high-fat meal, separated by a 10-day washout. PK parameters including time to maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared using geometric least-squares mean ratios (GLSMR), with the fasted state as the reference. A 90% CI for the GLSMR within 80-125% indicated no significant food effect. A low-fat meal (n = 23) did not affect the PK profile of FCN-159: G LSMR for AUC from time 0 to t (AUC0-t), 106.9% (90% CI 99.9-114.4%); AUC from time 0 to infinity (AUC0-∞), 106.8% (90% CI 100.0-114.0%); Cmax, 96.4% (90% CI 83.9-110.8%). A high-fat meal (n = 24) did not affect exposure to FCN-159 (GLSMR for AUC0-t, 99.4%; 90% CI 99.0-106.3%; AUC0-∞, 99.5 5%; 90% CI 93.2-106.1%), but modestly reduced Cmax by 15% (GLSMR 84.9%; 90% CI 74.0-97.3%). Both the low-fat and high-fat meals slightly prolonged the median time to Cmax by 0.5h (90% CI 0.5-1.0h). FCN-159 was generally well tolerated, with a lower incidence of treatment-emergent adverse events following administration in the fasted state than with a low-fat or high-fat meal (20.8%, 39.1%, and 37.5%, respectively). Food did not affect the PK profile of FCN-159 to a clinically meaningful extent compared with administration in the fasted state.

A phase III, randomised, double-blind, multi-national clinical trial comparing SB12 (proposed eculizumab biosimilar) and reference eculizumab in patients with paroxysmal nocturnal haemoglobinuria.

Treatment of paroxysmal nocturnal haemoglobinuria (PNH) includes the monoclonal antibody eculizumab. This randomised, double-blind, multi-national cross-over Phase III study in PNH patients aimed to demonstrate the equivalence of the proposed eculizumab biosimilar SB12 and reference eculizumab (Soliris, ECU). PNH patients with lactate dehydrogenase (LDH) ≥1·5× upper limit of normal were randomised into treatment sequences SB12-ECU or ECU-SB12. Four weekly infusions of 600mg eculizumab were followed by fortnightly infusions of 900mg until week 50 (ECU/SB12 cross-over at week 26). Primary endpoints were LDH at week 26 and the time-adjusted area under the effect curve (AUEC) of LDH over weeks 14‒26 and 40‒52. Among 46 patients (92%) who completed the study, the least squares mean (LSM) difference in LDH at week 26 (34·48; 95% confidence interval [CI] -47·66‒116·62U/l) and geometric LSM ratio of time-adjusted AUEC of LDH (1·08; 90% CI 0·95‒1·23) were within pre-defined equivalence margins. Mean numbers of transfused red blood cell units, other secondary endpoints, pharmacokinetics, and pharmacodynamics were comparable. No patients developed anti-drug antibodies. Treatment-emergent adverse events were reported in 72% and 68% of patients in the SB12 and ECU treatment groups, respectively. The results demonstrate equivalence of SB12 to ECU and support SB12-use in PNH patients.

Efficacy and Safety of Biosimilar Candidate ABP 959 As Compared with Eculizumab Reference Product in Paroxysmal Nocturnal Hemoglobinuria

Introduction: ABP 959 is a biosimilar candidate to eculizumab reference product (RP). Eculizumab is a humanized recombinant immunoglobulin antibody that binds to the human complement component 5 protein to inhibit progression of complement cascades and is approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder. Methods: This multicenter, randomized, double-blind, active-controlled, 2-period crossover study compared the efficacy and safety of ABP 959 and eculizumab RP in adult patients with PNH who were stable on eculizumab 900 mg IV every 14 ± 2 days. The primary objective of this study was to evaluate the efficacy of ABP 959 compared to eculizumab RP based on control of intravascular hemolysis, with a secondary objective to compare their safety, pharmacokinetics (PK), and immunogenicity. Results from Period 1 of the crossover study are presented here. Patients were randomized 1:1 to receive either ABP 959 at 900 mg IV for 52 weeks in Period 1 followed by eculizumab RP 900 mg IV for 26 weeks in Period 2 (ABP 959/RP) or eculizumab RP 900 mg IV for 52 weeks followed by ABP 959 at 900 mg IV for 26 weeks (RP/ABP 959) (Figure). The primary efficacy endpoint for the parallel comparisons was hemolysis, measured by lactate dehydrogenase (LDH) at week 27; clinical similarity between treatments was assessed by comparing the 1-sided 97.5% upper confidence interval (CI) limit for the geometric least squares (LS) mean ratio between ABP 959 and eculizumab RP, with a non-inferiority (NI) margin of 2.873. To assess the robustness of the primary analysis result, a sensitivity analysis was conducted using a subset of randomized patients who did not experience any important protocol deviation affecting their primary efficacy evaluation. Secondary endpoints included total complement (50% total hemolytic complement activity [CH50]), LDH-time profile, number of units of packed red blood cells (pRBCs) transfused, safety, immunogenicity, and PK area under the serum concentration-time curve (PK AUC) of ABP 959 and eculizumab RP. Results: Forty-two patients (20 in the ABP 959/RP group; 22 in the RP/ABP 959 group) were randomized and treated in Period 1 across 25 centers. Forty-one (97.6%) patients (20 [100%] in ABP 959/RP and 21 [95.5%] in RP/ABP 959) completed Period 1 dosing. Baseline demographic and disease characteristics were comparable between the 2 treatment groups - mean (SD) age: 50.2 (16.6) years; time since original PNH diagnosis: 128.3 (116.1) months; duration of pre-study treatment: 68.4 (39.8) months. Results for week 27 LDH geometric LS means are presented below (Table). The ratio of the geometric LS means of LDH (ABP 959/RP) was 1.0628, with a 1-sided 97.5% upper CI of 1.1576 contained within the prespecified NI margin of 2.873, establishing similarity in clinical efficacy between ABP 959 and eculizumab RP in the parallel comparison; 95% CI was 0.9758 to 1.1576. Results from the sensitivity analysis were identical with results from the primary efficacy analysis. Total complement (CH50), total hemoglobin, serum-free hemoglobin, haptoglobin, bilirubin, and type III erythrocytes values were generally stable over time and results were comparable between the 2 treatment groups. The overall LDH profile and the mean number of units of pRBCs transfused during the study period were also comparable. Total PK AUC from week 13 to week 15 were similar between the 2 treatment groups. A comparable safety profile was observed in Period 1 between treatment groups, with only a single patient (4.5%) in the eculizumab RP group discontinuing the study due to any adverse event (grade 2 non-serious asthenia and grade 2 non-serious fatigue). The nominal difference in serious adverse event incidence was determined to be not clinically meaningful. Additionally, immunogenicity results through Period 1 were similar between ABP 959 and eculizumab RP groups. No patients in either treatment group tested positive for binding antidrug antibodies (ADAs), neutralizing ADAs, or treatment-boosted ADAs. Conclusions: Similarity in clinical efficacy was established between ABP 959 and eculizumab RP in the primary endpoint of hemolysis, measured by LDH at week 27. Additionally, comparable safety, PK, and immunogenicity results support the conclusion of clinical similarity between ABP 959 and eculizumab RP. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The complete bioavailability of asundexian is unaffected by tablet formulation, gastric pH or food

Abstract Background Anticoagulation and antiplatelet therapy, mainstays for the prevention of thromboembolic disorders, are associated with an increased bleeding risk. Asundexian, a novel, potent and reversible oral inhibitor of factor XIa, is independent of the extrinsic coagulation pathway and thus not expected to increase bleeding risk. Purpose To determine the absolute bioavailability (FAB), and to assess the impact of gastric pH modulators, tablet formulation, and food on the PK and safety of asundexian. Methods Four studies enrolled healthy White males aged 18–45 years. For FAB (20463), participants received a microdose of 50 μg stable [13C7,15N]-labelled asundexian intravenously (iv) 2 hours after 25 mg asundexian orally in the fasted state. The remaining studies randomized participants to each of 3 treatment sequences. Tablet formulation and food effects were explored in studies 19663 and 21660; participants received asundexian (immediate release [IR] vs amorphous solid dispersion [ASD] phase [Ph] 2 [19663] or ASD Ph 2 vs ASD Ph 3 [21660]) in the fasted states. Food effect was explored using the Ph 2 and Ph 3 tablets. Gastric pH modulators (omeprazole and antacid) were given with asundexian in the fasted state (20459). Blood samples were taken over 72–96 hours post dose. Key PK parameters were area under concentration/time curve (AUC; and AUC/dose [D]) and maximum observed concentration (Cmax; and Cmax/D). FAB was derived as (AUC/D)oral/(AUC/D)iv. Relative bioavailability (FR) was derived from the ratios (ASD Ph 2:IR or ASD Ph 3:ASD Ph 2) of AUC/D and Cmax/D (fasted); gastric pH modulation and food effect were derived from the ratios asundexian+pH modulator:asundexian and fed:fasted of AUC and Cmax, respectively. Results PK data were available for 59 participants. Asundexian was completely bioavailable (FAB, 103.9%). Ph 2 and Ph 3 ASD tablets exhibited a FR of 94.3% and 95.1% for AUC/D compared with the IR or Ph 2 ASD tablet, respectively. Cmax/D results were similar (95.5% and 88.7%, respectively). A high-calorie, high-fat meal reduced AUC and Cmax of asundexian to 91.1% and 78.3%, respectively (ASD Ph 2 tablet), and to 96.9% and 95.1%, respectively (ASD Ph 3 tablet). Coadministration of omeprazole had no influence on the PK of asundexian, whereas antacid slightly reduced AUC and Cmax by 10% and 16%, respectively. Geometric least-squares mean (90% confidence intervals) for the ratios of AUC(/D) and Cmax(/D) by treatment are shown in Figure 1. There were no serious adverse events (AEs) or deaths; most AEs were mild or moderate. Conclusions Orally administered asundexian was almost completely bioavailable. First pass metabolism in the gut and liver does not play an important role in the bioavailability of asundexian; there were no clinically relevant changes due to formulation, food conditions or gastric pH modulation. Results were used to guide dosing recommendations for subsequent Ph 2 (completed) and Ph 3 (planned) studies. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): BAYER AG

Effects of Hepatic Impairment on the Pharmacokinetics of the Dual GIP and GLP-1 Receptor Agonist Tirzepatide.

Background and ObjectiveTirzepatide, a novel, once-weekly, dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is approved in the US as a treatment for type 2 diabetes and is under development for long-term weight management, heart failure with preserved ejection fraction, and nonalcoholic steatohepatitis. This study evaluated the pharmacokinetics and tolerability of tirzepatide in participants with hepatic impairment (with or without type 2 diabetes) versus healthy participants with normal hepatic function.MethodsParticipants in this parallel, single-dose, open-label study were categorized by hepatic impairment defined by the baseline Child-Pugh (CP) score A (mild impairment; n = 6), B (moderate impairment; n = 6), or C (severe impairment; n = 7) or normal hepatic function (n = 13). All participants received a single subcutaneous 5-mg dose of tirzepatide. Blood samples were collected to determine tirzepatide plasma concentrations to estimate pharmacokinetic parameters. The primary pharmacokinetic parameters of area under the drug concentration–time curve from zero to infinity (AUC0–∞) and maximum observed drug concentration (Cmax) were evaluated using an analysis of covariance. The geometric least-squares means (LSM) and mean ratios for each group, between control and hepatic impairment levels, and the corresponding 90% confidence intervals (CIs) were estimated. The analysis of the time to maximum observed drug concentration was based on a nonparametric method. The relationships between the pharmacokinetic parameters and CP classification parameters (serum albumin level, total bilirubin level, and international normalized ratio) were also assessed. Adverse events were monitored to assess safety and tolerability.ResultsTirzepatide exposure, based on AUC0–∞ and Cmax, was similar across the control and hepatic impairment groups. Statistical analysis showed no difference in the geometric LSM AUC0–∞ or Cmax between participants in the control group and the hepatic impairment groups, with the 90% CI for the ratios of geometric LSM spanning unity (AUC0–∞ ratio of geometric LSM vs control [90% CI 1.08 [0.879, 1.32], 0.960 [0.790, 1.17], and 0.852 [0.699, 1.04] and Cmax ratio of geometric LSM vs control [90% CI]: 0.916 [0.726, 1.16], 1.00 [0.802, 1.25], and 0.972 [0.784, 1.21] for mild, moderate and severe hepatic impairment groups, respectively). There was no change in median time to Cmax of tirzepatide across all groups (time to Cmax median difference vs control [90% CI]: 0 [− 4.00, 12.00], 0 [− 12.00, 12.00], and 0 [− 11.83, 4.17], respectively). There was no significant relationship between the exposure of tirzepatide and the CP score (p > 0.1 for AUC0–∞, Cmax, and apparent total body clearance). Similarly, there was no clinically relevant relationship between the exposure of tirzepatide and serum albumin level, total bilirubin level, or international normalized ratio. The geometric LSM half-life values were also similar across the control and hepatic impairment groups. No notable differences in safety profiles were observed between participants with hepatic impairment and healthy control participants.ConclusionsTirzepatide pharmacokinetics was similar in participants with varying degrees of hepatic impairment compared with healthy participants. Thus, people with hepatic impairment treated with tirzepatide may not require dose adjustments.Clinical Trial RegistrationClinicalTrials.gov identifier number NCT03940742.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-022-01140-3.

Effects of CYP3A Inhibition, CYP3A Induction, and Gastric Acid Reduction on the Pharmacokinetics of Ripretinib, a Switch Control KIT Tyrosine Kinase Inhibitor.

Ripretinib is a switch control KIT kinase inhibitor approved for treatment of adults with advanced gastrointestinal stromal tumors who received prior treatment with 3 or more kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are cleared mainly via cytochrome P450 enzyme 3A4/5 (CYP3A4/5), and ripretinib solubility is pH-dependent, thus the drug-drug interaction potentials of ripretinib with itraconazole (strong CYP3A inhibitor), rifampin (strong CYP3A inducer), and pantoprazole (proton pump inhibitor) were each evaluated in open-label, fixed-sequence study designs. Overall, 20 participants received ripretinib 50mg alone and with itraconazole 200mg once daily, 24participants received ripretinib 100mg alone and with rifampin 600mg once daily, and 25 participants received ripretinib 50mg alone and with pantoprazole 40mg once daily. Ripretinib exposure increased with concomitant itraconazole, with geometric least-squares (LS) mean ratios of ripretinib area under the concentration-time curve from 0 to ∞ (AUC0-∞ ) and maximum observed concentration (Cmax ) of 199% and 136%. Ripretinib exposure decreased with concomitant rifampin: geometric LS mean ratios for ripretinib AUC0-∞ and Cmax were 39% and 82%. Pantoprazole coadministration had no effect on ripretinib pharmacokinetics. No unexpected safety signals occurred. No dose adjustment is required for ripretinib coadministered with gastric acid reducers and strong CYP3A inhibitors; patients also receiving strong CYP3A inhibitors should be monitored more frequently for adverse reactions. Concomitant ripretinib use with strong CYP3A inducers should be avoided. Prescribers should refer to approved labeling for specific dose recommendations with concomitant use of strong and moderate CYP3A inducers.

Bioequivalence Studies of New Generic Formulations of Vildagliptin and Fixed-Drug Combination of Vildagliptin and Metformin Versus Respective Originator Products in Healthy Volunteers.

IntroductionVildagliptin and metformin are two well-established oral antidiabetics with a complementary mechanism of action. Two new generic products, vildagliptin and its fixed-drug combination (FDC) with metformin, were tested for bioequivalence versus the approved originator reference products (Galvus® and Eucreas®).MethodsThree randomized studies with two-treatment, two-period, two-sequence crossover design were conducted in healthy adults. One study evaluated vildagliptin 50 mg tablets as single dose under fasting conditions. Vildagliptin–metformin FDC tablet strengths of 50/850 mg and 50/1000 mg were evaluated in separate studies as single dose under fed conditions, given 30 min after a standardized high-fat, high-calorie breakfast following 10 h overnight fasting. Blood samples for analysis were collected until 24 h after dosing in each study period. Bioequivalence between test (T) and reference (R) products required 90% confidence interval (CIs) for the geometric least square (LS) mean T/R ratio to be within 80–125% for the pharmacokinetic parameters, maximum plasma concentration (Cmax), and area under the curve (AUC0–t).ResultsThe 90% CIs of geometric LS means of T/R ratio for Cmax and AUC0–t with vildagliptin tablets of 50 mg were 92.22–103.94% and 99.00–102.66%, respectively; corresponding results with FDC tablets for 50/850 mg tablets were 94.81–115.41% and 95.28–106.00% for vildagliptin and 90.87–101.18% and 90.56–100.09% for metformin; for 50/1000 mg tablets Cmax and AUC0–t were 105.56–122.30% and 98.30–107.55%, respectively, for vildagliptin and 92.14–103.73% and 94.60–101.81%, respectively, for metformin. Other parameters such as AUC0–∞, time to maximum concentration (Tmax), and terminal half-life (t1/2) were comparable between test and reference products. Adverse events (AEs), mainly vomiting, were reported without relevant difference between test and reference products in each study. AEs were generally mild and transient. No severe or serious AEs occurred.ConclusionsThe new generic drug products of vildagliptin and the FDCs of vildagliptin and metformin demonstrated bioequivalence to the approved originator products and are therefore expected to provide similar therapeutic effects.

Ixekizumab Citrate-Free Formulation: Results from Two Clinical Trials

IntroductionSubcutaneous (SC) injection is a common route of drug administration; however, injection site pain (ISP) might create a negative patient experience. We evaluated ISP, bioequivalence, and overall safety of the citrate-free (CF) formulation of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A.MethodsTwo phase 1, single-blind studies were conducted in healthy participants. The crossover study A (NCT03848403) evaluated pain intensity on injection as measured by visual analog scale of pain (VAS) scores. Subjects (N = 70) were randomized 1:1:1 at the beginning to three possible treatment sequences and received a 1 mL SC injection of the three formulations sequentially in the abdomen on days 1, 8, and 15, respectively. A mixed-effects repeated measures analysis model was used to analyze VAS score by time post-injection. Study B (NCT04259346) evaluated the bioequivalence of a single 80 mg dose of CF formulation compared to the original commercial formulation. Subjects (N = 245) were randomized 1:1 to either commercial or CF formulation and received a single SC injection into the abdomen, arm, or thigh.ResultsPrimary endpoint was achieved in both studies. In study A, least-squares mean (LSM) difference of VAS scores immediately post injection between commercial (n = 61) and CF formulation (n = 63) was − 21.7 (p < 0.0001), indicating a lower degree of pain associated with CF formulation. In study B, bioequivalence of the CF formulation was established as 90% CIs for the ratio of geometric LSM AUC0–tlast, AUC0–∞, and Cmax between treatments were contained within the prespecified limits of 0.8 and 1.25. Except for less ISP in the CF formulation, overall safety profile was comparable.ConclusionIxekizumab CF formulation proved to be bioequivalent, was associated with less ISP, and had no other notable differences in the safety profile compared to the original commercial formulation.Trail RegistrationClinicalTrials.gov identifier NCT03848403, NCT04259346. Video Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02126-0.

Effects of rifampicin on antineoplastic drug pyrotinib maleate pharmacokinetics in healthy subjects.

Pyrotinib (PTN), an irreversible EGFR/HER2 dual tyrosine kinase inhibitor used for treating HER2-positive breast cancer, is primarily metabolized by cytochrome P450 (CYP)3A4 isozyme. Rifampicin (RIF) is a strong index CYP3A4 inducer. Therefore, the study aimed to elucidate the effect of RIF on PTN pharmacokinetics (PK) in Chinese healthy volunteers. This phase I, open-label study investigated the effects of steady-state RIF administration on single-dose PK of PTN. 18 healthy participants were enrolled in this trial, who received a single oral dose of 400mg of PTN on days 1 and 13, and were administrated with RIF 600mg qd on days 6 through 16. RIF was administrated on an empty stomach, PTN were administrated orally in the morning 30min after the start of the standard meal. Serial PK samples for PTN were collected on days 1 and days 13. Safety assessments were performed via clinical laboratory tests throughout the study. 18 subjects were enrolled and 16 completed the study. RIF significantly reduced PTN exposure: Geometric least-squares mean ratios (90% CI) for PTN + RIF versus PTN alone were 0.04 (0.034,0.049), 0.04 (0.037,0.054), and 0.11 (0.09,0.124) for area under the curve from time zero to time of last quantifiable concentration (AUC0 - t), area under the curve from time zero to infinity (AUC0-∞ ), and maximum observed plasma concentration(Cmax), respectively. PTN alone and co-administered with RIF was well tolerated. The exposure of PTN was significantly affected by the action of RIF. The findings suggest that concomitant strong CYP3A4 inducers should be avoided during PTN treatment. Concurrent administration of PTN and RIF was well tolerated.

Occupational differences in personal care product use and urinary concentration of endocrine disrupting chemicals by gender.

In most societies, women and men systematically differ in consumption of cosmetics and household products, which are interlinked with gendered norms and occupational segregation. We investigated the differences in personal care product (PCP) use and exposure to endocrine disrupting chemicals (EDCs) based on occupation and gender. We utilized data from the first to third Korean National Environmental Health Survey analyzing 9218 participants aged 20-59 years engaged in their current occupation for ≥3 months. Frequent PCP use (≥once/week) and exposure to EDCs were analyzed by gender and occupation. We used least-square geometric means (LSGMs) of urinary concentrations of the five EDCs adjusted for covariates. Manual occupation was most common in men and no paid occupation was most frequent in women. In general, clerical, service, and sales workers showed the highest prevalence of frequent use of hair and body products. Women used body and makeup products more frequently than men. For all five EDCs, similarly, women showed higher urinary levels in all occupation groups. When stratified by gender, the differences in urinary concentration of EDCs across occupation groups were not observed in men. Among women, clerical, service, and sales workers showed higher bisphenol A (BPA) and mono-n-butyl phthalate (MnBP) levels than manual workers. Differentials in exposure to EDCs by occupation groups were not evident for men. Given the higher urinary concentration of EDCs in women compared to men, interventions to reduce the exposure to EDCs would need to focus on women, especially in clerical, service, and sales occupations.

Pharmacokinetics of a new fixed-dose combination of candesartan cilexetil, hydrochlorothiazide, and rosuvastatin in healthy adult subjects.

A fixed-dose combination (FDC) of candesartan cilexetil, hydrochlorothiazide and rosuvastatin (CC/HCTZ/RSV) has been developed to enhance patient compliance in the primary prevention of cardiovascular diseases. To evaluate if the combination of the product components in the new FDC capsule formulation affects their respective pharmacokinetic and in vitro dissolution patterns. In vitro dissolution profiles were compared in USP-43 and in biorelevant dissolution media. In vivo comparisons were obtained in a randomized, open-label, single-dose, two-treatment, two-way crossover study in 24 healthy subjects. During each treatment period, subjects received the test formulation (FDC hard capsule containing CC/HCTZ/RSV) or the reference formulation (co-administration of a FDC CC/HCTZ tablet and a RSV tablet). Plasma samples were collected periodically over 48 hours post-dose. Safety and tolerability were assessed. Dissolution profiles of all active drugs in the Test (capsule) and Reference Products (as tablets) were within the tolerance dissolution criteria of USP-43 conditions. HCTZ dissolution profiles were closely similar whereas those for RSV and CC did not match at specific pHs. In the pharmacokinetic study, the 90% confidence intervals (CIs) for the geometric least-square mean ratios of Cmax, AUC0-last, and AUC0-inf were 0.95-1.18, 0.95-1.15 and 0.95-1.13 (CC); 0.91-1.10, 0.96-1.08, and 0.96-1.09 (HCTZ) and 0.82-1.23, 0.81-1.13, and 0.82-1.12 (RSV), respectively. All adverse events were mild. The new FDC product (Sinlip Prevent), a stable FDC hard capsule, was bioequivalent (similar pharmacokinetics) when compared to the co-administration of the components and may be considered as a suitable and simplified medication for cardiovascular disease management.

Evaluation of the potential for pharmacokinetic interaction between tirabrutinib and levonorgestrel/ethinyl estradiol in healthy female volunteers.

Tirabrutinib (TIRA), a potent and nonreversible oral Bruton tyrosine kinase inhibitor, is evaluated for treatment of certain hematological malignancies and inflammatory diseases. A drug–drug interaction study to evaluate the effect of TIRA on the pharmacokinetics of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted in healthy female participants (N = 26). Participants received a single dose of LEVO (150 mcg)/EE (30 mcg) alone (reference), and on day 12 of a 15‐day regimen of TIRA 160 mg once‐daily (test). Intensive blood sampling for determination of LEVO, EE, and TIRA plasma concentrations was conducted, and safety was assessed throughout the study. Pharmacokinetic interactions were evaluated using 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of the test versus reference treatments. The GLSM (90% CI) ratios of area under the concentration‐time curve from zero to infinity (AUCinf; LEVO: 0.95, 95% CI: 0.88–1.03, EE: 1.10, 95% CI: 1.05–1.16) and maximum plasma concentration (Cmax; LEVO: 0.85, 95% CI: 0.74–0.98, EE: 1.07, 95% CI: 0.98–1.18) were within the prespecified 0.70 to 1.43 no effect bounds; and the AUC ratios met the stricter 0.80 to 1.25 equivalence bounds. Study treatments were generally well‐tolerated. In conclusion, co‐administration with TIRA did not alter the exposure of LEVO/EE, and accordingly LEVO/EE containing oral contraceptives can serve as a contraception method for participants on TIRA 160 mg (or lower) daily doses.

An Open-label, Crossover Study Comparing EPA+DPA-Free Fatty Acids and EPA-Ethyl Esters in Adults with Elevated Triglycerides: ENHANCE-IT

<h3>Lead Author's Financial Disclosures</h3> K.C.M. has received consulting fees from Matinas BioPharma, Inc., Acasti Pharma, Inc., New Amsterdam Pharma, Pharmavite, and 89Bio. He has received research grant support from Matinas BioPharma, Inc, and Pharmavite. <h3>Study Funding</h3> Matinas BioPharma, Inc. <h3>Background/Synopsis</h3> Few head-to-head studies have directly compared the efficacy of prescription omega-3 fatty acid (OM-3) products. Both the degree of triglyceride (TG) lowering and the achieved blood levels of individual OM-3 fatty acids are important predictors of clinical efficacy. MAT9001 is a unique OM-3 free-fatty-acid (FFA) formulation, containing mainly eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA). A prior crossover study comparing EPA+DPA-FFA and icosapent ethyl (EPA-EE - an ethyl ester EPA formulation) showed enhanced TG lowering and higher EPA levels with EPA+DPA-FFA when both agents were administered with a very-low fat diet and once daily dosing. <h3>Objective/Purpose</h3> To compare pharmacodynamic responses and plasma OM-3 levels following 28-day twice daily treatment with EPA+DPA-FFA and EPA-EE in hypertriglyceridemic subjects consuming a Therapeutic Lifestyle Changes diet. <h3>Methods</h3> This open-label, 2-way crossover trial was conducted at 8 centers in the US and included 100 subjects with fasting TG 150-499 mg/dL (median 204 mg/dL; 57% female, average age 60.3 years). Participants were randomized to EPA+DPA-FFA or EPA-EE for 28 days, washed out for at least 28 days, and then crossed over to the other therapy. Both drugs were given as 2 g twice daily, with meals. The primary endpoint was least squares geometric mean (LSGM) % change from baseline in plasma TG. Additional measurements included other lipoprotein-related markers, high-sensitivity C-reactive protein (hs-CRP) and plasma levels of individual OM-3 fatty acids. <h3>Results</h3> Ninety-four subjects had analyzable data for both treatment periods. EPA+DPA-FFA and EPA-EE reduced TG from baseline: 20.9% and 18.3%, respectively (p=NS). EPA+DPA-FFA reduced hs-CRP by 5.8% compared with an increase of 8.5% with EPA-EE (p = 0.034). EPA+DPA-FFA increased LSGM plasma EPA, DPA, and total OM-3 concentrations by 848%, 692%, and 177% respectively, which were greater than corresponding changes with EPA-EE of 140%, 205%, and 165%, respectively (all p < 0.001). EPA+DPA-FFA increased docosahexaenoic acid (DHA) by 1.7%; EPA-EE decreased DHA by 3.3% (p = 0.011). Responses for lipoprotein cholesterol levels (total, VLDL, LDL, HDL) and apolipoprotein (A-1, B and C-3) did not differ between treatments. <h3>Conclusions</h3> These results demonstrate that a FFA formulation of EPA+DPA produced significantly higher plasma EPA, DPA and total OM-3 levels compared with an EE formulation of EPA, and support the

Clinical study of drug-drug interaction between omeprazole and pyrotinib after meal.

We aimed to investigate the effect of omeprazole on the pharmacokinetics (PK) of pyrotinib and determine the safety of this combination in healthy Chinese volunteers. Eighteen healthy volunteers were enrolled in this single-dose and self-controlled study. Pyrotinib (400 mg per oral) was administered 30 minutes after the standard meal. Omeprazole was administered from day 6 (D6) to D10 (40 mg, per oral). On D10, the subjects took omeprazole under fasting conditions, followed by pyrotinib 30 minutes after the standard meal. Blood samples for PK analyses in each phase were collected for analysing the drug concentration. Safety was assessed via clinical laboratory tests and physical examinations. Compared with a single dose of pyrotinib, pyrotinib coadministered with omeprazole showed no significant difference in exposure, elimination, half-life and apparent clearance rate. The mixed-effects model revealed that the least-squares geometric mean ratios of area under the concentration-time curve (AUC)0-t , AUC0-∞ and maximum plasma concentration (Cmax, 90% confidence intervals) of pyrotinib alone and pyrotinib coadministered with omeprazole were 0.94 (0.82, 1.08), 0.94 (0.83, 1.08) and 0.91 (0.806, 1.038), respectively, indicating the absence of significant differences in AUC0-t , AUC0-∞ and Cmax . During the treatment period, 6 subjects (33.3%) reported 8 adverse events during pyrotinib monotherapy and omeprazole administration, respectively; 10 subjects (55.6%) reported 34 adverse events in the combined administration phase. Omeprazole, a proton-pump inhibitor, did not significantly impact the PK properties of pyrotinib, and a good safety profile was observed on coadministration.