Median Tmax Research Articles

Investigation of the Effect of Lasmiditan on the Pharmacokinetics of P-Glycoprotein and Breast Cancer Resistance Protein Substrates.

Lasmiditan is an invitro inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters. We aimed to confirm predictions from physiologically based pharmacokinetic models of lasmiditan, and assess the safety and tolerability of rosuvastatin and dabigatran co-administered with lasmiditan. In this open-label, post-marketing drug-drug interaction, phase1 clinical trial, eligible participants were adults aged 21-70years with a body mass index of 18.5-35.0kg/m2 . Part1 (P-gp, 150mg dabigatran etexilate with 200mg lasmiditan) and part2 (BCRP, 10mg rosuvastatin with 200mg lasmiditan) employed similar designs: a single dose of probe substrate administered on day-2 with pharmacokinetic evaluation; 1-week washout; lasmiditan administered on days8 and 9 alone; lasmiditan co-administered with a single dose of probe substrate on day10, with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty-six participants were included in part1 and 30 participants were included in part2. Following dabigatran co-administration with lasmiditan, versus dabigatran alone, 90% confidence intervals for geometric least-squares (LS) mean ratios of area under the plasma concentration-time curve from time0 extrapolated to infinity (AUC0-∞ ) and maximum observed drug concentration (Cmax ) were not contained within the non-effect boundaries (0.80 to 1.25). Dabigatran AUC0-∞ increased by 25% and Cmax increased by 22%. The median time of maximum observed drug concentration (tmax ) for dabigatran was 2.0 to 3.0hours. Following rosuvastatin co-administration with lasmiditan, versus rosuvastatin alone, 90%CIs for geometric LS mean ratios of AUC0-∞ and Cmax were contained within non-effect boundaries (0.80-1.25). Rosuvastatin AUC0-∞ increased by 15% and Cmax increased by 7%. The median tmax for rosuvastatin was 4.0hours. Results suggest that lasmiditan has a weak effect on P-gp substrates and no clinically relevant effect on BCRP substrates.

Possible Influence of Ethnicity on Computed Tomography Perfusion Parameter Thresholds in Acute Ischaemic Stroke

Introduction: Tissue at risk, as estimated by CT perfusion utilizing Tmax+6, correlates with final infarct volume (FIV) in acute ischaemic stroke (AIS) without reperfusion. Tmax thresholds are derived from Western ethnic populations but not from ethnic Asian populations. We aimed to investigate the influence of ethnicity on Tmax thresholds. Methods: From a clinical-imaging registry of Australian and Indonesian stroke patients, we selected a participant subgroup with the following inclusion criteria: AIS under 24 h and absence of reperfusion therapy. Clinical data included demographics, time metrics, stroke severity, pre-morbid, and 3-month Modified Rankin Score. Baseline computed tomography perfusion and MRI <72 h were performed. Volumes of Tmax utilizing different thresholds and FIVs were calculated. Spearman correlation was used to evaluate relationship involving ordinal variables and calculate the optimal Tmax threshold against FIV in both populations. Results: Two hundred patients were included in the study sample, 100 in Jakarta and 100 in Geelong. The median National Institutes of Health Stroke Scale (IQR) were 6 (3–11) and 3 (1–5), respectively. The median Tmax+6 (IQR) was 0 (0–46.5) in Jakarta group and 0 (0–7.5) in Geelong group. The median FIV (IQR) was 0 (0–30.5) and 0 (0–5.5). Tmax+8 s in Jakarta population against FIV showed Spearman’s coefficient ρ = 0.72, representing the optimal Tmax threshold. Tmax+6 s showed Spearman’s coefficient ρ = 0.51 against FIV in the Geelong population. Conclusion: Tmax thresholds approximating FIV were possibly different in the Asian when compared with the non-Asian populations. Future studies are required to extend and confirm the validity of our findings.

A phase 1 study of dimdazenil to evaluate the pharmacokinetics, food effect and safety in Chinese healthy subjects.

Background and objective: As a partial positive allosteric modulator of the gamma-aminobutyric acid A (GABAA) receptor, dimdazenil was used for the treatment of insomnia with the potential to alleviate associated side effects compared to full agonists. The objective of this trial is to assess the safety, tolerability, food effect and pharmacokinetics following single and multiple doses of dimdazenil in Chinese healthy subjects. Methods: In this phase 1 trial, 36 healthy subjects aged ≥18years were assigned to receive a single dose of 1.5, 2.5, or 5mg dimdazenil, with each dose cohort consisting of 12 subjects, and 14 subjects were assigned to receive a multiple 2.5mg daily dose of dimdazenil for 5days. Safety, tolerability, and pharmacokinetic characteristics were evaluated. Results: Of the 50 subjects enrolled and 49 completed the trial, the incidences of treatment-emergent adverse events (AEs) in the single-dose groups of 1.5, 2.5, and 5mg were 16.7%, 58.3% and 66.7% respectively, while 61.5% in the multiple-dose group. There were no serious AEs, deaths, AEs leading to discontinuation or AEs of requiring clinical intervention in any treatment groups. The most treatment-emergent AEs were dizziness (n = 4, 8.2%), hyperuricemia (n = 2, 6.1%), upper respiratory tract infection (n = 2, 6.1%), diastolic blood pressure decreased (n = 2, 6.1%), blood TG increased (n = 2, 6.1%) and RBC urine positive (n = 2, 6.1%). All AEs were mild-to-moderate and transient, and no severe AEs were documented in any study phase. The PK profile of dimdazenil and its active metabolite Ro46-1927 was linear across 1.5-5mg oral doses in humans. The median Tmax for dimdazenil was in the range of 0.5-1.5h, and the apparent terminal t1/2z ranged from 3.50 to 4.32h. Taking Dimdazenil with food may delay Tmax and decrease Cmax, without affecting the total exposure (AUC). No relevant accumulations of dimdazenil and Ro 46-1927 were observed in multiple-dose group. Conclusion: Dimdazenil was generally well tolerated in healthy Chinese subjects after single and 5days-multiple dosing. The pharmacokinetic properties of dimdazenil are compatible with a drug for the treatment of insomnia. Clinical Trial Registration: chinadrugtrials.org.cn, identifier CTR20201978.

SLN124, a GalNAc conjugated 19-mer siRNA targeting tmprss6, reduces plasma iron and increases hepcidin levels of healthy volunteers.

SLN124, an N-acetylgalactosamine conjugated 19-mer short interfering RNA, is being developed to treat iron-loading anemias (including beta-thalassemia and myelodysplastic syndromes) and myeloproliferative neoplasms (polycythemia vera). Through hepatic targeting and silencing of the TMPRSS6 gene, SLN124 increases endogenous hepcidin synthesis. This is the first clinical report of an siRNA targeting a component of iron homeostasis. This first-in-human, phase 1 study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of SLN124 (1.0, 3.0, and 4.5 mg/kg) in healthy volunteers. Twenty-four participants were randomized in three sequential cohorts of eight subjects, each to receive a single dose of either SLN124 or placebo (6:2 randomization), administered subcutaneously. There were no serious or severe adverse events, or discontinuations due to adverse events, and most treatment-emergent adverse events were mild, including transient mild injection site reactions, resolving without intervention. SLN124 was rapidly absorbed, with a median tmax of 4-5 h across all treatment groups, and largely eliminated from plasma by 48 h. Plasma concentrations increased in a greater than dose proportional fashion between treatment groups. In all SLN124 groups, a dose-related effect was observed across iron metabolism markers, and across erythroid markers, SLN124 resulted in increased plasma hepcidin levels, peaking around Day 29, and consequent dose-related sustained reductions in plasma iron and transferrin saturation with decreased reticulocyte production, MCHC, and MCV. Results suggest duration of action lasting up to 56 days after a single SLN124 dose, on hepcidin and hematological parameters of iron metabolism (serum iron and TSAT).

A feasibility and safety study of afamelanotide in acute stroke patients – an open label, proof of concept, phase iia clinical trial

BackgroundNeuroprotective agents have the potential to improve the outcomes of revascularisation therapies in acute ischemic stroke patients (AIS) and in those unable to receive revascularisation. Afamelanotide, a synthetic α-melanocyte stimulating hormone analogue, is a potential novel neuroprotective agent. We set out to assess the feasibility and safety of afamelanotide for the first time in AIS patients.MethodsAIS patients within 24 h of onset, with perfusion abnormality on imaging (Tmax) and otherwise ineligible for revascularisation therapies were enrolled. Afamelanotide 16 mg implants were administered subcutaneously on Day 0 (D0, day of recruitment), D1 and repeated on D7 and D8, if not well recovered. Treatment emergent adverse events (TEAEs) and neurological assessments were recorded regularly up to D42. Magnetic resonance imaging (MRI) with FLAIR sequences were also performed on D3 and D9.ResultsSix patients (5 women, median age 81, median NIHSS 6) were recruited. Two patients received 4 doses and four patients received 2. One patient (who received 2 doses), suffered a fatal recurrent stroke on D9 due to a known complete acute internal carotid artery occlusion, assessed as unrelated to the study drug. There were no other local or major systemic TEAEs recorded. In all surviving patients, the median NIHSS improved from 6 to 2 on D7. The median Tmax volume on D0 was 23 mL which was reduced to a FLAIR volume of 10 mL on D3 and 4 mL on D9.ConclusionsAfamelanotide was well tolerated and safe in our small sample of AIS patients. It also appears to be associated with good recovery and radiological improvement of salvageable tissue which needs to be tested in randomized studies.ClinicalTrials.gov IdentifierNCT04962503, First posted 15/07/2021.

Pharmacokinetics of Nasal Esketamine in Patients with Allergic Rhinitis with and Without Nasal Decongestant Pretreatment and in Healthy Subjects with and Without Nasal Corticosteroid Pretreatment.

Nasal esketamine is indicated for the treatment of adults with treatment-resistant depression and depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Primary objectives of this study were to evaluate the effect of nasal decongestant pretreatment in patients with allergic rhinitis and the impact of daily nasal corticosteroid administration by healthy subjects on nasal esketamine pharmacokinetics. Patients with allergic rhinitis self-administered 56 mg of nasal esketamine after pretreatment with nasal oxymetazoline (0.05%) at 1h before esketamine and without oxymetazoline pretreatment. They were exposed to grass pollen in an allergen challenge chamber to induce allergic rhinitis symptoms at approximately 2 h before each esketamine administration until 1 h after. Healthy subjects self-administered esketamine (56mg) before and after administration for 16consecutive days of mometasone (200µg), with the second esketamine dose administered 1h after the last mometasone dose. The plasma pharmacokinetics of esketamine and noresketamine were assessed after each esketamine administration. The tolerability of esketamine, including effects on dissociative and potential psychotomimetic symptoms and level of sedation and suicidal ideation and behavior, was evaluated. The rate of esketamine absorption was slightly greater in patients exhibiting symptoms of allergic rhinitis (decrease in median tmax from 32min to 22min). Increases in esketamine Cmax and AUC were also small (mean, ≤ 21%). The pharmacokinetics of esketamine was not affected by oxymetazoline or mometasone pretreatment. Esketamine was well tolerated when it was administered with or without pretreatment of oxymetazoline or mometasone. Patients exhibiting symptoms of rhinitis may receive nasal esketamine spray without dose adjustment. In addition, esketamine may be administered 1 h after using a nasal decongestant or corticosteroid. The study was registered in the Clinical Trials (NCT02154334) and EudraCT (2014-000534-38) registries.

95-LB: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Novel Oral Small Molecule GLP-1 Receptor Agonist (HRS-7535) in Healthy Subjects —A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Dose Study

Background: HRS-7535, a novel, oral small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, has demonstrated no strict food restriction, and has been found to obviously improve glucose tolerance, promote insulin secretion, and reduce food consumption in preclinical studies. This study aimed to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses (SAD and MAD) of HRS-7535 in healthy subjects. Methods: This was a randomized, double-blind, multi-part, phase 1 trial (NCT05347758). Overtly healthy adults 18-55 yrs were eligible, with the body mass index of 19.0-28.0 kg/m2 and the HbA1c of &amp;lt;6.2%. In the SAD, healthy subjects were randomized (6:2) to receive HRS-7535 (15, 60, and 120 mg) or placebo. In the MAD, healthy subjects were randomized (18:6) to receive daily HRS-7535 (120 mg [30/60/90/120 mg titration scheme]) or matching placebo for 4 wks. Results: 24 subjects participated in SAD and 24 participated in MAD, respectively. Most common treatment-emergent adverse events in both SAD and MAD were nausea and vomiting; all TEAEs were mild in severity. PKs were approximately proportional; In SAD, the median Tmax was 5.98-5.99 h and geometric mean t1/2 was 5.28-9.08 h across the HRS-7535 dosing range. In MAD, the median Tmax was 5.98-10.98 h and geometric mean t1/2 was 6.48-8.42 h on Day 28 across the HRS-7535 dosing range. In MAD, the mean reduction in body weight from baseline on Day 29 was 4.38 kg in subjects with HRS-7535. Conclusion: Both SAD and MAD of HRS-7535 showed acceptable safety profile and favorable PKs/PDs. The obvious reductions in body weight could be observed in healthy subjects. These finding support further clinical exploration of HRS-7535 in patients with metabolic syndromes. Disclosure J. Wu: None. S. Feng: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. C. Shu: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Shen: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Fan: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. W. Hu: None. Y. Du: None. Q. Zhang: None. R. Zhou: None. Q. Zhang: None. H. Qin: None. Z. Ye: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Xu: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Funding Jiangsu Hengrui Pharmaceuticals Co., Ltd.

56-OR: A Long-Acting Glucose-Dependent Insulinotropic Polypeptide Receptor Agonist Shows Weight Loss without Nausea or Vomiting

The contributions of glucose-dependent insulinotropic polypeptide (GIP) to overall metabolic and weight effects of incretin therapies are unclear. Weight loss efficacy has been observed with glucagon-like peptide 1 (GLP-1) and GIP receptor agonist tirzepatide, but weight loss efficacy has also been observed with GLP-1 agonism mixed with GIP antagonism. LY3537021 (LY), a selective, long-acting GIP receptor agonist, was tested in single [SAD, LY vs placebo (PBO)] and multiple ascending doses (MAD, LY vs PBO once weekly for 4 weeks) to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics. In SAD, healthy participants (N=39) had a mean age of 43.5 yrs and mean weight of 74.4 kg. People with T2D (N=6) had a mean age of 58.5 yrs and mean weight of 75.1 kg. Median Tmax was 12 to 84 hrs post dose and mean terminal T½ was approximately 11 to 14 days. PK in people with T2D appeared comparable to healthy participants. In MAD, healthy participants (N=18) had a mean age of 38.3 yrs and mean weight of 75.4 kg. People with T2D (N=18) had a mean age of 57.1 yrs and mean weight of 74.3 kg. In healthy MAD participants at day 57, numerically greater mean weight loss was reported in those who received LY (-1.1 to -2.2 kg) versus PBO (-0.4 kg). In people with T2D, numerically greater mean weight loss was reported for those receiving LY (-1.9 to -3.1 kg) versus PBO (-0.4 kg). LY did not result in gastric emptying delay. No serious adverse events or hypoglycemia occurred. Study participants had few mild gastrointestinal (GI) adverse events. Study findings included decreased appetite (LY: n=4, PBO: n=1), abdominal pain (LY: n=1, PBO: n=0) and diarrhea (LY: n=1, PBO: n=2). No nausea or vomiting was observed. Repeated dosing of a long-acting GIP receptor agonist, once weekly for 4 weeks, induced weight loss without gastric emptying delay or nausea and vomiting. The results suggest that GIP agonism can contribute to weight loss effects seen with multi-agonist incretins such as tirzepatide. Disclosure F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. S.Urva: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M.Rettiganti: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. C.Benson: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. W.Roell: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. K.J.Mather: Employee; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. E.J.Pratt: Employee; Eli Lilly and Company.

763-P: Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of a Dual GLP-1/GIP Receptor Agonist (HRS9531) in Healthy Subjects—A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose (SAD and MAD) Study

Background: Accumulating evidences suggest that dual GLP-1/GIP receptor agonist can achieve prominent glycemic control and body weight loss. Here we report the results of a phase 1 SAD and MAD study of HRS9531 in healthy subjects (NCT05152277). Methods: In the SAD, healthy subjects were randomized (4:1) to receive subcutaneous injection of HRS9531 (0.1, 0.3, 0.9, 2.7, 5.4, and 8.1 mg) or placebo. In the MAD, healthy subjects were randomized (4:1) to receive HRS9531 (0.9, 2.7, and 5.4 mg [2.7/2.7/4.0/5.4 mg titration]) or placebo once a week for 4 wks. The primary endpoints for both parts were safety and tolerability. Results: Sixty and 30 subjects were recruited into SAD and MAD respectively. The most common adverse events were abdominal distension and nausea in SAD, and urine ketone body present and nausea in MAD; all considered mild to moderate in severity (mostly mild). No severe hypoglycemia or serious events occurred. Drug exposure were proportional to dose from 0.9-8.1 mg. The median Tmax and mean t1/2 were 48-72 h and 156-182 h in SAD, and 48-72 h and 169-192 h after the fourth dosing in MAD, respectively. Fasting plasma glucose (FPG) levels decreased dose-dependently after single and multiple dosing. The 0 to 2 h glucose AUC during oral glucose tolerance test (OGTT) on D23 decreased dose-dependently relative to placebo in MAD. In SAD, body weight loss was dose-dependent and the maximal mean loss on D8 was 3.8 kg (4.9%) in 8.1 mg group. In MAD, the mean weight loss on D29 (after 4 wks treatment) ranged 4.3-7.7 kg (6.7%-9.3%) across 0.9-5.4 mg groups, and maximal loss (8.0 kg, 10.0%) occurred on D36 in 5.4 mg group. Conclusions: HRS9531 was well tolerated, had favorable PK, and led to evident glucose decrease and body weight loss. These data support further clinical development of HRS9531 for metabolism-related disorders such as T2DM and obesity. Disclosure K.He: None. F.Wei: None. H.Chen: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y.Zhang: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Z.Sheng: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Q.Wen: None. Funding Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Pharmacokinetics and Safety of iGlarLixi in Healthy Chinese Participants: Results of a Phase 1 Randomized Study.

The Chinese Diabetes Society recommends basal insulin and glucagon-like peptide-1 receptor agonists as an add-on therapy to first-line oral antihyperglycemic drugs for people with type 2 diabetes (T2D). Fixed-ratio combination of insulin glargine 100 U/ml (iGlar) and lixisenatide (iGlarLixi) is known to improve glycemic control in adults with T2D. However, the pharmacokinetics of iGlarLixi has not been evaluated in Chinese participants. The present study evaluated pharmacokinetics and safety of two iGlarLixi (10 U/10μg and 30 U/15μg) doses following single subcutaneous administration in healthy Chinese participants. This was a Phase 1, single-center, open-label, parallel-group, randomized study in healthy Chinese adults who were randomized to receive a single dose of iGlarLixi with either 1:1 (10 U/10μg) or 2:1 (30 U/15μg) ratio of iGlar and lixisenatide. Primary objectives include assessment of pharmacokinetics of iGlar in iGlarLixi 30 U/15μg group and the pharmacokinetics of lixisenatide in both the groups (iGlarLixi 10 U/10μg and iGlarLixi 30 U/15μg). Safety and tolerability were also assessed. In iGlarLixi 30 U/15μg group, iGlar concentrations were low and quantifiable in three of ten participants, while its main metabolite (M1) was quantifiable in all participants, reflecting rapid conversion of iGlar to M1. Median INS-tmax was 14.00h for iGlar and 13.00h post-dose for M1. Absorption of lixisenatide was similar in both dose groups with median tmax of 3.25 and 2.00h post-dose in both groups. The exposure increase was dose proportionate with a 1.5-fold increase in the lixisenatide dose. Adverse events observed were consistent with those previously reported with iGlar or lixisenatide. iGlarLixi administration resulted in early absorption of both iGlar and lixisenatide with a good tolerability profile in healthy Chinese participants. These results are consistent with the previously published data from other geographic regions. U1111-1194-9411.

#4328 CHK-336, A FIRST-IN-CLASS ORALLY ADMINISTERED LDH INHIBITOR: SAFETY, PK AND TARGET ENGAGEMENT IN A FIRST-IN-HUMAN PHASE 1 HEALTHY VOLUNTEER STUDY

Abstract Background and Aims CHK-336 is a first-in-class, orally bioavailable, liver-targeted small molecule lactate dehydrogenase (LDH) inhibitor for the treatment of primary hyperoxalurias and other kidney stone disorders caused by oxalate overproduction. The primary objectives of this first-in-human (FIH) study were characterization of the safety and pharmacokinetics (PK) of CHK-336 following single and repeat doses in healthy volunteers (HVs). Exploratory objectives were demonstration of proof of mechanism in HVs based on inhibition of hepatic oxalate production using a stable-label 13C2-glycolate tracer for hepatic LDH target engagement and characterization of the exposure-response relationship. Method This Phase 1, placebo-controlled (6:2 randomization within a cohort), dose escalation study explored single ascending (SAD, 15-500 mg) and multiple ascending (MAD, 30 mg and planned up to 500 mg QD, 14 consecutive days) doses. A total of 104 subjects will be enrolled in this study. A stable-label 13C2-glycolate tracer was administered orally at baseline and following CHK-336 administration to evaluate the inhibition of LDH-mediated production of [13C2]-oxalate by CHK-336, as a measure of hepatic LDH target engagement in HVs. Food-effect was evaluated following a single dose after a standard high fat meal. CHK-336 concentrations were determined in plasma and urine by a validated LC-MS/MS assay. Total oxalate and 13C2-oxalate were determined in urine by validated GC/MS assays. Results CHK-336 was generally well tolerated following single doses from 15 – 500 mg, with no dose-related trends in total adverse events (AEs) or types of AEs. There were no serious AEs, or severe treatment-related AEs (TRAEs). Treatment-emergent AEs were observed in 10 of 56 (17.9%) subjects, 7 (12.5%) of whom experienced TRAEs; all TRAEs were mild or moderate in severity. CHK-336 PK profiles were characterized with a median tmax of 6 hrs following absorption in fasted-state followed by bi-exponential decline and a terminal half-life of 18 ± 8 hrs. Dose-proportional increases in exposure AUC were observed from 15 up to 500 mg. Cmax increase was greater than dose-proportional at ≥60 mg with a concomitant decrease in median tmax from 6hr to 2hr. A high fat meal decreased CHK-336 AUC0-72h by 32% (AUC0-72h) and Cmax by 55%. Renal elimination of unchanged CHK-336 was quantitatively minor (&amp;lt;1% of administered dose). A direct effect inhibitory Imax-IC50 model adequately described the relationship between CHK-336 plasma concentrations and urinary 13C2-oxalate (% of control). Robust target engagement was demonstrated with an exposure-related reduction in urinary 13C2-oxalate from 15 – 60 mg, with maximum inhibition achieved at CHK-336 doses ≥60 mg. Conclusion CHK-336 is a first-in-class, orally administered, liver-targeted LDH inhibitor that was generally well-tolerated following single doses from 15 – 500 mg, with dose proportional increases in AUC exposure. Hepatic oxalate production was robustly reduced by CHK-336, as measured by urinary 13C2-oxalate, thus achieving proof of mechanism in HVs.

#3278 HUMAN PHARMACOKINETICS OF MULTIPLE, STEADY-STATE DOSING OF IPTACOPAN

Abstract Background and Aims Iptacopan (LNP023) is a first-in-class, oral, proximal complement inhibitor that specifically binds to Factor B and inhibits the alternative complement pathway (AP). Current Phase III studies of iptacopan focus on diseases associated with AP activation, such as paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis, IgA nephropathy, and atypical hemolytic uremic syndrome. Early modeling efforts suggested that an iptacopan concentration of ∼1000 ng/mL would provide near-maximal AP inhibition. The aim of this study was to evaluate the PK of oral iptacopan in healthy subjects to determine the dose that results in a ∼1000-ng/mL mean steady-state concentration over the entire 12-h dosing interval. Method In this blinded, controlled, randomized study, a total of 32 healthy subjects were enrolled into 5 cohorts receiving twice-daily dosing for 14 days: placebo (n = 8) or iptacopan 25, 50, 100, or 200 mg (n = 6 per group). Plasma iptacopan concentration was intensively measured for 72 hours post day 14 dose using a validated LC-MS/MS assay (LLOQ = 1 ng/mL). Results Iptacopan treatment was safe and well tolerated at all dose levels. Iptacopan steady-state concentration-time curves are shown below. Iptacopan was rapidly absorbed, with a median Tmax of approximately 2 hours (Figure 1). The mean half-life was moderately long at 18 to 25 hours. The inter-subject variability (CV%) of iptacopan Cmax and AUCinf was low at approximately 12% to 27%, and both parameters were under-dose proportional with increasing dose. At all time points from 0 to 12 hours, mean iptacopan concentration for the 200-mg dose cohort was &amp;gt;1000 ng/mL. Conclusion Iptacopan was rapidly absorbed, had low inter-subject variability, and a moderately long half-life. Only the 200-mg b.i.d dose produced mean iptacopan concentrations of ≥1000 ng/mL over the dosing interval, and thus is expected to result in near-complete, continuous AP inhibition. These results support the rationale for use of iptacopan 200 mg twice daily as the therapeutic dose in ongoing clinical trials and provide evidence of durable AP inhibition in patients administered oral iptacopan therapy.

An assessment of nicotine pharmacokinetics and subjective effects of the pulze heated tobacco system compared with cigarettes

Nicotine delivery and subjective effects are determinants of the ability of potentially less harmful tobacco products such as heated tobacco products (HTPs) to support adult smokers in switching away from cigarettes, and therefore to support tobacco harm reduction. This open-label, randomised, crossover, clinical study in 24 healthy adult smokers study assessed nicotine pharmacokinetics and subjective effects of the Pulze Heated Tobacco System (HTS; Pulze HTP device and three iD stick variants—Intense American Blend, Regular American Blend and Regular Menthol) compared with subjects’ usual brand cigarettes (UBC). Cmax and AUCt were highest for UBC and significantly lower for each Pulze HTS variant. Cmax and AUCt were significantly higher for Intense American Blend compared with Regular American Blend, while AUCt was significantly higher for Intense American Blend compared with Regular Menthol. Median Tmax was lowest (i.e., nicotine delivery was fastest) for subjects’ usual brand cigarettes and similar across the iD stick variants, although no between-product differences were statistically significant. All study products reduced urges to smoke; this effect was greatest for cigarettes although this was not statistically significant. Product evaluation scores for each Pulze HTS variant in the domains of ‘satisfaction’, ‘psychological reward’ and ‘relief’ were similar, and lower than those for UBC. These data demonstrate that the Pulze HTS effectively delivers nicotine and generates positive subjective effects, including satisfaction and reduced urge to smoke. This supports the conclusion that the Pulze HTS may be an acceptable alternative to cigarettes for adult smokers while having a lower abuse liability than cigarettes.

Phase 1, randomized, open-label, single-dose, crossover study to evaluate the bioequivalence of four formulations of oral rivoceranib tablets in healthy subjects.

e15122 Background: Rivoceranib is a novel oral tyrosine kinase inhibitor that potently and selectively inhibits VEGFR2. Rivoceranib is being investigated for indications targeted towards solid malignancies as either monotherapy or in combination with other anticancer therapies. Herein, we assessed the bioequivalence of a single dose of rivoceranib administered as 4 different formulations in healthy subjects. Methods: This single-center, open-label, randomized, single-dose, 4-way crossover study evaluated the bioequivalence of 4 different formulations of rivoceranib oral tablets in healthy adults. Each subject participated in 4 treatment periods, where they were randomized to 1 of 4 sequences: ABCD, BDAC, CADB, and DBAC (Formulation A = rivoceranib 250 mg tablet/clinical formulation used in the pivotal phase 3 study, Formulation B = rivoceranib 200 mg tablet/clinical formulation used in early clinical studies, Formulation C = rivoceranib 250 mg tablet/formulation to be developed for future use, Formulation D = rivoceranib 250 mg tablet/to-be-marketed formulation). Results: Of the 60 subjects enrolled, 66.7% were male, 88.3% were white, and median age was 43 years. The median plasma rivoceranib Tmax was similar following all treatments (2 hours post-dose). The 90% CIs around the geometric mean ratios (GMRs) of plasma rivoceranib AUC0-t, AUC0-inf, and Cmax for Formulation B vs. Formulation A and Formulation D vs. Formulation A were within the 80-125% reference interval, demonstrating bioequivalence between Formulation B and Formulation A as well as Formulation D and Formulation A. The 90% CIs around the GMRs of plasma rivoceranib AUC0-t, AUC0-inf, and Cmax for Formulation C vs. Formulation A were slightly outside of the 80%-125% reference interval. Conclusions: Formulations B (clinical formulation used in early clinical studies) and D (to-be-marketed formulation) were bioequivalent to Formulation A (clinical formulation used in the pivotal phase 3 study). Formulation C (formulation to be developed for future use) and Formulation A were similar, but the difference was slightly outside of the bioequivalence criteria. It remains to be evaluated whether the difference in bioavailability between Formulation C and Formulation A is clinically meaningful. Clinical trial information: NCT05287360 . [Table: see text]

GFH018, a small molecular inhibitor targeting TGF-βRI kinase, in patients with advanced solid tumors: Final results of the phase I study.

e15117 Background: TGF-β signaling pathway activation inhibits anti-tumor response, promoting tumor progression and metastasis. GFH018, a small molecule inhibiting TGF-βRI kinase, blocks TGF-β signaling transduction thus downregulates its pathway. GFH018 had significant growth inhibitory effects on several in vivo tumor models as monotherapy and demonstrated synergistic effects combined with anti-PD-1 antibody. This phase I study assessed safety, PK, and preliminary efficacy of GFH018 in pts with advanced solid tumors. Here we report the final results from the completed study. Methods: The study includes a modified 3 + 3 dose escalation and an expansion part. Adult pts with advanced solid tumors failed to standard treatments were enrolled. The starting dose was 5 mg and up to 8 cohorts were planned. In the escalation part, pts were administrated with GFH018 BID (14d-on/14d-off) two days after receiving single dose orally on C1D1. The subsequent cycle was 28 days. The safety of 85 mg BID 7d-on/7d-off was also explored. AEs were graded per NCI-CTCAE v5.0. PK was analyzed using a non-compartmental method. Efficacy was evaluated per RECIST 1.1. Blood samples were collected for biomarker analysis. Results: From Aug 1, 2019 to Aug 11, 2022, fifty pts (14d-on/14d-off: 5 mg [n = 4], 10 mg [n = 3], 20mg [n = 4], 30 mg [n = 7], 40 mg [n = 4], 50 mg [n = 4], 65 mg [n = 6] and 85 mg [n = 12]; 7d-on/7d-off: 85 mg [n = 6]) were enrolled. Thirty-seven pts (74.0%) had ≥3 prior systemic treatment lines. No DLT was observed, and the MTD was not reached. No significant cardiotoxicities or bleeding events were reported. Forty-three pts (86.0%) had at least one treatment related AE (TRAE), and 3 (6.0%) experienced ≥ G3 TRAEs. The most common TRAEs (all G/≥G3) were proteinuria (26.0%/2.0%), AST increased (18.0%/0), anemia (14.0%/2.0%), ALT increased (12.0%/0), GGT increased, ALP increased, and LDH increased (all 10.0%/0). Common TRAEs (≥2 pts) for 7d-on/7d-off was lymphocyte decreased (2/6) with no ≥ G3 reported. No significant differences were observed between the two regimens in safety. GFH018 was absorbed rapidly with median Tmax of 0.50 ~0.96h and displayed a linear pharmacokinetic behavior with T1/2 of 4.08~10.92 h (5~85 mg). Nine pts achieved stable disease (SD), among whom a pt with thymic carcinoma receiving 65 mg achieved tumor shrinkage (maximum target lesion decreased by 18.4%). Results for 85 mg BID, 14d-on/14d-off showed a DCR of 25.0%. The RP2D was 85 mg BID, 14d-on/14d-off. Serum TGF-β1 level was not associated with clinical responses. Available pharmacodynamic data of SMAD2 phosphorylation levels in peripheral blood mononuclear cells (PBMCs) were not reliable due to assay issues. Conclusions: GFH018 shows a favorable safety profile and preliminary anti-tumor activity. The clinical studies of GFH018 in combination with Toripalimab and with Toripalimab + concurrent chemoradiotherapy are ongoing. Clinical trial information: NCT05051241 .

First-in-human phase 1 study of pimicotinib (ABSK021), a CSF-1R inhibitor, in patients with advanced solid tumors.

3100 Background: Colony-stimulating factor 1 (CSF-1) pathway is involved in the development of various types of cancer. Pimicotinib is an orally available, selective, potent small molecule CSF-1R inhibitor with significant pre-clinical anti-tumor activity. Here we present the results of the phase 1 trial. Methods: The escalation part employed a 3+3 design with a starting dose of 25 mg QD (28-day/ cycle) to determine the maximum tolerated dose (MTD) and the recommended dose for expansion (RDE). Additional pts with selected tumor types including pancreatic carcinoma, triple-negative breast cancer, lung cancer, and sarcoma were treated at RDE in the expansion part for further evaluation. Tenosynovial giant cell tumor (TGCT) cohorts were analyzed and reported separately. Results: As of December 31, 2022, 74 pts received at least one dose of pimicotinib at 25 mg (n=6), 50 mg (n=58), 75 mg (n=8), or 100 mg (n=2) QD. respectively. Median age was 59 y; 68.9% were female; 47.3% were white, 33.8% were Asian and 18.9% were African American. 74.3% were ECOG PS 1; 85.1% had metastasis; 67.6% had ≥3 lines of prior systemic anti-tumor therapies. Median duration of treatment was 49.5 days (range 4-377). Treatment-related adverse events (TRAEs), Grade ≥3 TRAEs, and serious TRAEs occurred in 74.3%, 21.6%, and 4.1% of pts, respectively. The most common TRAEs (≥20%) were serum enzyme elevations, including CPK, AST and LDH, which were all believed to be pimicotinib MOA related, with CPK increase (14.9%) being the only Grade ≥3 TRAE reported in ≥10% of pts. 3 pts (4.1%) reported serious TRAEs of ascites, blood bilirubin increase, and vaginal hemorrhage. After single and multiple dosing, pimicotinib plasma exposure increased slightly less than dose proportion. The rapid oral absorption (median tmax of 0.87 - 1.52 hrs) with moderate terminal t1/2 (mean t1/2 ranges: 43.6 - 63.5 hrs) suggested sustained drug exposure was achieved with a once daily dosing schedule. No dose adjustment was needed based on tested covariates including weight, age and race. Pimicotinib treatment led to a more than 85% reduction of non-classical monocytes (NCM) across all dose levels. Plasma CSF-1 levels were significantly increased from 25mg QD to 50mg QD and reached a plateau at 50mg QD, with ~40-fold maximal induction. Reduced CD163+ macrophages in skin and tumor tissues were seen at 50mg QD. All tested doses showed adequate inhibition of NCM, and CSF-1 change showed a positive correlation with plasma pimicotinib concentration. The MTD and RDE were determined as 75 mg QD and 50 mg QD. Conclusions: Tolerable safety profile and favorable PK/PD properties supported pimicotinib to be further evaluated in advanced solid tumors, including combinations. Clinical trial information: NCT04192344 .

Pharmacokinetics, Mass Balance, Tissue Distribution, and Metabolism of [3H]Catalpol in Rats: the Main Bioactive Component of Rehmannia glutinosa for the Treatment of Ischemic Stroke.

Catalpol, one of the main bioactive components isolated from Rehmannia glutinosa, was developed by Suzhou Youseen for the treatment of ischemic stroke; however, preclinical information about its absorption, distribution, metabolism, and excretion (ADME) in animals is inadequate. This study aimed to illuminate the pharmacokinetics (PK), mass balance (MB), tissue distribution (TD), and metabolism of catalpol after a single intragastric administration of 30 mg/kg (300 μCi/kg) [3H]catalpol in rats. Radioactivity in plasma, urine, feces, bile, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling was characterized by UHPLC-β-ram and UHPLC-Q-Exactive plus MS. The radio pharmacokinetic results showed that catalpol was rapidly absorbed by Sprague‒Dawley (SD) rats, with a median Tmax of 0.75 h and an arithmetic mean half-life (t1/2) of the total radioactivity of approximately 1.52 h in plasma. The mean recovery of the total radioactive dose was 94.82%±1.96% over 168 h postdose (57.52%±12.50% in the urine and 37.30%±12.88% in the feces). The parent drug catalpol was the predominant drugrelated substance in rat plasma and urine, while M1 and M2, two unidentified metabolites, were detected in feces. When [3H]catalpol was incubated with β-glucosidase and rat intestinal flora, we found that the same metabolites M1 and M2 were produced in both incubation systems. Catalpol was excreted mainly through the urine. The drug-related substances were primarily concentrated in the stomach, large intestine, bladder, and kidney. Only the parent drug was detected in the plasma and urine, and M1 and M2 were detected in the feces. We speculate that the metabolism of catalpol in rats was mainly mediated by the intestinal flora, resulting in an aglycone-containing hemiacetal hydroxyl structure.

Pharmacokinetics, safety, and antitumor activity of talazoparib monotherapy in Chinese patients with advanced solid tumors

Talazoparib, a poly(ADP-ribose) polymerase inhibitor, has demonstrated efficacy in the treatment of advanced breast and prostate cancers in Western populations. This open-label, phase 1 study investigated the pharmacokinetics, safety, and antitumor activity of talazoparib monotherapy in Chinese patients with advanced solid tumors. Molecularly unselected patients (≥18 years) with advanced solid tumors resistant to standard therapy received talazoparib (oral, 1 mg once daily). Primary endpoint was characterization of single-dose and steady-state pharmacokinetics. Secondary endpoints evaluated safety, unconfirmed objective response rate (ORR), and duration of response. The safety population comprised 15 Chinese patients (median [range] age 53.0 [31.0–72.0] years). Single-dose median time to first occurrence of maximum observed concentration was 1.9 h; concentrations then declined with a mean terminal half-life (t1/2) of 67 h. Following multiple dosing, median Tmax was approximately 1.85 h with steady state generally achieved by Day 21. Treatment-related treatment-emergent adverse events (TEAEs) occurred in 86.7% (13/15) of patients (grade 3, 20.0%; grade 4, 13.3%). Two patients (13.3%) experienced serious treatment-related TEAEs. ORR (investigator-assessed) was 6.7% (95% CI: 0.2–31.9); one patient (6.7%) had a partial response. In patients with measurable disease at baseline, the ORR was 9.1% (1/11; 95% CI: 0.2–41.3; duration of response: 114 days); stable disease was achieved by 36.4% (4/11) of patients, and 54.5% (6/11) progressed by data cut-off. In Chinese patients with advanced solid tumors, the pharmacokinetic profile of talazoparib monotherapy (1 mg/day) was consistent with other patient populations. TEAEs were generally manageable with no unexpected safety findings. (ClinicalTrials.gov: NCT04635631 [prospectively registered November 19, 2020])

Does the Ethnic Difference Affect the Pharmacokinetics of Favipiravir? A Pharmacokinetic Study in Healthy Egyptian Volunteers and Development of Level C In-vitro In-vivo Correlation.

Favipiravir is an antiviral drug used to treat influenza and is also being investigated for the treatment of SARS-CoV-2. Its pharmacokinetic profile varies depending on ethnic group. The present research examines the pharmacokinetic features of favipiravir in healthy male Egyptian volunteers. Another goal of this research is to determine the optimum dissolution testing conditions for immediate release tablets. In vitro dissolution testing was investigated for favipiravir tablets in three different pH media. The pharmacokinetic features of favipiravir were examined in 27 healthy male Egyptian volunteers. The parameter "AUC0-t" vs. percent dissolved was used to develop level C in vitro in vivo correlation (IVIVC) to set the optimum dissolution medium to achieve accurate dissolution profile for favipiravir (IR) tablets. The in vitro release results revealed significant difference among the three different dissolution media. The Pk parameters of twenty-seven human subjects showed mean value of Cpmax of 5966.45 ng/mL at median tmax of 0.75 h with AUC0-∞ equals 13325.54 ng.h/mL, showing half-life of 1.25 h. Level C IVIVC was developed successfully. It was concluded that Egyptian volunteers had comparable Pk values to American and Caucasian volunteers, however they were considerably different from Japanese subjects. AUC0-t vs. % dissolved was used to develop level C IVIVC to set the optimum dissolution medium. Phosphate buffer medium (pH 6.8) was found to be the optimum dissolution medium for in vitro dissolution testing for Favipiravir IR tablets.

Rilzabrutinib, a reversible covalent Bruton's tyrosine kinase inhibitor: Absorption, metabolism, excretion and absolute bioavailability in healthy participants.

This single-center, open-label, non-randomized, two-part, phase I study was conducted 1) to evaluate the absolute oral bioavailability of rilzabrutinib 400 mg tablet following an IV microtracer dose of ~100 μg [14C]-rilzabrutinib (~1 μCi) and single oral dose of 400 mg rilzabrutinib tablet (Part 1), and 2) to characterize the absorption, metabolism, and excretion (AME) of 14C-radiolabeled rilzabrutinib following single oral dose (300 mg) of [14C]-rilzabrutinib (~1000 μCi) (administered as a liquid) in healthy male participants (Part 2). A total of 18 subjects were enrolled (n=8 in Part 1; n=10 in Part 2). The absolute bioavailability of 400 mg rilzabrutinib oral tablet was low (less than 5%). In Part 1, rilzabrutinib was absorbed rapidly after single oral dose of rilzabrutinib 400 mg tablet with a median (range) tmax value of 2.03 h (1.83-2.50). The geometric mean (CV%) t1/2 following the oral dose and IV microtracer dose of ~100 μg [14C]-rilzabrutinib, were 3.20 (51.0%) and 1.78 (37.6%) hours, respectively. In Part 2, rilzabrutinib was also absorbed rapidly following single oral dose of 300 mg [14C]-rilzabrutinib solution with a median (range) tmax value of 1.00 h (1.00-2.00). The majority of total radioactivity was in the feces for both non-bile collection subjects (92.9%) and bile collection subjects (87.6%), and approximately 5% of radioactivity was recovered in urine after oral administration. Urinary excretion of unchanged rilzabrutinib was low (3.02%). The results of this study advance the understanding of the absolute bioavailability and AME of rilzabrutinib and can help inform its further investigation.