Primary Pharmacokinetic Endpoints Research Articles

A three-arm clinical study to compare pharmacokinetic and pharmacodynamic similarity of the denosumab biosimilar LY06006 with reference denosumab in healthy male subjects

ABSTRACT Background This study aimed to evaluate the pharmacokinetic (PK), pharmacodynamic (PD) similarity, comparable safety, and immunogenicity between LY06006, European Union-sourced denosumab (EU-DEN), and United States-sourced denosumab (US-DEN). Research design and methods In this double-blind, parallel-group, and single-dose study, 300 healthy male subjects were randomized 1:1:1 to receive a 60 mg dose of either LY06006, EU-DEN, or US-DEN subcutaneously. This study lasted for 253 days. Primary PK endpoints included maximum serum concentration (Cmax), area under the concentration-time curve (AUC) from time zero to last quantifiable concentration (AUC0-t), and AUC from time zero to infinity (AUC0-inf). Pharmacokinetic equivalence was concluded if the two-sided 90% confidence interval (CI) for the geometric least squares mean ratio (GLSMR) of primary endpoints were within 80%-125%. Other PK parameters, PD parameters, safety, and immunogenicity assessments were also conducted during the study. Results The 90% CIs for ratios of GLSMR were within the predefined equivalence margin for AUC0-inf (89.0%–111.1%), AUC0-t (89.7%–111.3%), and Cmax (92.3%–106.7%). The PD parameters, safety, and immunogenicity of LY06006 were also comparable to US-DEN and EU-DEN. Conclusion LY06006 was highly similar to US-DEN and EU-DEN in terms of PK, PD, safety and immunogenicity in healthy male subjects. Clinical trial registration www.clinicaltrials.gov identifier is NCT06095427

Pharmacokinetics and Safety of Intravenous Candidate Biosimilar CT-P47 and Reference Tocilizumab: A Randomized, Double-Blind, Phase 1 Study.

CT-P47 is a candidate biosimilar of tocilizumab. This 12-week, randomized, double-blind, parallel-design, phase 1 study aimed to demonstrate pharmacokinetic (PK) equivalence of CT-P47 and reference tocilizumab. Participants were healthy Japanese adults aged 18-55 years. Participants were randomized (1:1:1) to receive a single intravenous dose (8 mg/kg) of CT-P47, EU-approved tocilizumab (EU-tocilizumab), or US-licensed tocilizumab (US-tocilizumab). Primary PK endpoints were area under the concentration-time curve (AUC) from time zero to infinity, AUC from time zero to the last quantifiable concentration, and maximum serum concentration. Additional PK variables, safety, and immunogenicity were evaluated. The study was conducted from January 20 to May 26, 2023, in three centers in Japan. In total, 133 male participants were randomized (n = 45 to CT-P47, n = 44 to EU-tocilizumab, and n = 44 to US-tocilizumab). For all primary PK variables, 90% confidence intervals of the ratio of geometric least squares means were within the predefined equivalence margin of 0.80-1.25. Secondary PK variables were similar across groups. The most common treatment-emergent adverse event (TEAE) was neutrophil count decreased, occurring in 15 (33.3%), 13 (30.2%), and 12 (27.3%) participants in the CT-P47, EU-tocilizumab, and US-tocilizumab groups, respectively. There were no serious TEAEs, deaths, or study drug discontinuations due to TEAEs. Few participants were anti-drug antibody (ADA)- or neutralizing antibody (NAb)-positive. At the end of study, four (8.9%), one (2.3%), and two (4.5%) participants in the CT-P47, EU-tocilizumab, and US-tocilizumab groups, respectively, were ADA-positive; two (4.4%), zero (0%), and one (2.3%) in the respective groups were NAb-positive. CT-P47 demonstrated PK equivalence and comparable safety to EU- and US-tocilizumab.

Pharmacokinetics, Safety, and Immunogenicity of a Biosimilar of Nivolumab (LY01015): A Randomized, Double-Blind, Parallel-Controlled Phase I Clinical Trial in Healthy Chinese Male Subjects.

Nivolumab (Opdivo®) is the first anti-PD-1 antibody approved in the world. LY01015 is a potential biosimilar of nivolumab. This phase I study aimed to establish the pharmacokinetic equivalence between LY01015 and the original investigational nivolumab (Opdivo®) in healthy Chinese male subjects. Additionally, safety and immunogenicity were assessed. A randomized, double-blind, parallel-controlled, phase I trial was conducted with 176 healthy male adults receiving a single intravenous infusion of LY01015 or nivolumab at 0.3mg/kg. Pharmacokinetics, safety, and immunogenicity were evaluated over a 99-day period. The primary pharmacokinetics endpoint was AUC0-∞, and the secondary pharmacokinetic endpoints included AUC0-t and Cmax. Pharmacokinetic bioequivalence was confirmed using standard equivalence margins of 80.00-125.00%. This study is the first to report on the pharmacokinetics, safety, and immunogenicity of Opdivo® in healthy individuals. The pharmacokinetics profiles of LY01015 and Opdivo® were found to be comparable. The geometric mean ratios (90% confidence intervals) for the AUC0-∞, AUC0-t, and Cmax of LY01015 to Opdivo® were 94.49% (90.29-98.88%), 94.92% (88.73-101.54%), and 96.55% (93.32-99.90%), respectively, falling within the conventional bioequivalence criteria of 80.00-125.00%. The safety and immunogenicity were also comparable between the two groups. LY01015 demonstrated highly similar pharmacokinetics to nivolumab in healthy Chinese male subjects. Both drugs exhibited comparable safety and immunogenicity profiles. This trial is registered at the Chinese Clinical Trial Registry website ( https://www.chictr.org.cn/ #ChiCTR2200064771).

MB09, a denosumab biosimilar candidate: Biosimilarity demonstration in a phase I study in healthy subjects.

This was a Phase I, randomized, double-blinded, three-arm, single-dose, parallel study aimed to demonstrate pharmacokinetic (PK) similarity between MB09 (a denosumab biosimilar candidate) and reference denosumab (XGEVA® from European Union [EU-reference] and United States [US-reference]) in a healthy male population. The primary PK endpoints included: Area under the serum concentration versus time curve from time 0 to the last quantifiable concentration timepoint (AUC0-last); and maximum observed serum concentration (Cmax). Secondary endpoints included: AUC from time 0 extrapolated to infinity (AUC0-∞), time to reach maximum observed concentration, clearance, terminal phase half-life, pharmacodynamic, safety, and immunogenicity assessments. A total of 255 subjects were randomized (1:1:1) to receive a subcutaneous 35 mg dose of MB09 or reference denosumab. Cmax was reached after denosumab administration, followed by a decline in the concentration with similar terminal phase half-live across treatment arms. Systemic exposure of MB09 (AUC0-last and Cmax) was equivalent to the reference denosumab, as the 90% confidence intervals around the geometric least square mean ratios laid within the predefined acceptance limits (80.00%, 125.00%) across all comparisons. Pharmacodynamic parameters, based on the percent of change from baseline in serum C-terminal telopeptide of Type 1 collagen levels, were similar across the three arms. The treatments were considered safe and generally well tolerated, with 92 treatment-emergent adverse events reported (most Grade 2 and 3) and similarly distributed. Immunogenicity was low and similarly distributed. These results provide strong evidence that supports the biosimilarity between MB09 and denosumab reference products.

A comparative evaluation of bioequivalence of Gan & Lee glargine U300 and Toujeo® in Chinese healthy male participants.

To assess the bioequivalence between Gan & Lee (GL) glargine U300 and Toujeo® regarding pharmacokinetics (PK), pharmacodynamics (PD), and safety in Chinese healthy male participants. A single-center, randomized, double-blind, single-dose, two-preparation, two-sequence, four-cycle repeated crossover design study was performed to compare GL glargine U300 and Toujeo® in 40 healthy participants. The primary PK endpoints were the area under the curve of glargine metabolites, M1 concentration from 0 to 24 hours (AUC0-24h), and the maximum glargine concentration within 24 hours post-dose (Cmax). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 hours (AUCGIR.0-24h) and the maximum GIR within 24 hours post-dose (GIRmax). GL Glargine U300 demonstrated comparable PK parameters (AUC0-24h, Cmax, AUC0-12h, and AUC12-24h of M1) and PD responses [AUCGIR.0-24h, GIRmax, AUCGIR.0-12h, and AUCGIR.12-24h] to those of Toujeo®, as indicated by 90% confidence intervals ranging from 80% to 125%. No significant disparities in safety profiles were observed between the two treatment groups, and there were no reported instances of serious adverse events. The PK, PD, and safety of GL glargine U300 were bioequivalent to that of Toujeo®. https://www.chinadrugtrials.org.cn/, identifier CTR20212419.

A single-dose, randomized, open-label, four-period, crossover equivalence trial comparing the clinical similarity of the proposed biosimilar rupatadine fumarate to reference Wystamm® in healthy Chinese subjects.

The aim of this study was to evaluate the bioequivalence of two formulations of rupatadine (10-mg tablets) under fasting and fed conditions in healthy Chinese subjects. A total of 72 subjects were randomly assigned to the fasting cohort (n = 36) and fed cohort (n = 36). Each cohort includes four single-dose observation periods and 7-day washout intervals. Blood samples were collected at several timepoints for up to 72h post-dose. The plasma concentration of rupatadine and the major active metabolites (desloratadine and 3-hydroxydesloratadine) were analyzed by a validated HPLC-MS/MS method. The non-compartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation of the reference formulation, a reference-scaled average bioequivalence or average bioequivalence method was used to evaluate the bioequivalence of the two formulations. For the fasting status, the reference-scaled average bioequivalence method was used to evaluate the bioequivalence of the maximum observed rupatadine concentration (Cmax; subject standard deviation > 0.294), while the average bioequivalence method was used to evaluate the bioequivalence of the area under the rupatadine concentration-time curve from time 0 to the last detectable concentration (AUC0-t) and from time 0 to infinity (AUC0-∞). The geometric mean ratio (GMR) of the test/reference for Cmax was 95.91%, and the upper bound of the 95% confidence interval was 95.91%. For AUC0-t and AUC0-∞ comparisons, the GMR and 90% confidence interval (CI) were 98.76% (93.88%-103.90%) and 98.71% (93.93%-103.75%), respectively. For the fed status, the subject standard deviation values of Cmax, AUC0-t, and AUC0-∞ were all <0.294; therefore, the average bioequivalence method was used. The GMR and 90% CI for Cmax, AUC0-t, and AUC0-∞ were 101.19% (91.64%-111.74%), 98.80% (94.47%-103.33%), and 98.63% (94.42%-103.03%), respectively. The two-sided 90% CI of the GMR for primary pharmacokinetic endpoints of desloratadine and 3-hydroxydesloratadine was also within 80%-125% for each cohort. These results met the bioequivalence criteria for highly variable drugs. All adverse events (AEs) were mild and transient. The test drug rupatadine fumarate showed a similar safety profile to the reference drug Wystamm® (J. Uriach y Compañía, S.A., Spain), and its pharmacokinetic bioequivalence was confirmed in healthy Chinese subjects based on fasting and postprandial status. http://www.chinadrugtrials.org.cn/index.html, identifier CTR20213217.

A pharmacokinetic study comparing the biosimilar HEC14028 and Dulaglutide (Trulicity®) in healthy Chinese subjects.

This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar HEC14028 compared to reference Trulicity® (dulaglutide) in healthy male Chinese subjects. This study was a single-center, randomized, open, single-dose, parallel-controlled comparative Phase I clinical trial, including a screening period of up to 14 days, a 17-day observation period after administration, and a 7-day safety follow-up period. A total of 68 healthy male subjects were randomly assigned (1:1) to the test group (HEC14028) and the reference group (dulaglutide) (single 0.75 mg abdominal subcutaneous dose). The primary objective was to evaluate the pharmacokinetic characteristics of HEC14028 and compare the pharmacokinetic similarities between HEC14028 and dulaglutide. The primary PK endpoints were maximum plasma concentration (Cmax) and area under the blood concentration-time curve from zero time to the estimated infinite time (AUC0-∞). The study results showed that HEC14028 and dulaglutide were pharmacokinetically equivalent: 90% confidence interval (CI) of Cmax and AUC0-∞ geometric mean ratios were 102.9%-122.0% and 97.1%-116.9%, respectively, which were both within the range of 80.00%-125.00%. No grade 3 or above treatment emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to withdrawal from the trial, or TEAEs leading to death were reported in this study. Both HEC14028 and dulaglutide showed good and similar safety profiles, and no incremental immunogenicity was observed in subjects receiving HEC14028 and dulaglutide.

Pharmacokinetics and Tolerability of a Single Dose of Apraglutide, a Novel, Long-Acting, Synthetic glucagon-like peptide-2 Analog With a Unique Pharmacologic Profile, in Individuals With Impaired Renal Function.

Renal impairment is a common complication in patients with short bowel syndrome with intestinal failure (SBS-IF). Glucagon-like peptide-2 analogs, such as apraglutide, have been developed as a treatment option for SBS-IF. This study assessed the potential for apraglutide overexposure in individuals with severely impaired renal function versus healthy volunteers with normal renal function. In this phase 1, open-label, multicenter, nonrandomized, parallel-group study, a single dose of apraglutide 5 mg was administered subcutaneously to individuals with severely impaired renal function (<30 mL/min/1.73 m2) and healthy volunteers with normal renal function (≥90mL/min/1.73 m2). Primary pharmacokinetic endpoints were maximum observed concentration (Cmax) and exposure to apraglutide (area under the curve [AUC] from time 0 to infinity [AUCinf], and AUC from time 0 to the last quantifiable concentration [AUClast]). Each group comprised 8 individuals. Results show that patients with severe renal impairment do not have increased apraglutide exposure. Apraglutide achieved a lower Cmax and AUCinf in individuals with severe renal impairment versus those with normal renal function (Cmax = 36.9 vs 59.5 ng/L; AUCinf = 3100 vs 4470 h · ng/mL, respectively). The respective geometric mean ratios were 0.620 and 0.693 for Cmax and AUCinf, and the upper bound of their 90% confidence intervals were <2, indicating patients with severe renal impairment were not overexposed to apraglutide versus those with normal renal function. Adverse events were mild or moderate in severity. Apraglutide does not require dose reduction for any degree of renal impairment and could be used in a broader patient population of renally impaired patients without dose adjustment.

Compatible co-administration of BioThrax® vaccine and ciprofloxacin—Results of a randomized open-label drug-vaccine interaction trial

The recommended treatment for post-exposure prophylaxis (PEP) following known/suspected exposure to Bacillus anthracis involves immunization with anthrax vaccine adsorbed (AVA, i.e., BioThrax® vaccine) and a course of antimicrobial therapy. A drug-vaccine interaction clinical trial was conducted to determine whether this combined treatment might modify antimicrobial exposure or vaccine immunogenicity.A Phase 2, randomized, open-label, multi-center trial involving 154 healthy adult participants was completed to evaluate the effect of AVA immunization (three doses administered subcutaneously (SC) at weeks 0, 2 and 4) on the pharmacokinetics (PK) of ciprofloxacin, as well as the effect of ciprofloxacin administration (500 mg po bid) on the immunogenicity of AVA. PK parameters were derived using noncompartmental analysis of ciprofloxacin serum concentrations. Immunogenicity was assessed using a toxin neutralizing antibody (TNA) assay resulting in 50 % neutralization factor (NF50) values. Safety was assessed via reports of adverse events (AEs), clinically significant changes in laboratory parameters and vital signs, and collection of solicited local and systemic reactogenicity reactions.Statistical analyses of the steady state (SS) and single dose PK parameters Cmax and AUC0-–12h indicated that the AVA PEP regimen did not significantly modify ciprofloxacin exposure. Comparison of the geometric mean TNA NF50 values between participants receiving AVA + ciprofloxacin and those receiving AVA alone showed that the combined treatment was non-inferior to AVA alone. The trial met all prospectively defined success criteria for the primary PK endpoint and for the secondary PK and immunogenicity endpoints. There were no deaths, SAEs or AEs leading to drug discontinuation or study withdrawal during the trial.Overall, concomitant administration of ciprofloxacin and AVA produced no significant changes in the PK profile of ciprofloxacin nor in the immunogenicity of AVA. Furthermore, this trial demonstrated that the co-administration of ciprofloxacin and AVA was well tolerated in healthy adult participants.

Development of Oral Azacitidine with Cedazuridine for Myelodysplastic Syndrome (MDS) and Myeloproliferative Neoplasms (MPN) Including CMML (Chronic Myelomonocytic Leukemia) By Targeting Pharmacokinetic AUC Equivalence Vs Subcutaneous Azacitidine

Introduction/ Background: Hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DEC) are FDA-approved for patients with MDS/CMML and acute myeloid leukemia (AML). Treatment is generally administered parenterally as a daily injection or infusion over 5-7 days per four-week cycle. The oral fixed-dose combination of decitabine with cedazuridine, ASTX727, was approved by regulators in the USA and Canada for patients with MDS and CMML based upon the demonstration of biologically equivalent pharmacokinetics (PK) area under the curve (AUC) vs IV decitabine. ASTX030 is a combination of AZA and cedazuridine (CED), a cytidine deaminase inhibitor (CDAi), which enables oral AZA to achieve systemic AUC similar to that of parenteral (subcutaneous) AZA. Development and approval of an oral AZA providing equivalent PK exposure to the parenteral therapy has the potential to markedly reduce the treatment burden associated with parenteral treatment. This Phase I trial is designed to determine the dose combination for oral AZA plus CED to replicate SC AZA AUC exposures in subjects with MDS and MDS/MPN, including CMML. Methods: Adult patients with confirmed MDS, CMML, and other MDS/MPN or AML who are candidates to receive benefit from single agent AZA were enrolled in this open label Phase 1 trial. In addition to assessing safety and efficacy of each combination, the primary PK endpoint was to achieve oral AZA PK AUC 0-24 equivalence versus subcutaneous AZA (at the approved dose of 75 mg/m 2 over the span of 7 days). In the first cycle, patients received oral AZA alone on Day -3, followed by SC AZA at 75 mg/m 2 on Day 1. Subsequently, oral ASTX030 (combination of AZA with CED) was given at varying dose combinations of AZA and CED for each cohort. After cycle 1, patients received oral ASTX030 on Days 1-7 for each 28-day cycle. Dose levels for cohorts in escalation were determined by the data safety and review committee based on safety and PK results. Pharmacodynamic (PD) impact was assessed by changes in LINE-1 DNA methylation in peripheral blood cells. Clinical response assessments were based upon International Working Group (IWG) 2006 criteria for MDS patients and IWG 2015 criteria for MDS/MPN and CMML patients. Results: As of 05 JUL 2023, 65 patients were treated across 8 different dose combinations, with ≥6 patients per cohort. The median age was 72 years old (range 26-87), 36.9% (n=24) were female, 6.2% (n=4), had previously received HMA treatment (unlimited). Of the enrolled patients, 69% (n=45) had MDS, 25%(n=16) had CMML, and 6% (n=4) had MDS/MPN (other). Evaluated dose levels for AZA ranged from 60-136mg and CED dose ranged from 20-100 mg. In cohorts 1-2, tablet formulation was tested first (AZA ranging 80-100mg with CED ranging 80-100mg). Starting with cohort 3, capsule formulation was introduced for AZA to optimize the interaction effect of CDA inhibition by CED. In both tablet and capsule formulation, grade ≥3 AE's (regardless of causality) were observed in 75.9% of patients. The most common Grade ≥3 AE's regardless of relation to drug were leukopenia (25%), thrombocytopenia (20%), and anemia (20%). Gastrointestinal toxicity were similar (for example, nausea 70% ASTX030 vs 71% SC AZA) to those reported for SC AZA (VIDAZA USPI)). No dose limiting toxicity was observed in any of the cohorts. The CED dose of 20 mg resulted in ~100% bioavailability for AZA, suggesting inhibition in a linear range. LINE-1 demethylation results were similar to those reported historically with SC AZA. Although a clinical response comparable to SC AZA was observed, the immature nature of the data requires continued analysis to yield results on treatment efficacy. Conclusion: ASTX030 successfully achieved the primary endpoint of PK equivalence versus SC AZA based on total cycle AUC. The dose combinations evaluated were well tolerated, and the safety profile similar to that of SC AZA, with no unique AE's. LINE-1 demethylation and clinical response confirm the clinical activity of ASTX030. Phase 1B dose expansion for the ASTX030 study at the recommended dose combination of 144mg AZA with 20mg CED will begin soon to confirm PK equivalence for this dose level. An orally bioequivalent AZA based HMA offers significant opportunity for novel combinations and improved convenience for patients with high grade myeloid malignancy.

A phase I, randomized, double-blind, single-dose pharmacokinetic study to evaluate the biosimilarity of SB16 (proposed denosumab biosimilar) with reference denosumab in healthy male subjects

ABSTRACT Background SB16 is a biosimilar to reference denosumab (DEN). This study assessed pharmacokinetic (PK) equivalence and evaluated pharmacodynamic (PD), safety, tolerability, and immunogenicity between SB16, European Union-sourced DEN (EU-DEN), and United States-sourced DEN (US-DEN). Research design and methods In this double-blind, parallel group, and single-dose study, healthy male subjects were randomized 1:1:1 to receive a single 60 mg dose of either SB16, EU-DEN, or US-DEN subcutaneously. PK, PD, safety, and immunogenicity were evaluated for 197 days. Primary PK endpoints were area under the concentration-time curve (AUC) from time zero to infinity, AUC from time zero to the last quantifiable concentration, and maximum serum concentration (Cmax). Equivalence was determined if 90% confidence intervals (CIs) for the ratio of geometric least squares means (LS Means) were within the equivalence margin of 0.80 to 1.25. Results A total of 168 subjects (56 per treatment group) were randomized. All of the corresponding 90% CI of geometric LS Means ratio of primary PK parameters were within the pre-defined equivalence margin. PD, safety, and immunogenicity profiles were also comparable between the treatment groups. Conclusion This study demonstrated PK bioequivalence between SB16, EU-DEN, and US-DEN in healthy male subjects. TrialRegistration CT.gov identifier: NCT04621318

Pharmacokinetic and pharmacodynamic bioequivalence of Gan & Lee insulin analogues aspart (rapilin®), lispro (prandilin®) and glargine (basalin®) with EU- und US-sourced reference insulins.

For the successful approval and clinical prescription of insulin biosimilars, it is essential to show pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence to the respective reference products sourced from the European Union and the United States. Three phase 1, randomized, double-blind, three-period crossover trials compared single doses of the proposed biosimilar insulin analogues aspart (GL-Asp, n = 36), lispro (GL-Lis, n = 38) and glargine (GL-Gla, n = 113), all manufactured by Gan & Lee pharmaceuticals, to the respective EU- and US-reference products in healthy male participants (GL-Asp and GL-Lis) or people with type 1 diabetes (GL-Gla). Study participants received 0.2 U/kg (aspart and lispro) or 0.5 U/kg (glargine) of each treatment under automated euglycaemic clamp conditions. The clamp duration was 12 h (aspart and lispro) or 30 h (glargine). Primary PK endpoints were the total area under the PK curves (AUCins.total ) and maximum insulin concentrations (Cins.max ). Primary PD endpoints were the total area under the glucose infusion rate curve (AUCGIR.total ) and maximum glucose infusion rate (GIRmax ). Bioequivalence to both EU- and US-reference products were shown for all three GL insulins. Least squares mean ratios for the primary PK/PD endpoints were close to 100%, and both 90% and 95% confidence intervals were within 80%-125% in all three studies. There were no noticeable differences in the safety profiles between test and reference insulins, and no serious adverse events were reported for the GL insulins. GL-Asp, GL-Lis and GL-Gla are bioequivalent to their EU- and US-reference products.

Pharmacokinetics of a proposed tocilizumab biosimilar (MSB11456) versus US-licensed tocilizumab: results of a randomized, double-blind, single-intravenous dose study in healthy adults

ABSTRACT Background Tocilizumab, a recombinant monoclonal immunoglobulin G, targets the interleukin-6 receptor. MSB11456 is a proposed tocilizumab biosimilar. Objectives To assess pharmacokinetic equivalence of intravenous MSB11456 to US-licensed tocilizumab. Research design and methods In this double-blind, parallel-group, single-dose study, 128 healthy adults were randomized to a single one-hour 8 mg/kg IV infusion of either MSB11456 or US-licensed tocilizumab. Blood samples were collected pre-dose and at regular intervals up to day 48 post-dose. The primary endpoint pharmacokinetic parameter was analyzed using analysis of variance (ANOVA) model on the natural logarithm of the endpoint (AUC0–last), with treatment as a fixed effect. Immunogenicity and safety data were summarized descriptively. Results Subjects received either MSB11456 (N = 62) or US-licensed tocilizumab (N = 66). Pharmacokinetic bioequivalence, defined as 90% confidence intervals for the geometric least squares mean ratio entirely contained within the 80.00% to 125.00% equivalence limits, was demonstrated between MSB11456 and US-licensed tocilizumab for the primary and secondary pharmacokinetic endpoints. Anti-drug antibody responses, frequency of neutralizing antibodies against tocilizumab, and safety profiles showed no notable between-treatment differences. Safety was comparable between treatments. Conclusions Pharmacokinetic similarity of MSB11456 and US-licensed tocilizumab was demonstrated, with comparable immunogenicity and safety profiles, supporting MSB11455 as a biosimilar to US-licensed tocilizumab. The trial is registered at EudraCT, number 2019–003484-22.

Pharmacokinetics of a microdosed cocktail of three direct oral anticoagulants in children with congenital heart defects: study protocol for a single-centre clinical trial (DOAC-Child)

IntroductionDirect oral anticoagulants (DOACs) are direct inhibitors of coagulation factor Xa and are frequently used in adults for different indications such as deep vein thrombosis or non-valvular atrial fibrillation. Paediatric...

S918 Pharmacokinetic Equivalence of Biosimilar Adalimumab-aqvh and Adalimumab in Healthy Subjects

Introduction: This study assessed the pharmacokinetic (PK) bioequivalence between adalimumab-aqvh, an FDA-approved biosimilar, and the reference product adalimumab after a single dose administered to healthy subjects. Adalimumab is indicated for many inflammatory conditions such as psoriasis as well as inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease. Biosimilars are biologic drugs that are highly similar in purity, potency, efficacy, and safety to the reference biologic and are available at lower costs. Methods: This double-blind, single-dose, parallel-group study randomized healthy subjects (N = 210) 1:1 to receive one 40-mg dose of adalimumab-aqvh or adalimumab. The primary PK endpoints were maximum serum concentrations (Cmax) and the area under the serum concentration versus time curve extrapolated from 0 to infinity (AUC0-inf) of adalimumab-aqvh versus adalimumab. Other PK endpoints included the time to reach Cmax, terminal elimination half-life, AUC calculated from 0 to the last measurable concentration, and apparent volume of serum cleared of drug per unit time. Safety and immunogenicity were also assessed. Results: The Cmax geometric mean ratio (GMR) was 98.6% (90% CI 90.7–107.3) and the AUC0-inf GMR was 102.7% (90% CI 92.2–114.3); PK bioequivalence was demonstrated, as both endpoints were contained within the predefined 90% CI GMR range (80%–125%). The other PK endpoints were similar between adalimumab-aqvh and adalimumab. Treatment-emergent adverse events (TEAEs) and study drug–related TEAEs were similar for each treatment, and most were mild or moderate in severity; no new safety signals were identified. Immunogenicity was similar after treatment with adalimumab-aqvh and adalimumab. Conclusion: The study demonstrated PK bioequivalence between adalimumab-aqvh and adalimumab following a single dose in healthy subjects. The safety profile, including immunogenicity, of adalimumab-aqvh was also similar to that of adalimumab.

A Phase 1, open-label, crossover study evaluating the effect of a single dose of sodium zirconium cyclosilicate on the pharmacokinetics of tacrolimus and cyclosporin.

Sodium zirconium cyclosilicate (SZC) is an oral, highly selective potassium binder approved for the treatment of hyperkalaemia in adults. SZC may change the absorption of co-administered drugs that exhibit pH-dependent bioavailability. This study evaluated whether the pharmacokinetic (PK) profiles of tacrolimus and cyclosporin were altered by concomitant SZC administration in healthy participants. This was an open-label, randomised sequence, two-cohort crossover, single-centre study. Healthy adults were assigned to one of two cohorts: Cohort 1 (tacrolimus) received a single dose of tacrolimus 5mg and tacrolimus 5mg+SZC 15g in a random order; Cohort 2 (cyclosporin) received a single dose of cyclosporin 100mg and cyclosporin 100mg+SZC 15g in a random order. Primary PK endpoints were maximum observed blood concentration (Cmax) and area under the concentration-time curve (AUC) from time zero to infinity (AUCinf). Differences in mean Cmax and AUCinf were analysed using a mixed effects model. Thirty participants in Cohort 1 and 29 in Cohort 2 completed the study. Tacrolimus exposure was lower with tacrolimus+SZC versus tacrolimus alone: Cmax geometric mean ratio (GMR) 71.10% [90% confidence interval (CI) 65.44-77.24], AUCinf 62.91% (55.64-71.13). Cyclosporin exposure was similar with cyclosporin+SZC compared with cyclosporin alone: Cmax GMR 102.9% (90% CI 96.11-110.10), AUCinf 97.23% (92.93-101.70). Tacrolimus exposure was lower when co-administered with SZC 15g and should be administered ≥2h before or after SZC. The PK profile of cyclosporin was not affected by SZC co-administration.

Pharmacokinetics/pharmacodynamics by race: Analysis of a peginterferon β-1a phase 1 study

Black/African American participants are underrepresented in clinical trials for multiple sclerosis but can experience a greater burden of disease than other racial groups in the United States. A phase 1, open-label, crossover study that demonstrated bioequivalence of subcutaneous and intramuscular injection of peginterferon β-1a in healthy volunteers enrolled similar proportions of Black and White participants, enabling a post hoc subgroup analysis comparing these groups. Peginterferon β-1a (125μg) was administered by subcutaneous or intramuscular injection, followed by a washout period before a second injection using the alternative method. The primary pharmacokinetic and pharmacodynamic endpoints were maximum observed concentration (Cmax) and area under the concentration-time curve from hour 0 to infinity (AUCinf) of study drug and serum concentration of neop-terin, respectively. Safety and tolerability were included as secondary endpoints. This analysis included 70 (51.5%) Black and 59 (43.3%) White participants. Peginterferon β-1a Cmax was 29.8% higher in Black than in White participants following subcutaneous administration but was similar following intramuscular administration. Mean AUCinf was 31.0% and 11.8% greater in Black than in White participants with subcutaneous and intramuscular administration, respectively. Pharmacodynamics and safety signals were similar between groups, although Black participants reported numerically fewer adverse events. No clinically meaningful differences were identified between Black and White participants related to peginterferon β-1a administration, supporting the approved dose of 125μg/mL peginterferon β-1a. Future clinical studies should include sufficiently diverse populations to ensure accurate assessments of treatment response. Funding for medical writing support was provided by Biogen (Cambridge, MA, USA).

PB1903: TRIAL IN PROGRESS: A MULTICENTER, OPEN-LABEL, PHASE IB/II STUDY TO DETERMINE THE DOSE AND SAFETY OF ASCIMINIB IN PEDIATRIC PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP)

Background: Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients (pts) with CML-CP. Five TKIs are approved for adults: imatinib, dasatinib, nilotinib, bosutinib, and ponatinib. However, only imatinib, dasatinib, and nilotinib are approved for pediatric pts. Efficacy and safety profiles of TKIs are similar in adult and pediatric pts; however, growth retardation has been reported in the pediatric population, in whom long-term adverse effects are unknown. Therefore, safer and more efficacious options are needed for pediatric pts. Asciminib is a recently approved drug that inhibits BCR::ABL1 by Specifically Targeting the ABL Myristoyl Pocket (STAMP). In the phase III ASCEMBL trial for adults with heavily pretreated CML-CP, asciminib (40 mg twice daily [BID]) had an improved major molecular response rate (25.5% vs 13.2%) at week 24 and a better safety profile compared with bosutinib (500 mg once daily). Here we present the phase Ib/II trial evaluating asciminib in pediatric pts. Aims: The primary objectives of this study are to characterize the pharmacokinetic (PK) profile of asciminib in pediatric pts and identify a pediatric formulation dose leading to an asciminib exposure comparable to the adult dose, 40 mg BID. Methods: This is a multicenter, open-label study (NCT04925479). Eligible pts have Philadelphia chromosome–positive CML-CP treated with ≥1 prior TKI, do not have a T315I mutation, and are aged ≥1 to <18 years, provided informed consent. Adolescent pts aged ≥14 to <18 years and weighing ≥40 kg will be enrolled in the exploratory adult formulation group, receiving the adult dose, until the pediatric formulation is available. In part 1 (dose-determining cohort), 4 to 6 pts aged ≥1 to <18 years will receive the pediatric formulation (body weight–adjusted dose of asciminib taken with food) to obtain ≥4 participants evaluable for PK data. This evaluation will determine whether median exposure in pediatric pts is comparable to asciminib 40 mg BID taken without food in adult pts. PK and safety will be assessed during the first 28 days after treatment initiation. In part 2 (expansion cohort), the body weight–adjusted dose determined in part 1 will be used, and the total pts enrolled on pediatric formulation will be increased to 30, including those from part 1 (15 pts aged 1 to <12 years and 15 pts aged 12 to <18 years). Pts receiving the adult formulation may switch to the pediatric formulation in part 2 but will not be counted toward the 30 pts enrolled in part 2. A 2nd interim PK and safety analysis will be conducted after all pts in part 2 have completed 28 days of treatment. The total duration of the study treatment period is 5 years (Figure). The primary PK endpoints, safety, and pharmacodynamics will be assessed after all pts have been on study for 52 weeks or discontinued earlier. After all pts have been on study for 5 years or discontinued earlier, a final analysis will be performed. Pts who discontinue the study early will be followed up for survival until the study is complete. Results: The primary endpoints include PK parameters. Secondary endpoints include hematologic and molecular responses, safety, acceptability, and palatability of asciminib. Image:Summary/Conclusion: Data from this study will be used to provide a pediatric dose and support a strategy of full extrapolation from adult data to use in the pediatric setting.

Pharmacokinetic and pharmacodynamic equivalence of Biocon's biosimilar Insulin 70/30 with US-licensed HUMULIN® 70/30 formulation in healthy subjects: Results from the RHINE-3 (Recombinant Human INsulin Equivalence-3) study.

AimTo establish the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of proposed biosimilar insulin 70/30 (Biocon's Insulin‐70/30) and HUMULIN® 70/30 (HUMULIN‐70/30; Eli Lilly and Company, IN).Materials and MethodsIn this phase 1, automated euglycaemic glucose clamp study, 78 healthy subjects were randomized (1:1) to receive a single dose of 0.4 IU/kg of Biocon's Insulin‐70/30 and HUMULIN‐70/30. Plasma insulin concentrations and glucose infusion rates (GIRs) were assessed over 24 hours. Primary PK endpoints were area under the insulin concentration‐time curve from 0 to 24 hours ‐ AUCins.0−24h ‐ and maximum insulin concentration ‐ Cins.max. Primary PD endpoints were area under the GIR time curve from 0 to 24 hours ‐ AUCGIR.0−24h ‐ and maximum GIR ‐ GIRmax.ResultsEquivalence was shown between Biocon's Insulin‐70/30 and HUMULIN‐70/30 for the primary PK/PD endpoints. The 90% confidence intervals of the treatment ratios were entirely within the acceptance range of 80.00%‐125.00%. The secondary PK/PD profiles were also comparable. There were no clinically relevant differences in the safety profiles of the two treatments and no serious adverse events were reported.ConclusionPK/PD equivalence was demonstrated between Biocon's Insulin‐70/30 and HUMULIN‐70/30 in healthy subjects. Treatment with Biocon's Insulin‐70/30 and HUMULIN‐70/30 was well tolerated.

Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies).

Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric patients with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) in five participating European countries. Children were treated for 8 weeks with ODMTs according to an age-appropriate dosing schedule. The primary objective was to describe PK parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (t-max)) of enalapril and its active metabolite enalaprilat. Of 102 patients, 89 patients (n = 26, DCM; n = 63 CHD) were included in the primary PK endpoint analysis. Rate and extent of enalapril and its active metabolite enalaprilat were described and etiology and age could be identified as potential PK modifying factors. The dosing schedule appeared to be tolerated well and did not result in any significant drug-related serious adverse events. The PK analysis and the lack of severe safety events supports the applied age-appropriate dosing schedule for the enalapril ODMTs.