Similar Pharmacokinetics Research Articles

MINIMAL IMPACT OF FOOD, DRINK, OR TEMPERATURE ON THE PHARMACOKINETICS OF A SUBLINGUAL FILM USING AA NOVEL PRODRUG OF EPINEPHRINE (DESF)

<h3>Introduction</h3> DESF is a novel alternative dosage form to Epinephrine injection. A pre-clinical study was conducted to test the effect of sublingual temperature (SL) and if exposure of the sublingual mucosa to food or drink prior to administration of DESF has an impact on the PK profile of epinephrine <i>in vivo</i>. <h3>Methods</h3> A total of 18 male Yucatan miniature swine, separated into three groups and dosed with DESF 12 mg, were used for this study. Group 1 did not receive a pre-treatment. Groups 2 and 3 were pretreated with either full-fat whole milk or extra virgin olive oil or with either warm or cool compresses at the dose site. Following dosage, the animals had Pharmacokinetics (PK) blood samples obtained at multiple timepoints, with Oral Mucositis Assessment Scale scores performed at pre-dose, 4-, and 24-hours post-dose. <h3>Results</h3> Similar PK profiles were observed for epinephrine regardless of pretreatment of food and drink. Groups pretreated with milk or oil displayed a mean Cmax and AUC similar to or higher than the control group. Tmax was similar for all treatment groups, between 25 to 30 minutes. As for the impact of temperature, pre-treatment with a warm or cool compress did not result in significantly different SL temperatures. Similar PK profiles were also observed for epinephrine regardless of pre-treatment. Simple linear regression analysis suggests that there was not a strong relationship between SL temperature and Cmax. <h3>Conclusion</h3> These results suggest that food, drink, and temperature each have minimal impact on the PK profiles of DESF.

Joint analysis of PK and immunogenicity outcomes using factorization model − a powerful approach for PK similarity study

Biological products, whether they are innovator products or biosimilars, can incite an immunogenic response ensuing in the development of anti-drug antibodies (ADA). The presence of ADA’s often affects the drug clearance, resulting in an increase in the variability of pharmacokinetic (PK) analysis and challenges in the design and analysis of PK similarity studies. Immunogenic response is a complex process which may be manifested by product and non-product-related factors. Potential imbalances in non-product-related factors between treatment groups may lead to differences in antibodies formation and thus in PK outcome. The current standard statistical approaches dismiss any associations between immunogenicity and PK outcomes. However, we consider PK and immunogenicity as the two correlated outcomes of the study treatment. In this research, we propose a factorization model for the simultaneous analysis of PK parameters (normal variable after taking log-transformation) and immunogenic response subgroup (binary variable). The central principle of the factorization model is to describe the likelihood function as the product of the marginal distribution of one outcome and the conditional distribution of the second outcome given the previous one. Factorization model captures the additional information contained in the correlation between the outcomes, it is more efficient than models that ignore potential dependencies between the outcomes. In our context, factorization model accounts for variability in PK data by considering the influence of immunogenicity. Based on our simulation studies, the factorization model provides more accurate and efficient estimates of the treatment effect in the PK data by taking into account the impact of immunogenicity. These findings are supported by two PK similarity clinical studies with a highly immunogenic biologic.

Single-Dose Bioequivalence Study of Rivaroxaban-Containing Medicinal Products in Healthy Volunteers

Therapeutically, new oral anticoagulants (NOACs) are considered to be non-inferior or superior to vitamin K antagonists (warfarin). NOACs are included in current guidelines for the treatment of various cardiovascular diseases. Rivaroxaban medicinal products have been shown to effectively fight thrombotic complications of the new coronavirus infection, COVID-19. The wide clinical use of rivaroxaban products motivates the development of generics.The aim of the study was to compare the pharmacokinetics and safety of rivaroxaban medicinal products in a single-dose bioequivalence study in healthy volunteers under fasting conditions.Materials and methods: the bioequivalence study compared single-dose oral administration of Rivaroxaban, 10 mg film-coated tablets (NovaMedica Innotech LLC, Russia), and the reference product Xarelto®, 10 mg filmcoated tablets (Bayer AG, Germany), in healthy volunteers under fasting conditions. The open, randomised, crossover trial included 46 healthy volunteers. Each of the medicinal products (the test product and the reference product) was administered once; blood samples were collected during the 48 h after the administration. The washout between the study periods lasted 7 days. Rivaroxaban was quantified in plasma samples of the volunteers by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS).Results: no adverse events or serious adverse events were reported for the test and reference products during the study. The following pharmacokinetic parameters were obtained for Rivaroxaban and Xarelto®, respectively: Cmax of 134.6 ± 58.0 ng/mL and 139.9 ± 49.3 ng/mL, AUC0–48 of 949.7 ± 354.5 ng×h/mL and 967.6 ± 319.9 ng×h/mL, AUC 0–∞ of 986.9 ± 379.7 ng×h/mL and 1003.6 ± 320.4 ng×h/mL, T1/2 of 8.2 ± 3.2 h and 7.8 ± 3.3 h. The 90% confidence intervals for the ratios of Cmax, AUC0–48, and AUC0–∞ geometric means were 88.04–108.67%, 89.42–104.92% and 89.44–104.81%, respectively.Conclusions: the test product Rivaroxaban and the reference product Xarelto® were found to have similar rivaroxaban pharmacokinetics and safety profiles. The study demonstrated bioequivalence of the medicinal products.

224 (PB104) - Preliminary results from HERKULES-1: a phase 1b/2, open-label, multicenter study of ERAS-007, an oral ERK1/2 inhibitor, in patients with advanced or metastatic solid tumors

Background: The RAS/MAPK pathway is dysregulated in a broad range of cancers, resulting in downstream activation of ERK1/2. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK with a prolonged target residence time (550 min). The first-in-human Phase 1 study of ERAS-007 identified the 250 mg once weekly (QW) schedule for further evaluation based on a manageable toxicity profile and encouraging signs of clinical activity (NCT03415126). Pharmacokinetic (PK) modeling suggests that an alternative intermittent regimen (twice a day, once a week; BID-QW) is expected to have lower peak concentrations (Cmax) and similar overall PK exposures (area under the curve, AUC) compared to QW, which may improve Cmax-driven adverse events (AE) while maintaining comparable efficacy.

A novel transdermal ketoprofen formulation for analgesia in cattle.

Ketoprofen is registered in many countries for injectable administration in cattle. Because it is soluble in a wide range of excipients, development of a novel transdermal (TD) ketoprofen formulation was pursued to provide a convenient and pain-free route of administration in cattle. One hundred and six excipient combinations were screened using in vitro techniques (Franz diffusion cells), with a 20%(w/v) ketoprofen formulation dissolved in a combination of 45%:45%(v/v) ethanol and isopropyl myristate (IPM) and 10%(v/v) eucalyptus oil achieving maximal penetration of ketoprofen through bovine skin. A bioavailability study was then conducted using a randomized cross-over design (n=12), including IV, IM (both 3mg/kg) and TD (10mg/kg) ketoprofen formulations administered with a one-week washout period between administrations. The IV and IM formulation pharmacokinetic results were as expected. The CMAX , Tmax and AUC0-Last were significantly higher (arithmetic mean ± SD) after TD administration (20.0 ± 6.5μg/ml, 115 ± 17 min and 3940 ± 1324 μg*min/ml, respectively), compared to IM (11.0 ± 4.0μg/ml, 74 ± 43 min and 2376 ± 738 μg*min/ml, respectively), although there were no significant differences for T½β . However, dose corrected values CMAX and AUCinf were significantly higher for IM compared to TD. The arithmetic mean bioavailability (F) of the transdermal formulation was 50%. The plasma concentration of the TD formulation at a dose of 10mg/kg was similar to the IM formulation at 3mg/kg by 30 min post-dosing with an arithmetic mean ± SD of 7.97 ± 4.38 vs. 8.02 ± 3.55 μg/ml, respectively. The TD formulation was generally well tolerated by cattle, although some local irritation along the site of application was noted after 12 h of exposure during the bioavailability study. Results indicate that this novel TD formulation provides a substantial improvement in administration convenience, may improve animal welfare and end-user safety through needle-free administration, and achieves similar plasma pharmacokinetics to the IM product when administered at 10mg/kg.

GP2017-HCF, a high concentration formulation, demonstrates similar pharmacokinetics, immunogenicity and safety to GP2017, an approved adalimumab biosimilar

ABSTRACT Background GP2017 is an adalimumab biosimilar. The objective of this study is to compare the pharmacokinetics (PK) of GP2017 in its approved formulation and GP2017-high concentration formulation (HCF) in a randomized, double-blind, two-arm PK bridging study. Research design and methods Healthy male subjects received a single 40 mg subcutaneous injection of either GP2017-HCF (n = 162) or GP2017 (n = 168). PK, safety, and immunogenicity were assessed over 72 days post-injection. Results The 90% confidence intervals [CIs] of geometric mean ratios between GP2017-HCF and GP2017 for Cmax, AUC0-inf, AUC0-360 and AUC0-last were within the pre-defined margin of 0.80 to 1.25; thus, PK comparability between GP2017-HCF and GP2017 was demonstrated. Subgroup analysis of PK comparability by anti-drug antibody (ADA) subpopulation showed that the 90% CIs of geometric mean ratios between GP2017-HCF and GP2017 for Cmax, AUC0-inf, AUC0-360 and AUC0-last were within the margin of 0.80 to 1.25 in ADA-positive and ADA-negative subjects. The proportions of subjects with positive ADA responses and with neutralizing antibodies were comparable between the GP2017-HCF and GP2017 groups. GP2017-HCF and GP2017 were well tolerated, and there were no reports of deaths or other serious adverse events. Conclusion Results show PK comparability between GP2017-HCF and GP2017 and comparable safety and tolerability.

Harmine and 7,8-dihydroxyflavone synergistically suitable for amyotrophic lateral sclerosis management: An in silico study

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by progressive degeneration of both upper and lower motor neurons, resulting in paralysis and eventually leads to death from respiratory failure typically within 3 to 5 years of symptom onset. The aim of this work was to predict the pharmacokinetics and identify unique protein targets that are associated with potential anti-ALS phytochemicals and FDA-approved drugs, by in silico approaches.&#x0D; Materials and methods: Standard computational tools (webserver and software) were used, and the methods used are clustering analysis, pharmacokinetics and molecular target predictions, and molecular docking simulation.&#x0D; Results and discussion: The results show that riluzole, β-asarone, cryptotanshinone, harmine and 7,8-dihydroxyflavone have similar pharmacokinetics properties. Riluzole and harmine show 95% probability of target on norepinephrine transporter. Huperzine-A and cryptotanshinone show 100% probability of target on acetylcholinesterase. 7,8-dihydroxyflavone shows 35% probability of target on several carbonic anhydrases, 40% probability of target on CYP19A1, and 100% probability of target on inhibitor of nuclear factor kappa B kinase beta subunit and neurotrophic tyrosine kinase receptor type 2, respectively. Harmine also shows 95% probability of target on dual specificity tyrosine-phosphorylation-regulated kinases, threonine-protein kinases (haspin and PIM3), adrenergic receptors, cyclin-dependent kinases (CDK5 and CDK9), monoamine oxidase A, casein kinase I delta, serotonin receptors, dual specificity protein kinases (CLK1, CLK2, and CLK4), and nischarin, respectively. Also, the results of gene expression network show possible involvement of CDK1, CDK2, CDK4, ERK1, ERK2 and MAPK14 signaling pathways. This study shows that riluzole and harmine have closely similar physicochemical and pharmacokinetics properties as well as molecular targets, such as norepinephrine transporter (SLC6A2). Harmine, huperzine-A and cryptotanshinone could modulate acetylcholinesterase (AChE), which is involved in ALS-pathogenesis. The impact of 7,8-dihydroxyflavone on several carbonic anhydrases (CA) I, II, VII, IX, XII, and XIV, as well as CYP19A1, could help in remediating the respiratory failure associated with ALS.&#x0D; Conclusion: Overall, harmine is found to be superior to riluzole, and the combination of harmine with 7,8-dihydroxyflavone can provide more effective treatment for ALS than the current regime. Further work is needed to validate the predicted therapeutic targets of harmine identified in this study on ALS model or clinical trials, using in silico, in vitro and in vivo techniques.&#x0D; Graphical abstract:

A randomized, double-blind, single-dose, parallel phase I clinical trial to compare the bioequivalence, immunogenicity, and safety of bevacizumab biosimilar and bevacizumab in healthy Chinese subjects

ABSTRACT Background Bevacizumab, a humanized monoclonal antibody against VEGF, can be used as a target therapy for colorectal cancer. A phase I clinical trial was conducted to compare the bioequivalence, immunogenicity, and safety of bevacizumab biosimilar (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.) and Bevacizumab (Roche Diagnostics GmbH) in healthy Chinese males. Research design & method Healthy Chinese subjects (N = 98) were randomly divided into two groups. A single-dose bevacizumab biosimilar or Bevacizumab was given per cycle. Plasma drug concentrations were detected by liquid chromatography–tandem mass spectrometry (LC-MC/MS) assay. We detected the levels of anti-drug antibody (ADA) to evaluate drug immunogenicity and the safety of drugs throughout the study. Results The geometric mean ratios (GMRs) of AUC0-t, Cmax, and AUC0-∞ for bevacizumab biosimilar and Bevacizumab were 96.27%, 93.69%, and 97.01%, respectively. The 90% CIs were all within 80–125%, meeting the bioequivalence standards. The levels of ADA were similar. In addition, the two drugs both demonstrated excellent safety in the trial. Conclusion This study showed that bevacizumab biosimilar and Bevacizumab had similar pharmacokinetics (PK) parameters and safety in healthy Chinese subjects.

Comparative Preclinical Study of Lidocaine and Mepivacaine in Resilient Hyaluronic Acid Fillers.

Background: Hyaluronic acid-based filler injections are now well-established aesthetic procedures for the correction of skin tissue defects and volume loss. Filler injections are becoming increasingly popular, with a growing number of injections performed each year. Although classified as a minimally invasive procedure, the introduction of a needle or a canula may remain painful for the patient. A major improvement was achieved with the incorporation of local anesthetics into the formulation for pain relief. Methods: In this study, two well-known anesthetics, lidocaine and mepivacaine, were systematically compared to assess their influence on filler mechanical and biological features. The impact of each anesthetic was monitored in terms of gel rheological properties, stability, durability, and degradation. The release profiles of each anesthetic were also recorded. Finally, the pharmacokinetics of each anesthetic in rats were assessed. Results: For all the rheological and biological experiments performed, lidocaine and mepivacaine influences were comparable. The addition of either anesthetic into a soft-tissue filler showed no significant modifications of the stability, durability, and degradability of the gel, with similar release profiles and pharmacokinetics at an equivalent concentration. Conclusions: Substituting lidocaine with mepivacaine does not impact the properties of the gels, and thus both can be equally incorporated as anesthetics in soft-tissue fillers.

A randomized, placebo-controlled study to evaluate safety and pharmacokinetics of inhaled ribavirin.

Ribavirin is an inosine monophosphate dehydrogenase inhibitor. Studies suggest ribavirin aerosol could be a safe and efficacious treatment option in the fight against coronaviruses. However, current treatment is long (12–18 h per day, 3–7 days), limiting clinical utility. A reduction in treatment time would reduce treatment burden. We aimed to evaluate safety and pharmacokinetics (PK) of four, single‐dose regimens of ribavirin aerosol in healthy volunteers. Thirty‐two subjects were randomized, to four cohorts of aerosolized ribavirin (active) or placebo. Cohort 1 received 50 mg/ml ribavirin/placebo (10 ml total volume); cohort 2, 50 mg/ml ribavirin/placebo (20 ml total volume); cohort 3, 100 mg/ml ribavirin/placebo (10 ml total volume); and cohort 4, 100 mg/ml ribavirin/placebo (20 ml total volume). Intense safety monitoring and PK sampling took place on days 1, 2, 3, and 40. Subjects were (mean ± SD, active vs. placebo) aged 57 ± 4.5 vs. 60 ± 2.5 years; 83% vs. 88% were female; and 75% vs. 50% were Caucasian. Some 12.5% (3/24) and 25% (2/8) experienced at least one treatment‐emergent adverse event (TEAE) (two moderate; five mild) in the active and placebo groups, respectively. No clinically significant safety concerns were reported. Mean maximum observed concentration (C max) and area under the curve (AUC) values were higher in cohort 4, whereas cohorts 2 and 3 showed similar PK values. Ribavirin absorption reached C max within 2 h across cohorts. Four single‐dose regimens of ribavirin aerosol demonstrated systemic exposure with minimal systemic effects. Results support continued clinical development of ribavirin aerosol as a treatment option in patients with coronaviruses.

P865: BIOMARKER ANALYSIS TO SUPPORT DOSE OPTIMIZATION OF IBERDOMIDE AS MONOTHERAPY AND IN COMBINATION WITH STANDARD OF CARE TREATMENTS FOR MULTIPLE MYELOMA FROM A PHASE 1/2 TRIAL

Background: Iberdomide (IBER), a novel cereblon E3 ligase modulator (CELMoD®) compound, induces ubiquitination and proteasome-dependent degradation of Ikaros and Aiolos proteins, resulting in tumoricidal and immunomodulatory activity in multiple myeloma (MM). IBER is being investigated for the treatment of relapsed/refractory MM (RRMM) in a phase 1/2 study (NCT02773030). Due to the recent focus by health authorities on dose selection for oncology products other than the maximum tolerated dose (MTD), a comprehensive analysis of pharmacodynamics (PD) and pharmacokinetics (PK) was implemented to support dose optimization of IBER. Aims: To inform dose selection of IBER as monotherapy, and in combination with dexamethasone (DEX; Iber+d) and with DEX and daratumumab (DARA; IberDd). Methods: PK samples were collected on treatment of cycles (C) 1–4 to estimate IBER exposure using population PK (area under the concentration curve over 24-h dosing interval [AUCτ]). Biomarkers included analysis of peripheral blood samples on C1 day (D)1 and mid-cycle through C4 for immunophenotyping, absolute neutrophil counts (ANC), and assessment of serum free light chain (sFLC), as a biomarker of tumor burden. Bone marrow samples were collected at screening and C2D15 for immunohistochemistry. Results: IBER AUCτ increased in a dose-proportional manner between 0.3 and 1.0 mg as monotherapy and 0.3 and 1.6 mg in combination with DEX, with moderate variability. Median time to maximum serum concentration of IBER was 2–4 h post dose with an elimination half-life of ~12 h. Comparable IBER exposure was observed between monotherapy and Iber+d. Reductions in Ikaros/Aiolos protein levels in tumor cells were observed at all dose levels in both cohorts with a >90% reduction at the 0.45-mg dose. However, a >50% decrease in sFLCs was observed only at doses ≥0.9 mg, and doses of 1.6 mg induced faster and deeper decreases vs lower doses. In the immune compartment, IBER treatment induced similar dose-/exposure-dependent PD changes as monotherapy and Iber+d, which appeared to saturate at higher doses. A >80% reduction in mature B cells and ~2-fold increase in proliferating/activated T and NK cells were observed at doses ≥1.0 mg. PD activity of IBER was not attenuated by prior refractoriness to immunomodulatory drugs (IMiD® agents) or anti-CD38 therapy. Based on these results, doses between 1.0 and 1.6 mg were tested in the IberDd cohort. PK and PD of IBER were similar with concomitant administration of DARA. In this cohort, a reduction in mature B cells and sFLCs was more consistently observed at 1.6 mg vs lower doses; however, higher IBER exposures were associated with more pronounced decreases in ANC when compared with Iber+d. This was clinically manageable and the MTD of IBER was not determined in any cohort. Summary/Conclusion: Similar PK and PD results were observed in patients treated with IBER monotherapy, Iber+d, and IberDd. Across all cohorts, a >20% difference in dose was needed for meaningful change in IBER exposure, immune PD began to saturate at doses ≥1.0 mg, and decreases in tumor burden were greatest at the 1.6-mg dose. Based on these results, IBER doses of 1.0, 1.3, and 1.6 mg were chosen for dose optimization of IberDd for RRMM. Taken together with data suggesting immune surveillance is a driver of maintenance therapy efficacy and a desire to increase IBER tolerability with long-term treatment, doses of 0.75, 1.0, and 1.3 mg were selected for dose optimization of IBER monotherapy in the newly diagnosed MM maintenance setting.

Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer’s Disease in Rat and Dog

PurposeWe have recently demonstrated the brain-delivery of an Amyloid-ß oligomer (Aßo)-binding peptide-therapeutic fused to the BBB-crossing single domain antibody FC5. The bi-functional fusion protein, FC5-mFc-ABP (KG207-M) lowered both CSF and brain Aß levels after systemic dosing in transgenic mouse and rat models of Alzheimer’s disease (AD). For development as a human therapeutic, we have humanized and further engineered the fusion protein named KG207-H. The purpose of the present study was to carry out comparative PK/PD studies of KG207-H in wild type rat and beagle dogs (middle-aged and older) to determine comparability of systemic PK and CSF exposure between rodent species and larger animals with more complex brain structure such as dogs.MethodBeagle dogs were used in this study as they accumulate cerebral Aß with age, as seen in human AD patients, and can serve as a model of sporadic AD. KG207-H (5 to 50 mg/kg) was administered intravenously and serum and CSF samples were serially collected for PK studies and to assess target engagement. KG207-H and Aβ levels were quantified using multiplexed selected reaction monitoring mass spectrometry.ResultsAfter systemic dosing, KG207-H demonstrated similar serum pharmacokinetics in rats and dogs. KG207-H appeared in the CSF in a time- and dose-dependent manner with similar kinetics, indicating CNS exposure. Further analyses revealed a dose-dependent inverse relationship between CSF KG207-H and Aß levels in both species indicating target engagement.ConclusionThis study demonstrates translational attributes of BBB-crossing Aβ-targeting biotherapeutic KG207-H in eliciting a pharmacodynamic response, from rodents to larger animal species.

Extension of the Alternative Intravenous Dosing Regimens of Atezolizumab into Combination Settings through Modeling and Simulation.

Atezolizumab is approved as an intravenous (IV) infusion for use as a single agent and in combination with other therapies in a number of indications. The objectives of this publication are to characterize atezolizumab pharmacokinetics (PK) across indications with the available clinical data from one phaseI and eight phaseIII studies, to determine the exposure-response (ER) relationships in combination settings across a variety of tumor types, and to provide the clinical safety to support the extension of the 840mg q2w, 1200mg q3w, and 1680mg q4w IV dosing regimens across various indications in combination settings. Across all clinical studies, atezolizumab PK remained in the dose-linear range and were similar across tumor types when used in combination therapy or as a monotherapy. In the combination studies, efficacy was independent of the exposures tested and there was no significant increase in adverse events with increasing atezolizumab exposure (flat ER). The safety profile of atezolizumab in the individual combination studies was generally consistent with the established safety profile of atezolizumab, the combination partners, and the disease under study. The similar atezolizumab PK across monotherapy and combination therapy settings as well as the flat ER in new tumor types and combination therapies support the use of the 3 interchangeable atezolizumab dosing regimens in the combination setting. Atezolizumab is now approved with 3 interchangeable IV dosing regimens of 840mg q2w, 1200mg q3w, and 1680mg q4w for single-agent and combination therapy use in the USA and EU.

Pharmacokinetics, safety, tolerability, and immunogenicity of FKB238, a new biosimilar of bevacizumab, in healthy participants

To compare the pharmacokinetics (PK), safety, tolerability, and immunogenicity of single intravenous doses of FKB238, a proposed biosimilar of bevacizumab, with European Union (EU)-approved and United States (US)-licensed bevacizumab in healthy participants. In a randomized, double-blind, parallel-group study, 99 healthy men received 5mg of FKB238, EU-bevacizumab, or US-bevacizumab in a 1:1:1 ratio by intravenous infusion. PK, immunogenicity, adverse events, local tolerability, vital signs, electrocardiogram, and safety tests of blood and urine were assessed before and up to 99 days after treatment. The 90% confidence interval for the ratios of the primary (area under the curve ((AUC)0-t and AUC0-inf) and secondary (maximum concentration (Cmax) and elimination half-life (T1/2)) geometric mean PK parameters were entirely within the acceptance range for bioequivalence of 0.80 - 1.25 for all 3 pairwise comparisons by analysis of covariance, with baseline characteristics of age and body weight as covariates. FKB238 was well tolerated in healthy participants, and anti-drug antibody (ADA) incidence was low and similar in all treatment groups. The study demonstrated the PK similarity of FKB238 to both EU-bevacizumab and US-bevacizumab after a single intravenous infusion. FKB238 was well tolerated in healthy participants, and there was no difference in ADA incidence among the 3 products.

A Model-Based Approach to Bridging Plasma and Dried Blood Spot Concentration Data for Phase 3 Verubecestat Trials

In-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS-plasma verubecestat concentration relationship, with the intention of discontinuing DBS or plasma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a stability issue resulting in generally lower DBS verubecestat concentrations with longer collection-to-assay times was subsequently discovered (associated with non-compliance in DBS sample handling), prompting reintroduction of plasma sampling. To enable inclusion of DBS data in population PK analyses, a conversion algorithm for calculating plasma-equivalent concentrations (accounting for DBS sample instability) was developed using paired (time-matched) plasma and DBS data from the EPOCH study. Verubecestat population PK models developed from pooled phase 1/1b and EPOCH data using either (1) plasma-only data or (2) plasma and plasma-equivalent concentrations (calculated from non-paired DBS samples) yielded similar results. The algorithm robustness was demonstrated using DBS data from paired samples from the APECS study and comparison between plasma and plasma-equivalent concentrations. The population PK model was updated with APECS data (both plasma and, if no plasma sample available, plasma equivalents). The results demonstrated similar PK in the two phase 3 populations and exposures consistent with expectations from phase 1 data. This case study illustrates challenges with employing new sampling techniques in large, global trials and describes lessons learned.

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.

Radiation dosimetry and efficacy of an 89Zr/225Ac-labeled humanized anti-MUC5AC antibody

IntroductionTheranostic applications are currently difficult to achieve owing to the limited evaluation of suitable chelators for therapeutic nuclides, such as 225Ac and 227Th. With a focus on targeted α therapy and theranostics using human IgG as a drug-delivery system (i.e., combining highly cytotoxic α-particle emitter radiation with efficient tumor targeting), we developed a recombinant humanized Nd2 (hNd2) as an anti-MUC5AC antibody since MUC5AC is highly expressed in patients with pancreatic cancer. Therefore, we aimed to evaluate the performance of 89Zr- (for diagnosis) and 225Ac- (for therapy) labeling of these antibodies using well-controlled radioisotope (RI)-labeling technology in pancreatic cancer mouse models. Methods89Zr-labeled hNd2 (NMK89) and 225Ac-labeled hNd2 (NMT25) were manufactured by chemical conjugation using affinity peptides. A binding assay and the evaluation of plasma stability were performed in vitro to confirm the properties of NMK89 and NMT25. In vivo, we evaluated biodistribution, positron emission tomography (PET)/computed tomography (CT) imaging, antitumor effects, and toxicity. Moreover, the exposure dose in humans was estimated based on the biodistribution evaluation in normal mice. ResultsNMK89 and NMT25 showed binding specificity to MUC5AC and stability with radiochemical purity ≥90% in mice and human plasma following incubation for 168 h. NMK89 showed high accumulation in tumors and low non-specific accumulation in normal tissues. The antitumor effect of NMT25 was dose-dependent and significantly suppressed tumor growth in the NMT25 treatment groups compared with the control group (p < 0.05). NMK89 and NMT25 showed similar pharmacokinetics and biodistribution characteristics. Additionally, the human estimated exposure dose of NMK89 and NMT25 was confirmed, and the effective dose of NMK89 and NMT25 was 0.33 mSv/MBq and 177.5 mSv/MBq, respectively. ConclusionNMK89 showed specific accumulation in the MUC5AC-expressing tumors, while NMT25 showed strong antitumor effects. These results suggest NMK89 and NMT25 as promising theranostic agents for pancreatic cancer.

Abstract P5-17-05: A phase I/Ib study of inavolisib (GDC-0077) in combination with fulvestrant in patients (pts) with PIK3CA-mutated hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer

Abstract Background Dysregulating mutations in PIK3CA, which encodes the catalytic PI3K p110α subunit, are common in breast cancer and other solid tumors. There are limited data available on the role of PI3Kα inhibition in the post-cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) setting. Inavolisib is a PI3Kα-selective inhibitor and degrader of mutated PI3Kα that has demonstrated encouraging preliminary antitumor activity in patients with PIK3CA-mutated HR+ breast cancer as a single agent, and in combination with antiestrogen therapy. An open-label, phase I/Ib dose-escalation study of inavolisib alone and in combination with endocrine and targeted therapies is ongoing (NCT03006172; GO39374). Data for inavolisib in combination with fulvestrant in female pts with PIK3CA-mutated, HR+/HER2- breast cancer (Arm D) are presented. Methods Safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary antitumor activity (assessed every 2 cycles via RECIST v1.1; clinical benefit rate [CBR]: stable disease for ≥24 weeks, partial response [PR], or complete response; progression-free survival [PFS]) of 9 mg inavolisib administered orally once daily in combination with 500 mg intramuscular fulvestrant on Day 1 (and Day 15 of Cycle 1) of 28-day cycles were assessed until intolerable toxicity or disease progression. Early dynamics of PIK3CA-mutation allele frequency were assessed from circulating tumor (ct)DNA samples. Results At clinical cutoff (April 5, 2021), 55 pts were enrolled in Arm D and enrollment was ongoing. Thirty-seven pts (67%) had received ≥2 prior lines of therapy for metastatic breast cancer, 19 (35%) had received chemotherapy in the metastatic setting, 26 (47%) had received prior fulvestrant, and 53 (96%) had received a prior CDK4/6i. Median inavolisib treatment duration was 5.3 months (range 0.2-31.9); cumulative dose intensity was 98%. Thirty-two pts (58%) had dose modifications (interruptions, reductions, and/or discontinuations) due to adverse events (AEs). The most common treatment-related AEs (≥15% of pts) were hyperglycemia (31 pts, 56%), diarrhea (21 pts, 38%), stomatitis (grouped term; 19 pts, 35%), nausea (17 pts, 31%), and dysgeusia (nine pts, 16%). Grade ≥3 treatment-related AEs in ≥2 pts were hyperglycemia (13 pts, 24%) and alanine aminotransferase increased (two pts, 4%). No grade 3 rash was observed. Thirty-eight pts (70%) discontinued treatment: 36, due to radiographic or clinical disease progression; one, due to physician’s decision; and one, due to death (unrelated serious AE of hypertrophic cardiomyopathy). No treatment-related AE resulted in treatment discontinuation. Overall, 12/49 pts with measurable disease achieved a PR (25%; three of the responding pts had received prior fulvestrant; 11, prior CDK4/6i). Nine pts (18%) had a confirmed PR. CBR was 49% (27/55 pts). Preliminary median PFS was 7.1 months (0-29). Analysis of ctDNA from most pts demonstrated decreased PIK3CA-mutation allele frequency during treatment. The PK of inavolisib in combination with fulvestrant was similar to single-agent inavolisib PK. Conclusion Inavolisib in combination with fulvestrant demonstrated a manageable safety profile, encouraging preliminary antitumor activity, similar PK to inavolisib alone, and pharmacodynamic modulation (i.e., decreased PIK3CA-mutation allele frequency in ctDNA), including in patients who previously progressed on a CDK4/6i. Inavolisib continues to be developed in breast cancer and other solid tumors. Citation Format: Dejan Juric, Phillippe L Bedard, Andrés Cervantes, Valentina Gambardella, Mafalda Oliveira, Cristina Saura, Kevin M Kalinsky, Erika Hamilton, Antoine Italiano, Ian E Krop, Peter Schmid, Nicholas C Turner, Andrea Varga, Stephanie Royer-Joo, Katherine E Hutchinson, Jennifer L Schutzman, Komal L Jhaveri. A phase I/Ib study of inavolisib (GDC-0077) in combination with fulvestrant in patients (pts) with PIK3CA-mutated hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-05.

Similar Pharmacokinetics and Pharmacodynamics of Biosimilar SAR342434 Insulin Lispro and Japan-Approved Humalog Insulin Lispro in Healthy Japanese Subjects.

This phase 1 study compared the pharmacokinetic (PK) and glucose pharmacodynamic (PD) characteristics of biosimilar SAR342434 insulin lispro and Japan‐reference Humalog insulin lispro. This was a randomized, double‐blind, 2‐period, crossover study. Thirty‐six healthy Japanese male subjects underwent a 10‐hour euglycemic clamp following a single subcutaneous 0.3‐U/kg dose of SAR342434 or Humalog. Insulin lispro concentration and blood glucose were measured, and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. Primary PK end points were maximum plasma insulin lispro concentration and area under the plasma insulin concentration–time curve (AUC) from time 0 to the last quantifiable concentration. Primary PD end points were area under the GIR–time curve from time 0 to 10 hours and maximum GIR. PK exposure (maximum plasma concentration and AUC from time 0 to the last quantifiable concentration) and PD activity (GIR‐AUC from time 0 to 10 hours and maximum GIR) were similar between treatments. Geometric mean ratios were close to 1, and the corresponding 90% and 95%CIs (PK and PD activity, respectively) were within the 0.80 to 1.25 equivalence range. SAR342434 and Humalog were well tolerated. In healthy Japanese males, SAR342434 and Humalog showed similar PK exposure profiles and PD potency, in support of SAR342434 use as a biosimilar product.

Bone-Specific Enhancement of Antibody Therapy for Breast Cancer Metastasis to Bone.

Despite the rapid evolution of therapeutic antibodies, their clinical efficacy in the treatment of bone tumors is hampered due to the inadequate pharmacokinetics and poor bone tissue accessibility of these large macromolecules. Here, we show that engineering therapeutic antibodies with bone-homing peptide sequences dramatically enhances their concentrations in the bone metastatic niche, resulting in significantly reduced survival and progression of breast cancer bone metastases. To enhance the bone tumor-targeting ability of engineered antibodies, we introduced varying numbers of bone-homing peptides into permissive sites of the anti-HER2 antibody, trastuzumab. Compared to the unmodified antibody, the engineered antibodies have similar pharmacokinetics and in vitro cytotoxic activity, but exhibit improved bone tumor distribution in vivo. Accordingly, in xenograft models of breast cancer metastasis to bone sites, engineered antibodies with enhanced bone specificity exhibit increased inhibition of both initial bone metastases and secondary multiorgan metastases. Furthermore, this engineering strategy is also applied to prepare bone-targeting antibody–drug conjugates with enhanced therapeutic efficacy. These results demonstrate that adding bone-specific targeting to antibody therapy results in robust bone tumor delivery efficacy. This provides a powerful strategy to overcome the poor accessibility of antibodies to the bone tumors and the consequential resistance to the therapy.