Similar Pharmacokinetics Research Articles

Clinical Factors Impact on Pharmacokinetics of CT-P10 and Reference Rituximab in Patients with Advanced-Stage Follicular Lymphoma

Background: CT-P10 is the first biosimilar to the innovator rituximab (RTX), which was approved by the European Medicines Agency for all indications for which RTX is approved. Pharmacokinetic equivalence and comparable efficacy was demonstrated in advanced-stage follicular lymphoma patients (Kim WS et al. Lancet Haematol. 2017; S2352-3026(17)) as well as in rheumatoid arthritis (Yoo DH, et al. Arthritis Rheumatol. 2016; 68 (suppl 10)). It is known that there are several factors affecting on pharmacokinetics (PK) of rituximab. However, there are limited data on comparing PK data between a biosimilar of rituximab and RTX with different subgroups in advanced-stage follicular lymphoma (AFL) patients.Objective: This report is to investigate the PK of CT-P10 according to the several relevant clinical factors and to compare with RTX in the post-hoc analysis of randomized controlled trial to compare CT-P10 and RTX in advanced-stage follicular lymphoma (NCT02162771).Methods: A total of 121 patients of PK population were included in this analysis. Fifty nine patients in the CT-P10 group and 62 patients in the RTX group received CT-P10 or RTX (375 mg/m2 i.v) plus CVP (cyclophosphamide, vincristine and prednisone) for every 3 weeks over 8 cycles. Area Under the Concentration-time curve at steady state (AUCtau) and the maximum serum concentration at steady state (CmaxSS) at Cycle 4 and trough serum concentration (Ctrough) at Cycle 4 and Cycle 8 were calculated by standard non-compartmental methods using Phoenix WinNonlin. The parameters were analysed by subgroups of Gender (male vs. female), Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. ≥1), Follicular Lymphoma International Prognostic Index (FLIPI) Score (0-2 vs. 3-5) and its component (Age (≥60 vs. <60), Hemoglobin [Hb] (≥120g/L vs. <120g/L), Lactate dehydrogenase [LDH] (>UNL vs. ≤UNL), number of nodal sites (>4 vs. ≤4)), presence of bulky lesion at baseline (≥7cm vs. <7cm) and Complete response (CR)/Complete response unconfirmed (CRu) as best overall response assessed by International Working Group 1999 in the each and combined group of CT-P10 and RTX. Outliers which determined by robust regression outlier testing were excluded in this analysis. For AUCtau, 7 patients (5 in the CT-P10 group and 2 in the RTX group) and among them, 4 patients (2 patients in each group) for CmaxSS were defined as outliers.Result: Higher AUCtau and CmaxSS were observed in patients who are female, under 60 years old, good ECOG Performance Status, low FLIPI score, normal Hb and LDH levels, and non-bulky disease at baseline as shown in Table 1. In patients who achieved CR/CRu as their best overall response during 8 cycles showed higher AUCtau, CmaxSS and Ctrough than in patients who did not achieve CR/CRu response in both CT-P10 and RTX groups. At Cycle 4 and Cycle 8, mean Ctrough in the CR/CRu responder were 72 μg/mL, 108 μg/mL, respectively, and those concentrations are 56 μg/mL, 96 μg/mL in the CR/CRu non-responder. Importantly, there was no statistically significant difference between the CT-P10 and RTX in any of subgroup analyses; confidence interval of the ratio of geometric mean of CT-P10 to RTX contains 1 using Satterthwaite approximation for each comparison.Conclusion: Female gender, younger age (<60), better ECOG Performance Status, lower FLIPI score, LDH and Hb levels in normal range, absence of bulky disease at baseline and better response are factors associated with increased serum rituximab concentration in the combined treatment groups. No statistically significant differences were found between CT-P10 and RTX groups in PK at all subgroup analyses. Therefore, this result shows that the PK of CT-P10 is in accordance with the RTX from historical data and further supports the PK similarity between CT-P10 and RTX. [Display omitted] DisclosuresKim:Celltrion, Inc: Consultancy, Honoraria; Roche: Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Donga: Research Funding; J&J: Research Funding; Takeda: Research Funding. Coiffier:Celltrion, Inc: Consultancy, Honoraria. Buske:Hexal: Honoraria; Celltrion, Inc.: Consultancy, Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Ogura:SymBio: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Astrazeneca: Honoraria; Takeda: Consultancy, Honoraria; Mundipharma: Consultancy; MeijiSeika Pharma: Consultancy; Celltrion, Inc: Consultancy, Honoraria. Kwak:Celltrion, Inc: Consultancy; InnoLifes: Consultancy, Equity Ownership; Pepromene Bio: Consultancy, Equity Ownership. Lee:Celltrion, Inc: Employment. Bae:Celltrion, Inc: Employment. Kim:Celltrion, Inc: Employment. Kim:Celltrion, Inc: Employment. Lee:Celltrion, Inc: Employment. Kwak:Celltrion, Inc: Employment. Lee:Celltrion, Inc: Employment.

A Randomized, Double-Blind, Single-Dose Study Comparing the Biosimilarity of HOT-1010 With Bevacizumab (Avastin®) in Chinese Healthy Male Subjects.

Objective: This study was conducted to compare the pharmacokinetics, safety and immunogenicity of HOT-1010 with bevacizumab (Avastin®) in Chinese healthy male subjects. Methods: A single-center, randomized, double-blind, single-dose, parallel trial was performed in 84 Chinese healthy male subjects who randomly (1:1) received a single intravenous infusion of 1 mg/kg HOT-1010 or Avastin® for 90 min and followed up for 85 days. Serum concentrations of bevacizumab were analyzed by enzyme-linked immunosorbent assay. Primary pharmacokinetic parameters, Cmax, AUC0-t and AUC0-∞, were calculated and evaluated the bioequivalence between HOT-1010 and Avastin®, the safety and immunogenicity of investigational drugs were also assessed. Results: A total of 82 subjects completed the study. The 90% Confidence Intervals for geometric mean ratios of Cmax, AUC0-t and AUC0-∞ were 91.81–103.64%, 85.19–95.39% and 85.04–95.36%, which were all within the bioequivalence margin. Treatment-emergent adverse events were reported in 27 (65.9%) subjects in HOT-1010 group and 23 (56.1%) subjects in Avastin® group. Most TEAEs were mild or moderate. No TEAEs, Serious Adverse Events or deaths leading to discontinuation was reported. Subjects were all tested negative for Anti-drug Antibody. Conclusion: HOT-1010 exhibited the similar pharmacokinetics, safety and immunogenicity profiles of bevacizumab (Avastin®) in Chinese healthy male subjects. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html, CTR20181610.

P428 Early and Late Fecal Calprotectin Remission - Analysis of a proactive Therapeutic Drug Monitoring Treatment Protocol

Abstract Background Fecal calprotectin (Fc) is an adequate surrogate marker for endoscopic activity in inflammatory bowel disease. The timing of Fc remission may have prognostic implications in patients under biologic therapy. Methods Using a prospectively maintained database we followed 135 patients under a proactive therapeutic drug monitoring (pTDM) protocol aiming at an Infliximab trough level (IFXTL) between 5-10 µg/mL with sequential measurements of Fc. We evaluated the rates of early (at week 14) and late (after week 14) Fc remission (&amp;lt;250 µg/g) and associated clinical outcomes at 2-years of follow up. Results 77 patients (57.0%) reached early Fc remission and 30 patients (22.2%) reached late Fc remission. Patients with late Fc remission presented higher Fc at baseline (1708.5 μg/g [681-3483] vs 803 μg/g [339-1477], P=0.006) and lower IFXTL at week 14 (2.71 µg/mL [1.24-6.30] vs 6.59 µg/mL [3.41-10.63], P=0.001) than patients with early Fc remission. However, by the end of follow-up, IFXTL were similar in both groups: 7.94 µg/mL (4.79-11.25) vs 8.54 µg/mL (6.49-11.07), P=0.514. In patients without early Fc remission, week 14 IFXTL did not differ between those with and without late Fc remission (2.71 µg/mL [1.24-6.30] vs 3.47 µg/mL [0.945-6.94], P=0.957), but significantly increased in late responders by the end of follow-up: 8.54 µg/mL (6.49-11.07) vs 4.37 µg/mL (1.77-7.49), P=0.002. Patients with early and late Fc remission presented similar rates of clinical remission (88.3% vs 83.0%, P=0.493), steroid-free clinical remission (79.1% vs 92.9% P=0.239), lower rates of IFX discontinuation (14.3% vs 16.7%, P=0.756), hospitalization (11.7% vs 13.3%, P=0.815), and surgery (1.3% vs 3.3%, P=0.485). Conclusion The magnitude of Fc at baseline and IFXTL at week 14 significantly influence the timing of Fc remission. The use of PTDM results in similar pharmacokinetics and clinical outcomes in both groups.

Comparison of single subject and population-based pharmacokinetics for optimizing prophylaxis with simoctocog alfa in patients with haemophilia A.

The use of pharmacokinetic assessment for optimal prophylactic dosing of factor concentrates in haemophilia has gained increasing enthusiasm over the last decade. However, blood sampling on several occasions is burdensome and limited sampling using population-based PK is appealing. To compare the pharmacokinetics and dosing recommendations for prophylaxis using six-point single subject versus population-based method (WAPPS-Hemo) for simoctocog alfa (Nuwiq® ). Twelve adult patients with severe haemophilia A received a factor VIII (FVIII) dose of ≈50IU/kg, and the activity was measured pre-infusion and at 30min, 6, 9, 24 and 48h post-infusion. Half-life (t1 /2 ), weight-normalized AUC and time to troughs of 5%, 3% and 1% were calculated. The correlation between the PK algorithms was assessed using intraclass correlations (ICC) and dosing estimations were provided. WAPPS-Hemo yielded a slightly longer mean t1 /2 , but the overall correlation between the methods was good (ICC ≥0.79) The time to troughs of 5%, 3% and 1% showed ICCs ≥0.86. For all variables, the most converging limited time point was 6+48h. Additional time points did not improve the correlation. Despite similar pharmacokinetics, the mean estimated dose for a specific trough level varied from 60% less to 20% more using the population-based approach. The time to 1% and the corresponding dose was sensitive to the baseline assumption. Our data support the use of population-based PK for patients on simoctocog alfa prophylaxis but also indicates differences, stressing the importance of the sampling scheme and monitoring actual FVIII levels achieved.

Similar pharmacokinetics and pharmacodynamics of a new biosimilar and reference insulin aspart in healthy Chinese males

Insulin aspart (IAsp) is one of the main therapies used to control blood glucose after a meal. This study aimed to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 2 rapid-acting IAsp products: a new IAsp biosimilar (RD10046) and NovoRapid. In a single-center, randomized, single-dose, 2-period, crossover, euglycemic clamp study (registry number: CTR20180517, registration date: 2018-05-30), healthy Chinese males were randomized to receive 0.2 U/kg of the IAsp biosimilar RD10046 and NovoRapid under fasted conditions on two separate occasions. PK and PD were assessed for up to 10 h. Of the 30 randomized subjects, all 30 completed both treatment periods. The PK (area under the curve [AUC] of total IAsp; maximum observed IAsp concentration [Cmax]) and PD (maximum glucose infusion rate [GIRmax]; total glucose infusion during the clamp [AUCGIR,0–10h]) were similar between the new IAsp biosimilar RD10046 and NovoRapid. In all cases, the 90% CIs for the ratios of the geometric means were completely contained in the prespecified acceptance limits of 0.80–1.25. No hypoglycemic events, allergic reactions, or local injection adverse reactions occurred in this trial. We concluded that the studied IAsp biosimilar (RD10046) was bioequivalent to NovoRapid.

Nonclinical Pharmacokinetics and Absorption, Distribution, Metabolism, and Excretion of Givosiran, the First Approved N-Acetylgalactosamine-Conjugated RNA Interference Therapeutic.

Givosiran is an N-acetylgalactosamine-conjugated RNA interference therapeutic that targets 5'-aminolevulinate synthase 1 mRNA in the liver and is currently marketed for the treatment of acute hepatic porphyria. Herein, nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion properties of givosiran were characterized. Givosiran was completely absorbed after subcutaneous administration with relatively short plasma elimination half-life (t1/2; less than 4 hours). Plasma exposure increased approximately dose proportionally with no accumulation after repeat doses. Plasma protein binding was concentration dependent across all species tested and was around 90% at clinically relevant concentration in human. Givosiran predominantly distributed to the liver by asialoglycoprotein receptor-mediated uptake, and the t1/2 in the liver was significantly longer (∼1 week). Givosiran was metabolized by nucleases, not cytochrome P450 (P450) isozymes, across species with no human unique metabolites. Givosiran metabolized to form one primary active metabolite with the loss of one nucleotide from the 3' end of antisense strand, AS(N-1)3' givosiran, which was equipotent to givosiran. Renal and fecal excretion were minor routes of elimination of givosiran as approximately 10% and 16% of the dose was recovered intact in excreta of rats and monkeys, respectively. Givosiran is not a substrate, inhibitor, or inducer of P450 isozymes, and it is not a substrate or inhibitor of uptake and most efflux transporters. Thus, givosiran has a low potential of mediating drug-drug interactions involving P450 isozymes and drug transporters. SIGNIFICANCE STATEMENT: Nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion (ADME) properties of givosiran were characterized. Givosiran shows similar pharmacokinetics and ADME properties across rats and monkeys in vivo and across human and animal matrices in vitro. Subcutaneous administration results in adequate exposure of givosiran to the target organ (liver). These studies support the interpretation of toxicology studies, help characterize the disposition of givosiran in humans, and support the clinical use of givosiran for the treatment of acute hepatic porphyria.

Application of a Physiologically Based Pharmacokinetic Model to Develop a Veterinary Amorphous Enrofloxacin Solid Dispersion.

Zoonotic intestinal pathogens threaten human health and cause huge economic losses in farming. Enrofloxacin (ENR) shows high antibacterial activity against common intestinal bacteria. However, its poor palatability and low aqueous solubility limit the clinical application of ENR. To obtain an ENR oral preparation with good palatability and high solubility, a granule containing an amorphous ENR solid dispersion (ENR-SD) was prepared. Meanwhile, a PBPK model of ENR in pigs was built based on the physiological parameters of pigs and the chemical-specific parameters of ENR to simulate the pharmacokinetics (PK) of ENR-SD granules in the intestinal contents. According to the results of parameter sensitivity analysis (PSA) and the predicted PK parameters at different doses of the model, formulation strategies and potential dose regimens against common intestinal infections were provided. The DSC and XRD results showed that no specific interactions existed between the excipients and ENR during the compatibility tests, and ENR presented as an amorphous form in ENR-SD. Based on the similar PK performance of ENR-SD granules and the commercial ENR soluble powder suggesting continued enhancement of the solubility of ENR, a higher drug concentration in intestinal contents could not be obtained. Therefore, a 1:5 ratio of ENR and stearic acid possessing a saturated aqueous solubility of 1190 ± 7.71 µg/mL was selected. The predictive AUC24h/MIC90 ratios against Campylobacter jejuni, Salmonella, and Escherichia coli were 133, 266 and 8520 (>100), respectively, suggesting that satisfactory efficacy against common intestinal infections would be achieved at a dose of 10 mg/kg b.w. once daily. The PSA results indicated that the intestinal absorption rate constant (Ka) was negatively correlated with the Cmax of ENR in the intestine, suggesting that we could obtain higher intestinal Cmax using P-gp inducers to reduce Ka, thus obtaining a higher Cmax. Our studies suggested that the PBPK model is an excellent tool for formulation and dose design.

Pharmacokinetics of oral firocoxib in un-weaned calves.

The objective of this study was to determine the pharmacokinetics of firocoxib after oral administration in un-weaned calves. Eight Holstein calves with a mean age of 36days and a mean weight of 55kg were administered a single oral dose of 227mg firocoxib. The resulting mean dosage was 4.2mg/kg (range 3.5-5.0mg/kg). Blood was collected prior to drug administration and at 2, 4, 6, 8, 24, 48, 72, and 96h after treatment. Firocoxib concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Using computer software, pharmacokinetic parameters were found to fit best with a one-compartment model. Mean Cmax was 0.9μg/ml (range 0.570-1.254), and Tmax was estimated to be 7h (range 4-8h). The estimated T1/2 was 15.3h. The pharmacokinetics of firocoxib after oral dosing are similar to those in dogs, with the exception of a T1/2 that is approximately twice as long. Based on the similar pharmacokinetics, it is possible that a dose of 227mg firocoxib orally could provide an analgesic effect in un-weaned calves.

Randomised study of PF-06410293, an adalimumab (ADL) biosimilar, compared with reference ADL for the treatment of active rheumatoid arthritis: results from weeks 26–52, including a treatment switch from reference ADL to PF-06410293

ObjectiveTo investigate the efficacy, safety, immunogenicity and pharmacokinetics of biosimilar adalimumab (ADL) PF-06410293 (ADL-PF; adalimumab-afzb) versus EU-sourced reference ADL (ADL-EU) in patients with active rheumatoid arthritis (RA) on longer-term treatment...

Analytical comparability assessment on glycosylation of ziv-aflibercept and the biosimilar candidate

Ziv-aflibercept (aflibercept) is a recombinant fusion protein which combines the portions of human vascular endothelial growth factor receptors extracellular domains fused to the Fc portion of human IgG1. It is a highly sialylated glycoprotein with 5 N-glycosylation sites. In this study, a comprehensive strategy for comparability study of the complex glycosylation was developed between aflibercept and the biosimilar candidate including the investigations on N-glycosylation sites, site occupancy, site-specific glycoforms, released glycans and sialic acids. The results indicated that same N-glycosylation sites were identified, site occupancy were 100% except N68 site, site-specific glycoforms and released glycans showed similar glycan species, contents of NANA were at a same level for two products. Minor differences were found between two products. The biosimilar candidate presented lower level of aglycosylation, lower level of glycans containing one terminal sialic acid, higher level of glycans containing two terminal sialic acids, higher level of G0F and Man5, lower level of G1F and G2F compared with aflibercept. However, further studies exhibited no differences were observed in the cell-based biological potency and Fc effector function. Moreover, the biosimilar candidate showed a similar pharmacokinetics curve and bioequivalence compared with aflibercept.

Abstract PD1-02: A phase I/Ib study evaluating GDC-0077 + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)

Abstract Background GDC-0077 is a PI3Kα-selective inhibitor and mutant PI3Kα degrader that demonstrates antitumor activity in PIK3CAmut BC xenograft models. A phase I/Ib study of GDC-0077 alone and combined with endocrine therapy ± the CDK4/6 inhibitor (i) palbo is ongoing (NCT03006172). Data from GDC-0077 + palbo + fulvestrant in pts with PIK3CAmut, HR+/HER2- mBC are presented herein. Methods Safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary antitumor activity (clinical benefit rate [CBR]: RECIST v1.1 stable disease for ≥ 24 weeks, partial response [PR], or complete response) of 9 mg oral once daily GDC-0077 + 125 mg palbo 21/28 days + 500 mg intramuscular fulvestrant on day 1 (and day 15 of cycle 1) of 28-day cycles were assessed in Arms E and F, until intolerable toxicity or disease progression. In Arm F, pts were obese and/or pre-diabetic (body mass index ≥ 30 kg/m2 and/or HbA1c ≥ 5.7%) and also received metformin up to 2000 mg daily starting at 500 mg in cycle 1 day 1, prior to initiating GDC-0077 at cycle 1 day 15 instead of day 1 as in Arm E. Additional key eligibility criteria included Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, no prior PI3Ki therapy, no prior CDK4/6i, and ≤ 1 prior chemotherapy for Arm E (no restrictions on prior CDK4/6i or chemotherapy for Arm F). PIK3CAmut allele frequency was assessed in circulating tumor (ct) DNA from serial plasma collections. Results At clinical cutoff (03/20/2020), 28 pts were enrolled (13 in Arm E and 15 in Arm F). Median age was 55 years in Arm E and 65 years in Arm F. ECOG PS was 0 in 8 pts (62%) in Arm E and in 7 pts (47%) in Arm F. Three (23%) and 12 (80%) pts in Arm E and F, respectively, had received ≥ 2 prior lines of therapy for mBC. One pt (8%) in Arm E and 10 pts (67%) in Arm F received prior fulvestrant. Nine pts (60%) received prior CDK4/6i (all Arm F). Median GDC-0077 treatment duration was 7.8 months (range 0.1-13.9) in Arm E and 6.5 months (1.2-11.2) in Arm F. GDC-0077 cumulative dose intensity was 98% in Arm E and 88% in Arm F. Thirteen pts (46%) discontinued treatment: 11, due to radiographic disease progression (3 in Arm E, 8 in Arm F); 1, due to an adverse event (AE; treatment-related grade 2 panniculitis in Arm F); and 1 pt withdrew (Arm F). The most common treatment-related AEs (≥ 4 pts) were stomatitis (grouped term; 92%), neutropenia (85%), diarrhea and hyperglycemia (62% each), fatigue (38%), alopecia, nausea, and thrombocytopenia (31% each) in Arm E; and hyperglycemia (67%), diarrhea and neutropenia (53% each), nausea (47%), stomatitis (grouped term; 47%), anemia, decreased appetite, and blurred vision (27% each) in Arm F. Grade ≥ 3 treatment-related AEs (≥ 2 pts) were neutropenia (62%) and hyperglycemia (23%) in Arm E; and hyperglycemia and neutropenia (47% each), and anemia (13%) in Arm F. AEs led to GDC-0077 dose reduction in 2 pts (15%) in Arm E and 4 pts (27%) in Arm F. The PK of GDC-0077 in combination with palbo + fulvestrant was similar to single agent GDC-0077. Overall, 7/25 pts (28%) with measurable disease had a PR (5/10 [50%] pts in Arm E; 2/15 [13%] pts in Arm F, both received prior fulvestrant), of whom 6 pts (24%; 4 in Arm E; 2 in Arm F) had a confirmed PR. CBR was 61% (17/28 pts: 8 in Arm E; 9 in Arm F). PIK3CAmut allele frequency by ctDNA analysis decreased during treatment in most pts. Conclusion This study demonstrated a manageable safety profile when combining GDC-0077 at its single agent recommended phase II dose of 9 mg with palbo + fulvestrant at standard doses, similar PK to GDC-0077 alone, preliminary anti-tumor activity, and modulation of PIK3CAmut allele frequency in ctDNA. In obese and/or pre-diabetic patients enrolled to Arm F, hyperglycemia was frequent despite initiating metformin prior to GDC-0077. A phase III study of GDC-0077 + palbo + fulvestrant is enrolling currently (NCT04191499). Citation Format: Philippe L Bedard, Komal Jhaveri, Andrés Cervantes, Valentina Gambardella, Erika Hamilton, Antoine Italiano, Kevin Kalinsky, Ian E Krop, Mafalda Oliveira, Cristina Saura, Peter Schmid, Nicolas Turner, Andrea Varga, Katherine E Hutchinson, Guiyuan Lei, Stephanie Royer-Joo, Piia Thomas, Jennifer L Schutzman, Dejan Juric. A phase I/Ib study evaluating GDC-0077 + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-02.

A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects

Purpose QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects. Design A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug. Results QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0–t andAUC0–∞ in both groups were within the range of 80–125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts. Conclusion The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects. Trial Registration The trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002) Key points This was the first clinical report of a new proposed tocilizumab biosimilar, QX003S. This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@). The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.

Pharmacokinetic comparison between a fixed-dose combination of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg and a corresponding loose combination of fimasartan/amlodipine 60/25 mg and hydrochlorothiazide 25 mg in healthy subjects.

For the treatment of hypertension, fixed-dose combinations (FDCs) of antihypertensive drugs can provide complementary benefits from improved compliance and cost-effectiveness compared with loose combinations of corresponding drugs. A new FDC of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg is undergoing clinical development. A randomized, open-label, single-dose, 3-period, 3-sequence, partially replicated crossover phase 1 study was conducted to compare the pharmacokinetics (PKs) between the FDC of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg and a loose combination of a dual-combination FDC (fimasartan/amlodipine 60/10 mg) and hydrochlorothiazide 25 mg. Sixty healthy subjects were randomized, and 55 subjects completed the study. Serial blood samples were collected, and plasma concentrations of fimasartan, amlodipine and hydrochlorothiazide were measured to analyze PK parameters. The PK profiles of the FDC were similar to those of the loose combinations. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to loose combinations for the maximum plasma concentration (Cmax) and area under the curve until the last measurable time point (AUClast) were within the conventional bioequivalent range of 0.80 to 1.25. The GMRs and 90% CIs of fimasartan, amlodipine and hydrochlorothiazide were 1.0163 (0.8681–1.1898), 0.9595 (0.9256–0.9946), and 1.1294 (1.0791–1.1821) for Cmax and 1.0167 (0.9347–1.1059), 0.9575 (0.9317–0.9841), and 1.0561 (1.0170–1.0967) for AUClast, respectively. Both the FDC and loose combinations were well tolerated. In conclusion, the FDC of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg showed similar PK profiles to those of the corresponding loose combination, and both treatments were well tolerated.

1276. Evaluation of CD377, a Novel Antiviral Fc-Conjugate (AVC), In Vitro Activity and In Vivo Efficacy in Immune-Competent and -Deficient (SCID) Lethal Mouse Models

BackgroundCidara’s AVCs are novel, potent, antiviral agents conjugated with the Fc domain of human IgG1. CD377 is an AVC development candidate being evaluated for prevention and treatment of seasonal and pandemic influenza, including in immune-deficient populations unable to benefit from vaccination. We evaluated CD377 in vitro and in SCID mice to determine the impact of compromised immune status on efficacy.MethodsCD377 and comparators (oseltamivir [OS], zanamivir [ZA], baloxavir marboxil [BM]) were evaluated in vitro by neuraminidase inhibition (NAI), and cytopathic effect (CPE) assays. The pharmacokinetics (PK) and efficacy of CD377 were determined in immune-competent (IC; BALB/c) and immune-deficient (ID; BALB/c SCID) mice. Efficacy was assessed by intranasal challenge at 3x the LD95 of influenza A/Puerto Rico/8/1934 (H1N1), followed by a single subcutaneous (SC) dose of CD377, 2 hours post-challenge. The SCID study also evaluated the efficacy of BM at 3 mg/kg (BID x 1 day). Body weights (BW) were monitored for 21 days, with 20% BW loss recorded as mortality.ResultsIn vitro evaluation by NAI showed CD377, OS, and ZA to be approximately equipotent, with IC50 values between 0.5 and 1.7 nM. However, by CPE, CD377 was ~4.5-fold more active than BM and >1,000-fold more active than OS and ZA.In vivo, the PK of CD377 was found to be comparable in IC and ID mice. In subsequent efficacy studies, CD377 was protective at 0.1 mg/kg in IC mice (P=0.0020 vs. vehicle), while control groups fully succumbed to infection by Day 7 (Fig. 1A).In a similar study with ID mice, CD377 dosed at 0.1 mg/kg was also fully protective (P=0.0020). In contrast, mice treated with 6 mg/kg (total dose) of BM were only partially protected until day 13 (40% mortality by study end) (Fig. 1B). The potency of CD377 was further supported by BW data, which mirrored the survival data in both studies.ConclusionCD377 exhibited potent in vitro activity and had similar PK in IC and ID mice. In efficacy studies, CD377 demonstrated robust potency in both IC and ID mouse models at equivalent doses (0.1 mg/kg, SC, single dose). These results support further development of CD377 as a novel antiviral for the prevention and treatment of influenza infection, including in people with immune deficiencies and higher risk of infection.Balb/c and Balb/c SCID DisclosuresJames Levin, PhD, Cidara Therapeutics (Shareholder) Karin Amundson, B.S., Cidara Therapeutics (Shareholder) Allen Borchardt, PhD, Cidara Therapeutics (Employee) Thanh Lam, PhD, Cidara Therapeutics (Shareholder) Tom Brady, PhD, Cidara Therapeutics (Shareholder) Elizabeth Abelovski, B.S., Cidara Therapeutics (Shareholder) Simon Döhrmann, PhD, Cidara Therapeutics (Shareholder) Jason Cole, PhD, Cidara Therapeutics (Shareholder) Voon Ong, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Les Tari, PhD, Cidara Therapeutics (Shareholder)

The Impact of Polymer Size and Cleavability on the Intravenous Pharmacokinetics of PEG-Based Hyperbranched Polymers in Rats.

A better understanding of the impact of molecular size and linkers is important for PEG-based hyperbranched polymers (HBPs) intended as tailored drug delivery vehicles. This study aimed to evaluate the effects of crosslinker chemistry (cleavable disulphide versus non-cleavable ethylene glycol methacrylate (EGDMA) linkers) and molecular weight within the expected size range for efficient renal elimination (22 vs. 48 kDa) on the intravenous pharmacokinetic and biodistribution properties of 89Zr-labelled HBPs in rats. All HBPs showed similar plasma pharmacokinetics over 72 h, despite differences in linker chemistry and size. A larger proportion of HBP with the cleavable linker was eliminated via the urine and faeces compared to a similar-sized HBP with the non-cleavable linker, while size had no impact on the proportion of the dose excreted. The higher molecular weight HBPs accumulated in organs of the mononuclear phagocyte system (liver and spleen) more avidly than the smaller HBP. These results suggest that HBPs within the 22 to 48 kDa size range show no differences in plasma pharmacokinetics, but distinct patterns of organ biodistribution and elimination are evident.

Alternating stealth polymer coatings between administrations minimizes toxic and antibody immune responses towards nanomedicine treatment regimens

In efforts to achieve minimal systemic toxicity and high tumor delivery efficiencies in cancer therapy, various nanomedicine formulations having stealth polymer coatings have been developed for minimizing immune cell uptake and off-target macrophage phagocyte system (MPS) organ accumulation. Despite an initial reduction in immune cell uptake, stealth nanoparticles still initiate an antibody immune response. This response acts on subsequent administrations in treatment regimens resulting in accelerated blood clearance of particles into MPS organs, particularly the liver, where they are retained for prolonged periods. Consequently, doses after the first administration in treatment regimens have diminished tumor accumulation and increased MPS toxicity. Here, we present a strategy reducing antibody responses to each dose in a treatment regimen by alternating between polyethylene-glycol and polymethyloxazoline polymers as the nanoparticle coating between administrations. In a weekly dosing regimen, we find that the first dose of particles having either coating display similar favorable pharmacokinetics and biodistributions, thus allowing the polymers to be used interchangeably. However, when maintaining the same coating in subsequent administrations, we find that particles are in circulation at the height of the antibody immune response resulting in 50–60% decreases of circulation half-lives and tumor accumulation along with 50% increases in liver accumulation. By alternating the polymers used in the nanoparticle coating between administrations, we find each dose maintains favorable in vivo behaviors at the height of the antibody immune response to the previous administration. Furthermore, our strategy increases the clearance of particles uptaken by macrophages and hepatocytes, resulting in marked decreases in hepatotoxicity.

Evaluation of biosimilarity of RinGlar® (GEROPHARM LLC, Russia) and Lantus® (Sanofi-Aventis Deutschland GmbH, Germany) using the euglycemic hyperinsulinemic clamp technique in patients with type 1 diabetes: double-blind randomized clinical trial

Background: Prevention of the development of micro-and macrovascular complications in patients with diabetes melli-tus (DM) encouraged the search for insulin analogues that allow imitating, as close as possible, a normal physiological insulin secretion in healthy people. Biosimilars (bioanalogues of reference products) play an important role in the full provision with high-quality insulin medications throughout patients. The program of clinical trials of insulin bioanalogues includes pharmacology studies: pharmacokinetics (PK), pharmacodynamics (PD) and clinical safety research.Aims: To test whether RinGlar® (GEROPHARM LLC, Russia) and Lantus® (Sanofi-Aventis Deutschland GmbH, Germany) have similar PK and PD profiles in a hyperinsulinemic euglycaemic clamp (HEC) setting in patients with type 1 diabetes mellitus. Permission of the Ministry of Health of the Russian Federation No. 150 of 03/03/2016.Materials and methods: The study was conducted in 42 patients with type 1 diabetes aged 18 to 65 years. A doubleblind, randomized, crossover study of comparative PK and PD of drugs was chosen as a study design. The investigational products were injected after achieving a state of euglycemia before the HEC in a single dose of 0.6 U/kg subcutaneously into the subcutaneous fat of the anterior abdominal wall. During the study, regular blood sampling was performed, the amount of insulin glargine in the samples was determined by ELISA. The results are used to calculate the PK parameters and generate the concentration-time curves. The glucose infusion rate was corrected based on the measurement of glycemia. These data are used to calculate the PD parameters.Results: RinGlar® and Lantus® interventions have comparable PK and PD profiles in HEC setting in patients with type 1 diabetes. This is confirmed by the similarity of the main PK/PD parameters, PK/PD curves, and comparable safety. The confidence intervals of the geometric mean ratio were 81.02% - 120.62% for the PK parameter AUCins0-T, and 85.43% - 115.64% for the PD-parameter AUCGIR0_T, which fall within the specified limits of 80% - 125% to establish comparability between drugs.Conclusions: Results of the clinical trial demonstrate the biosimilarity of the products RinGlar® and Lantus®.

Оценка биоподобия препаратов РинГлар® (ООО «Герофарм», Россия) и Лантус® («Санофи-Авентис Дойчланд ГмбХ», Германия) с использованием метода эугликемического гиперинсулинемического клэмпа у пациентов с сахарным диабетом 1 типа: двойное слепое рандомизированное клиническое исследование

Background: Prevention of the development of micro-and macrovascular complications in patients with diabetes melli-tus (DM) encouraged the search for insulin analogues that allow imitating, as close as possible, a normal physiological insulin secretion in healthy people. Biosimilars (bioanalogues of reference products) play an important role in the full provision with high-quality insulin medications throughout patients. The program of clinical trials of insulin bioanalogues includes pharmacology studies: pharmacokinetics (PK), pharmacodynamics (PD) and clinical safety research. Aims: To test whether RinGlar® (GEROPHARM LLC, Russia) and Lantus® (Sanofi-Aventis Deutschland GmbH, Germany) have similar PK and PD profiles in a hyperinsulinemic euglycaemic clamp (HEC) setting in patients with type 1 diabetes mellitus. Permission of the Ministry of Health of the Russian Federation No. 150 of 03/03/2016. Materials and methods : The study was conducted in 42 patients with type 1 diabetes aged 18 to 65 years. A doubleblind, randomized, crossover study of comparative PK and PD of drugs was chosen as a study design. The investigational products were injected after achieving a state of euglycemia before the HEC in a single dose of 0.6 U/kg subcutaneously into the subcutaneous fat of the anterior abdominal wall. During the study, regular blood sampling was performed, the amount of insulin glargine in the samples was determined by ELISA. The results are used to calculate the PK parameters and generate the concentration-time curves. The glucose infusion rate was corrected based on the measurement of glycemia. These data are used to calculate the PD parameters. Results: RinGlar® and Lantus® interventions have comparable PK and PD profiles in HEC setting in patients with type 1 diabetes. This is confirmed by the similarity of the main PK/PD parameters, PK/PD curves, and comparable safety. The confidence intervals of the geometric mean ratio were 81.02% - 120.62% for the PK parameter AUC ins0-T , and 85.43% - 115.64% for the PD-parameter AUC GIR0_T , which fall within the specified limits of 80% - 125% to establish comparability between drugs. Conclusions: Results of the clinical trial demonstrate the biosimilarity of the products RinGlar® and Lantus®.

Structural characterization and pharmacological assessment in vitro/in vivo of a new copper(II)-based derivative of enrofloxacin.

Enrofloxacin (EFX) was selected as the medicinal ligand to afford a new copper(ii)-based complex, EFX-Cu, which was structurally characterized by spectroscopic analyses including X-ray single crystal diffraction. It was also stable and could retain the coordination state in aqueous solution. The in vitro antibacterial activity of EFX-Cu against a panel of pathogenic bacteria was about the same as that of EFX, except that it was twice as active against E. coli. The in vivo test on mice gave a LD50 value of 8148 mg kg-1 for EFX-Cu, which was much lower than those for EFX (LD50, 5312 mg kg-1) and its clinically used sodium salt, EFX-Na (LD50, 1421 mg kg-1). In addition, no obvious lesions in the organs of the dead mice were found by histopathological examination. Pharmacokinetic studies on rats suggested similar pharmacokinetics between EFX-Cu and EFX. On the other hand, EFX-Cu showed higher acute toxicity than EFX-Na in zebrafish, which was inconsistent with that in mice. The ROS-related inflammation and anti-inflammatory assay of EFX-Cu, respectively, in normal cells and zebrafish could be ascribed to its ROS-related redox property. Unfortunately, the final in vivo therapeutic assay in the E. coli-infected mouse model indicated that the therapeutic effect of EFX-Cu, mainly in terms of mortality in mice, was found to be lower than that of EFX-Na at the same dosage (800 mg kg-1, continuous gavage), although the contradictory factors between toxicity and antibacterial activity could not be excluded in this trial.

A Phase I, Randomized, Double-Blind, Single-Dose, Parallel-Group Study to compare Pharmacokinetic Similarity, Safety, and Immunogenicity Between BAT2506 and Golimumab in Healthy Chinese Male Subjects

ABSTRACT Background: To compare the pharmacokinetic (PK) profile, safety, and immunogenicity between golimumab and the biosimilar BAT2506 in healthy Chinese male subjects. Research design and methods: A total of 180 healthy male subjects were recruited for this randomized, double-blinded, single-dose, parallel study. They received 50 mg BAT2506 or golimumab (1:1 ratio) by single subcutaneous injection. The evaluation index included maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC0-t, AUC0-∞), safety, and immunogenicity. Results: The results showed that the 90% confidence interval (CI) of the geometric mean ratio (GMR) of BAT2506 to reference drug (golimumab) for Cmax, AUC0–∞ and AUC0-t were 99.26% (90.59–108.76%), 102.06% (93.31%–111.64%), and 102.05% (93.51–111.38%), respectively. All 90% CIs were within the range of 80–125% range, which is the limitation of the equivalence margin. Furthermore, similarity of treatment-emergent adverse events was also found between the two drugs. A total of 14 subjects (7.8%) developed anti-drug antibody after administration. Conclusions: Our study confirmed the PK similarity between BAT2506 and golimumab, and showed good tolerance of BAT2506 in healthy subjects. There were no differences in safety and immunogenicity between the two drugs. Therefore, BAT2506 meets the criteria for biosimilarity to golimumab. Trial registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04152759).