Asciminib in Newly Diagnosed Chronic Myeloid Leukemia.

BACKGROUND: Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs). METHODS: In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum. RESULTS: A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, -5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%). CONCLUSIONS: In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).

Complete Substrate Inhibition of Cytochrome P450 2C8 by AZD9496, an Oral Selective Estrogen Receptor Degrader.

AZD9496 ((E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid) is an oral selective estrogen receptor degrader currently in clinical development for treatment of estrogen receptor-positive breast cancer. In a first-in-human phase 1 study, AZD9496 exhibited dose nonlinear pharmacokinetics, the mechanistic basis of which was investigated in this study. The metabolism kinetics of AZD9496 were studied using human liver microsomes (HLMs), recombinant cytochrome P450s (rP450s), and hepatocytes. In addition, modeling approaches were used to gain further mechanistic insights. CYP2C8 was predominantly responsible for biotransformation of AZD9496 to its two main metabolites whose rate of formation with increasing AZD9496 concentrations exhibited complete substrate inhibition in HLM, rCYP2C8, and hepatocytes. Total inhibition by AZD9496 of amodiaquine N-deethylation, a specific probe of CYP2C8 activity, confirmed the completeness of this inhibition. The commonly used substrate inhibition model analogous to uncompetitive inhibition fit poorly to the data. However, using the same model but without constraints on the number of molecules occupying the inhibitory binding site (i.e., nS1ES) provided a significantly better fit (F test, P< 0.005). With the improved model, up to three AZD9496 molecules were predicted to bind the inhibitory site of CYP2C8. In contrast to previous studies showing substrate inhibition of P450s to be partial, our results demonstrate complete substrate inhibition of CYP2C8 via binding of more than one molecule of AZD9496 to the inhibitory site. As CYP2C8 appears to be the sole isoform catalyzing formation of the main metabolites, the substrate inhibition might explain the observed dose nonlinearity in the clinic at higher doses.

Pharmacokinetics, Pharmacodynamics, Tolerability, and Food Effect of Cenerimod, a Selective S1P1 Receptor Modulator in Healthy Subjects.

The pharmacokinetics, pharmacodynamics, tolerability, and food effect of cenerimod, a potent sphingosine-1-phosphate subtype 1 receptor modulator, were investigated in three sub-studies. Two double-blind, placebo-controlled, randomised studies in healthy male subjects were performed. Cenerimod was administered either as single dose (1, 3, 10 or 25 mg; Study 1) or once daily for 35 days (0.5, 1, 2 or 4 mg; Study 2). A two-period cross-over, open-label study was performed to assess the food effect (1 mg, Study 3). The pharmacokinetic profile of cenerimod was characterised by a tmax of 5.0-6.2 h. Terminal half-life after single and multiple doses ranged from 170 to 199 h and 283 to 539 h, respectively. Food had no relevant effect on the pharmacokinetics of cenerimod. A dose-dependent decrease in lymphocyte count was observed after initiation of cenerimod and reached a plateau (maximum change from baseline: -64%) after 20-23 days of treatment. Lymphocyte counts returned to baseline values at end-of-study examination. One serious adverse event of circulatory collapse (25 mg dose group, maximum tolerated dose: 10 mg) and adverse events of mild-to-moderate intensity were reported. Treatment initiation was associated with transient decreases in heart rate and blood pressure at doses >1 and ≥10 mg, respectively.

Mass balance, pharmacokinetics and metabolism of the selective S1P1 receptor modulator ponesimod in humans.

1. Ponesimod [(R)-5-[3-chloro-4-(-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolyl-thiazolidin-4-one] is an orally administered, selective S1P1 receptor modulator that blocks the egress of lymphocytes from lymphoid organs and reduces the availability of circulating effector T/B-cells. 2. The mass balance, pharmacokinetics and metabolism of 40 mg (14)C-ponesimod were investigated in six healthy male subjects. The total radioactivity in whole blood, plasma, urine, faeces and expired CO2 was determined by liquid scintillation counting. Metabolite profiling was performed by high-performance liquid chromatography and detection by mass spectrometry. 3. The majority of the radioactivity (% of administered dose) was recovered in faeces (57.3-79.6%), followed by urine (10.3-18.4%) and a small proportion in CO2 from expired air (0.6-1.9%). The average cumulative recovery (mass balance) of (14)C-associated radioactivity in faeces and urine was 77.9% of the administered dose. Unchanged ponesimod made up 25.9% of total radioactivity in faeces; none was detected in urine. Ponesimod was extensively metabolised and two pharmacologically inactive metabolites, M12 (ACT-204426) and M13 (ACT-338375), were detected in the circulation. M12 corresponded to 8.1% and M13 to 25.7% of the total drug-related radioactive exposure (AUC0-∞) in plasma. M12 was highly abundant in faeces (22.3% of total radioactivity) and to a smaller extent in urine (2.5% of total radioactivity).

Effects of ponesimod, a selective S1P1 receptor modulator, on the pharmacokinetics of a hormonal combination contraceptive.

PURPOSE: To determine the effects of steady-state concentrations of the selective S1P1 receptor modulator ponesimod on the pharmacokinetics (PK) of a single dose of a combined oral contraceptive, containing 1 mg norethisterone (NET) and 35 µg ethinyl estradiol (EE) and to investigate the effects on heart rate at different ponesimod doses within an up-titration regimen prior to co-administration of the contraceptive. METHODS: Twenty-two healthy women (age: 29-60 years) received twice a single oral dose of the combined oral contraceptive, alone or in combination with multiple doses of 40 mg ponesimod attained by an up-titration regimen. Heart rate (HR) effects were assessed on the first day of each up-titration level. PK parameters of NET and EE were determined by non-compartmental analysis. RESULTS: Geometric mean ratios (ponesimod and contraceptive / contraceptive alone) of Cmax and AUC0-24 of NET were 0.87 (90 % CI: 0.80, 0.94) and 0.84 (90 % CI: 0.76, 0.93), respectively. Geometric mean ratios of Cmax and AUC0-24 of EE were 0.94 (90 % CI: 0.86, 1.03) and 0.95 (90 % CI: 0.89, 1.01), respectively. The maximum mean HR reduction after the first dose of 10 mg ponesimod was 12.4 bpm (SD ± 6.2) at 2.5 h post-dose. On Day 4 (first dose of 20 mg) and Day 7 (first dose of 40 mg) the maximum mean HR reduction was 4.3 bpm (SD ± 5.7) and 1.4 (SD ± 6.4), respectively, at 2.5 h post-dose compared to baseline. CONCLUSION: No clinically relevant PK interactions between ponesimod and the combined oral contraceptive were observed, therefore, efficacy of hormonal contraceptives is not expected to be affected by concomitant administration of ponesimod. The up-titration regimen showed that HR reductions are diminished upon repeated ponesimod administration.

Effects of ethnicity and sex on the pharmacokinetics and pharmacodynamics of the selective sphingosine-1-phosphate receptor 1 modulator ponesimod: a clinical study in Japanese and Caucasian subjects.

The aim of this study was to evaluate the relative pharmacokinetic (PK) and pharmacodynamic (PD) properties of a single dose of ponesimod, an oral and selective sphingosine-1-phosphate receptor 1 (S1P1) modulator, in Japanese and Caucasian healthy subjects and explore the effects of sex on PK. Subjects received a single 40-mg dose of ponesimod in a single-centre, open-label, parallel-group study design. Ten Japanese and 10 Caucasian healthy subjects (age: 22-45 years, 1:1 sex ratio) participated in the study and were matched for body weight (±10%). Ponesimod concentration in plasma was determined by liquid chromatography tandem mass spectrometry, and PK parameters were obtained by non-compartmental analysis. Total lymphocyte count served as PD marker. Adverse events (AEs), laboratory values, electrocardiography (12-lead ECG), and vital signs were assessed for safety and tolerability. Administration of ponesimod resulted in similar PK parameters between the two ethnic groups, with a 16% higher exposure [AUC0-∞ of 7,368 ng ∙ h/ml (95% CI: 6,059-8,962) vs. 6,353 ng ∙ h/ml (4,950-8,154)] and a 17% longer terminal elimination half-life [32.9 h (30.1-36.0) vs. 28.1 h (23.4-33.6)] in Japanese compared to Caucasian subjects. Exposure was slightly higher in female subjects [7,488 ng ∙ h/ml (5,983-9,371)] than in male subjects [6,252 ng ∙ h/ml (5,031-7,771)]. The maximum mean lymphocyte count decrease from baseline, observed 6 h after receiving the dose in both groups, was similar in Japanese subjects (61.8%) and Caucasians (62.5%). The maximum mean heart rate (ECG) reduction from baseline was similar, with a difference of 4.2 bpm between Caucasian and Japanese subjects, observed 2.5 h after receiving the dose in both ethnic groups. There were no clinically relevant changes in other safety variables. No serious AEs were reported during the study. This study showed that the PK and PD profile of ponesimod was similar in Japanese and Caucasian subjects. No unexpected safety findings were reported. No dose adjustment is deemed necessary for Japanese subjects compared to Caucasians.

Elucidation of the metabolic pathways and the resulting multiple metabolites of almorexant, a dual orexin receptor antagonist, in humans.

Almorexant [(2R)-2-{(1S)-6, 7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide], a tetrahydroisoquinoline derivative, is a dual orexin receptor antagonist with sleep-promoting properties in both animals and humans. This study investigated the disposition, metabolism, and elimination of almorexant in humans. After oral administration of a 200-mg dose of ¹4C-almorexant, almorexant was rapidly absorbed (Tmax = 0.8 hour), and the apparent terminal half-life (t(1/2)) was 17.8 hours. The radioactive dose was almost completely recovered with 78.0% of the administered radioactive dose found in feces and 13.5% in urine. Unchanged almorexant was not found in urine and represented 10% of the administered dose in feces. In total, 47 metabolites were identified of which 21 were shown to be present in plasma. There are four primary metabolites, the isomeric phenols M3 and M8, formed by demethylation, the aromatic isoquinolinium ion M5, formed by dehydrogenation, and M6, formed by oxidative dealkylation with loss of the phenylglycine moiety. Most of the subsequent products are formed by permutations of these primary metabolic reactions followed by conjugation of the intermediate phenols with glucuronic or sulfonic acid. The percentage of dose excreted in urine or feces for any of the metabolites did not exceed 10% of the administered radioactive dose, nor did any of the metabolites represent more than 10% of the total drug-related exposure. In conclusion, after rapid absorption, almorexant is extensively metabolized, and excretion of metabolites in feces is the predominant route of elimination in humans.

Differential modulation of ROS signals and other mitochondrial parameters by the antioxidants MitoQ, resveratrol and curcumin in human adipocytes.

Mitochondrial reactive oxygen species (ROS) have been demonstrated to play an important role as signaling and regulating molecules in human adipocytes. In order to evaluate the differential modulating roles of antioxidants, we treated human adipocytes differentiated from human bone marrow-derived mesenchymal stem cells with MitoQ, resveratrol and curcumin. The effects on ROS, viability, mitochondrial respiration and intracellular ATP levels were examined. MitoQ lowered both oxidizing and reducing ROS. Resveratrol decreased reducing and curcumin oxidizing radicals only. All three substances slightly decreased state III respiration immediately after addition. After 24 h of treatment, MitoQ inhibited both basal and uncoupled oxygen consumption, whereas curcumin and resveratrol had no effect. Intracellular ATP levels were not altered. This demonstrates that MitoQ, resveratrol and curcumin exert potent modulating effects on ROS signaling in human adipocyte with marginal effects on metabolic parameters.

Almorexant effects on CYP3A4 activity studied by its simultaneous and time-separated administration with simvastatin and atorvastatin.

PURPOSE: To characterise further the previously observed cytochrome P450 3A4 (CYP3A4) interaction of the dual orexin receptor antagonist almorexant. METHODS: Pharmacokinetic interactions were investigated (n = 14 healthy male subjects in two treatment groups) between almorexant at steady-state when administered either concomitantly or 2 h after administration of single doses of simvastatin (40 mg) or atorvastatin (40 mg). RESULTS: Almorexant dose-dependently increased simvastatin exposure (AUC0-∞) when administered concomitantly [geometric mean ratios (90 % CI): 2.5 (2.1, 2.9) (100 mg), 3.9 (3.3, 4.6) (200 mg)], but not Cmax [3.7 (3.0, 4.5) for both doses]. Time-separated administration resulted in relevant reductions of the interaction [AUC0-∞: 1.4 (1.2, 1.7) (100 mg), 1.7 (1.5, 2.0) (200 mg); Cmax: 1.5 (1.3, 1.9) (100 mg), 1.9 (1.6, 2.4) (200 mg)]. Similar results were obtained for hydroxyacid simvastatin. Independent of almorexant dose and relative time of administration, AUC0-∞ and Cmax of atorvastatin increased (ratios ranged from 1.1 to 1.5). AUC0-∞ and Cmax of o-hydroxy atorvastatin decreased dose-independently [AUC0-∞: 0.8 (0.8, 0.9) (100 mg), 0.6 (0.5, 0.6) (200 mg); Cmax: 0.3 (0.3, 0.4) (100 mg), 0.2 (0.2, 0.3) (200 mg)] when atorvastatin was concomitantly administered. Cmax of o-hydroxy atorvastatin slightly decreased (0.8 for both doses) following time-separated administration; AUC0-∞ was unchanged. CONCLUSIONS: Whereas almorexant increased simvastatin exposure dose- and relative time of administration-dependently, atorvastatin exposure increased to a smaller extent and irrespective of dose and time. This suggests that the observed interaction of almorexant with simvastatin is mainly caused by intestinal CYP3A4 inhibition, whereas the interaction with atorvastatin is more due to hepatic CYP3A4 inhibition.

Pharmacokinetic interactions of almorexant with midazolam and simvastatin, two CYP3A4 model substrates, in healthy male subjects.

PURPOSE: Pre-clinical experiments have shown that almorexant, a dual orexin receptor antagonist, is able to inhibit cytochrome P450 3A4 (CYP3A4). Therefore, a study was conducted to investigate the effects of multiple-dose almorexant on the pharmacokinetics of midazolam and simvastatin, two CYP3A4 model substrates. METHODS: Fourteen healthy male subjects were enrolled in an open-label, randomized, two-way crossover study. Treatment period A consisted of a single oral dose of 2 mg midazolam on day 1 and 40 mg simvastatin on day 3. In treatment period B, subjects received 200 mg almorexant once daily for 9 days together with a single oral dose of midazolam on day 7 and simvastatin on day 9. RESULTS: Concomitant administration of midazolam with almorexant at steady-state levels, achieved within 4-5 days, resulted in an increase of 1.2-fold [90 % confidence interval (CI) 1.0-1.4], 1.4-fold (90 % CI 1.2-1.6), and 1.3-fold (90 % CI 1.2-1.4) in the maximum plasma concentration (C(max)), area under the concentration-time curve from time 0 to infinity (AUC(0-∞)), and terminal half-life (t(1/2)), respectively, of midazolam; the time to peak plasma concentration (t(max)) was unchanged. Whereas C(max) and t(max) were not influenced by almorexant, the AUC(0-∞) of hydroxy-midazolam increased by 1.2-fold (90 % CI 1.1-1.4) and the t(1/2) by 1.3-fold (90 % CI 1.0-1.5). Concomitant administration of simvastatin with almorexant at steady-state resulted in an increase of 2.7-fold (90 % CI 2.0-3.7) and 3.4-fold (90 % CI 2.6-4.4) in C(max) and AUC(0-∞), respectively, for simvastatin; the t(1/2) and t(max) were unchanged. The C(max) and AUC(0-∞) of hydroxyacid simvastatin both increased by 2.8-fold, with 90 % CIs of 2.3-3.5 and 2.2-3.5, respectively; the t(max) increased by 2 h and the t(1/2) was unchanged. The urinary 6-ß-hydroxycortisol/cortisol ratio was unaffected by almorexant. CONCLUSIONS: Our results suggest that the observed interaction was caused by the inhibition of CYP3A4 activity, most probably at the gut level.

Relative Bioavailability and Food Effect of Asciminib Pediatric Mini-tablet Formulation Compared to the Reference Tablet Formulation in Healthy Adult Participants.

Asciminib, a first-in-class allosteric BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP) is used in the treatment of chronic myeloid leukemia. We describe a randomized, single-dose, open-label, four-period crossover study in healthy adult participants (N = 24) which evaluated the relative bioavailability of a single 40-mg dose of asciminib in pediatric formulation (1-mg mini-tablets) compared with the reference adult tablet under fasted conditions. Additionally, the effect of food on the bioavailability of the mini-tablet formulation was evaluated. Under fasted conditions, asciminib exposure was similar for both formulations (geometric mean [Gmean ] area under the concentration-time curve from time 0 to infinity [AUCinf ] 5970 and 5700 ng ×h/mL, respectively). Food decreased the AUCinf and maximum plasma concentration (Cmax ) of the asciminib mini-tablets; this effect was more pronounced with a high-fat meal (Gmean ratios [90% confidence interval]: fasted/low-fat meal, 0.42 [0.38-047], 0.32 [0.28-0.37], respectively; fasted/high-fat meal, 0.30 [0.27-0.34], 0.22 [0.19-0.25], respectively). The mini-tablets were assessed to be easy to ingest with good palatability. Asciminib doses for a pivotal pediatric clinical trial will be defined using physiologically based pharmacokinetic modeling, which will consider the age and the higher food effect observed with the mini-tablets.

Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results.

Asciminib is approved for patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10-200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.

Absolute oral bioavailability of almorexant, a dual orexin receptor antagonist, in healthy human subjects.

BACKGROUND/AIMS: The aim of this single-center, open-label study was to assess the absolute bioavailability of an oral (tablet) versus intravenous formulation of almorexant in healthy subjects. METHODS: A pilot phase in 3 healthy male subjects, which preceded the main study, consisted of a single 30-min intravenous infusion of 10 mg almorexant. Its objectives were to ensure the tolerability of the intravenous formulation and to select the intravenous dose for the main study. The main study was a randomized, two-way crossover study in 20 healthy subjects (10 males and 10 females). Subjects received a single oral dose of 200 mg almorexant and a single 30-min intravenous infusion of 20 mg almorexant. RESULTS: All 23 subjects completed the study as planned. Almorexant was well tolerated; the main observed adverse events were somnolence and fatigue. A geometric mean total body clearance of 43 l/h (95% CI 39-47) and a volume of distribution of 683 liters (95% CI 552-845) were determined. The absolute oral bioavailability of almorexant was 11.2% (90% CI 9.6-13.1). CONCLUSION: Almorexant seems to possess a pronounced first-pass effect and metabolism.

Pharmacokinetic drug interactions of asciminib with the sensitive cytochrome P450 probe substrates midazolam, warfarin, and repaglinide in healthy participants.

Asciminib, a first-in-class BCR-ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP), is a new treatment option for patients with chronic myeloid leukemia who no longer benefit from currently approved tyrosine kinase inhibitors. In vitro, asciminib reversibly inhibits cytochrome P450 (CYP) 3A4/5, CYP2C9, and CYP2C8. This phase I, open-label, two-stage study in healthy participants evaluated the effect of asciminib (40 mg b.i.d. at steady-state) as a potential perpetrator on single-dose pharmacokinetics of a two-drug cocktail containing midazolam (CYP3A substrate) and warfarin (CYP2C9 substrate) in stage 1 (n = 22), and of repaglinide (CYP2C8 substrate) in stage 2 (n = 25). For midazolam plus asciminib versus midazolam, geometric mean (Gmean ) ratios (90% confidence interval) for midazolam area under the curve from zero to infinity (AUCinf ) and maximum plasma concentration (Cmax ) were 1.28 (1.15, 1.43) and 1.11 (0.96, 1.28), respectively. For warfarin plus asciminib versus warfarin, Gmean ratios for S-warfarin AUCinf and Cmax were 1.41 (1.37, 1.45) and 1.08 (1.04, 1.13), respectively. Results for R-warfarin were in line with those for S-warfarin. For repaglinide plus asciminib versus repaglinide, Gmean ratios for AUCinf and Cmax were 1.08 (1.02, 1.14) and 1.14 (1.01, 1.28), respectively. The treatments were generally well tolerated, and the asciminib safety profile was consistent with previous studies of asciminib in the absence of probe substrates. Overall, the results indicate that asciminib (40 mg b.i.d.) is a weak inhibitor of CYP3A and CYP2C9 and has no meaningful effect on CYP2C8.

Pharmacokinetics of asciminib in the presence of CYP3A or P-gp inhibitors, CYP3A inducers, and acid-reducing agents.

Asciminib is a first-in-class inhibitor of BCR::ABL1, specifically targeting the ABL myristoyl pocket. Asciminib is a substrate of CYP3A4 and P-glycoprotein (P-gp) and possesses pH-dependent solubility in aqueous solution. This report summarizes the results of two phase I studies in healthy subjects aimed at assessing the impact of CYP3A and P-gp inhibitors, CYP3A inducers and acid-reducing agents (ARAs) on the pharmacokinetics (PK) of asciminib (single dose of 40 mg). Asciminib exposure (area under the curve [AUC]) unexpectedly decreased by ~40% when administered concomitantly with the strong CYP3A inhibitor itraconazole oral solution, whereas maximum plasma concentration (Cmax ) decreased by ~50%. However, asciminib exposure was slightly increased in subjects receiving an itraconazole capsule (~3%) or clarithromycin (~35%), another strong CYP3A inhibitor. Macroflux studies showed that cyclodextrin (present in high quantities as excipient [40-fold excess to itraconazole] in the oral solution formulation of itraconazole) decreased asciminib flux through a lipid membrane by ~80%. The AUC of asciminib was marginally decreased by concomitant administration with the strong CYP3A inducer rifampicin (by ~13-15%) and the strong P-gp inhibitor quinidine (by ~13-16%). Concomitant administration of the ARA rabeprazole had little or no effect on asciminib AUC, with a 9% decrease in Cmax . The treatments were generally well tolerated. Taking into account the large therapeutic window of asciminib, the observed changes in asciminib PK following multiple doses of P-gp, CYP3A inhibitors, CYP3A inducers, or ARAs are not considered to be clinically meaningful. Care should be exercised when administering asciminib concomitantly with cyclodextrin-containing drug formulations.

Exposure-Efficacy Analysis of Asciminib in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase.

Asciminib (Scemblix) is a first-in-class BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP) and has potent activity against the T315I mutation. This study aimed to characterize the effect of asciminib exposure on disease progression and to elucidate factors influencing efficacy. Our analysis included 303 patients with chronic myeloid leukemia in chronic phase recruited in a phase I study with dose ranging from 10 to 200 mg twice a day (b.i.d.) or 40 to 200 mg once a day (q.d.) (NCT02081378) and in the phase III ASCEMBL (Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs) study receiving asciminib 40 mg b.i.d. (NCT03106779). A total of 67 patients harbored the T315I mutation. A longitudinal pharmacokinetic/pharmacodynamic model was developed to characterize the exposure-efficacy relationship, in which the efficacy was assessed through BCR::ABL1 transcript levels over time. Specifically, a three-compartment model representing quiescent leukemic stem cells, proliferating bone marrow cells, and resistant cells was developed. Drug killing of the proliferating cells by asciminib was characterized by a power model. A subgroup analysis was performed on the patients with the T315I mutation using a maximum drug effect model to characterize the drug effect. The model demonstrated the appropriateness of a total daily dose of asciminib 80 mg in patients without the T315I mutation and 200 mg b.i.d. in patients with the T315I mutation with further validation in light of safety data. This model captured key characteristics of patients' response to asciminib and helped inform dosing rationale for resistant and difficult-to-treat populations.

Population Pharmacokinetics of Asciminib in Tyrosine Kinase Inhibitor-Treated Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic and Acute Phases.

BACKGROUND: Asciminib, a first-in-class, highly potent and specific ABL/BCR-ABL1 inhibitor, has shown superior efficacy compared to bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, treated with two or more tyrosine kinase inhibitors. This study aimed to describe pharmacokinetic (PK) properties of asciminib and to identify clinically relevant covariates impacting its exposure. METHODS: A population PK (PopPK) model was developed using a two-compartment model with delayed first-order absorption and elimination. The analysis included PK data from two clinical studies (Phases 1 and 3) involving 353 patients, with total daily dose of asciminib in the range of 20-400 mg. RESULTS: The nominal total daily dose was incorporated as a structural covariate on clearance (CL), and body weight (BW) was included as a structural covariate via allometric scaling on CL and central volume. Renal function and formulation were included as statistically significant covariates on CL and absorption (ka), respectively. The simulation results revealed a modest but clinically non-significant effect of baseline BW and renal function on ka. Correlations between covariates, such as baseline demographics and disease characteristics, heavy smoking status, hepatic function, and T315I mutation status, were not statistically significant with respect to CL, and they were not incorporated in the final model. Additionally, the final model-based simulations demonstrated comparable exposure and CL for asciminib 40 mg twice daily and 80 mg once daily (an alternative regimen not studied in the Phase 3 trial), as well as similar PK properties in patients with and without the T315I mutation. CONCLUSIONS: The final PopPK model adequately characterized the PK properties of asciminib and assessed the impact of key covariates on its exposure. The model corroborates the use of the approved asciminib dose of 80 mg total daily dose as 40 mg twice daily, and supports the use of 80 mg once daily as an alternative dose regimen to facilitate patient's compliance. TRIAL REGISTRATION NUMBER [DATE OF REGISTRATION]: First-in-human (CABL001X2101, Phase 1), ClinicalTrials.gov identifier: NCT02081378 [28 February 2014]; ASCEMBL (CABL001A2301, Phase 3), ClinicalTrials.gov identifier: NCT03106779 [10 April 2017].

Pharmacokinetics of Asciminib When Taken With Imatinib or With Food.

Asciminib, a first-in-class, Specifically Targeting the Abelson kinase Myristoyl Pocket (STAMP) inhibitor with the potential to overcome resistance to adenosine triphosphate-competitive tyrosine kinase inhibitors, is being investigated in leukemia as monotherapy and in combination with tyrosine kinase inhibitors including imatinib. This phase 1 study in healthy volunteers assessed the pharmacokinetics of asciminib (40 mg single dose) under 2 conditions: when taken with imatinib (steady state; 400 mg once daily) and a low-fat meal (according to imatinib prescription information), or when taken as single-agent under different food conditions. Asciminib plus imatinib with a low-fat meal increased asciminib area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration (geometric mean ratios [90% confidence interval], 2.08 [1.93-2.24] and 1.59 [1.45-1.75], respectively) compared with asciminib alone under the same food conditions. Asciminib plus food decreased asciminib area under the plasma concentration-time curve from time 0 to infinity compared with asciminib taken under fasted conditions (geometric mean ratios: low-fat meal, 0.7 [0.631-0.776]; high-fat meal, 0.377 [0.341-0.417]). Asciminib plus imatinib was well tolerated with no new safety signals. Overall, coadministration of asciminib with imatinib and a low-fat meal results in a moderate increase in asciminib exposure compared with asciminib alone under the same food condition. Food itself decreases asciminib exposure, indicating that single-agent asciminib should be administered in the fasted state to prevent potential suboptimal exposures.

Pharmacokinetics and tolerability of almorexant in Japanese and Caucasian healthy male subjects.

BACKGROUND/AIMS: The aim of this study was to compare the pharmacokinetics and tolerability of single doses of the dual orexin receptor antagonist almorexant in Japanese and Caucasian healthy male subjects (n = 10 in each group, body weight matched ±5%). METHODS: Almorexant (200 mg) was administered in the morning in the fasted state. The pharmacokinetic parameters of almorexant were calculated by noncompartmental analysis from the plasma concentration data. RESULTS: The pharmacokinetics of almorexant in Japanese and Caucasian subjects were similar. The plasma concentration-time profile of almorexant was characterized by a rapid absorption and disposition. Peak plasma concentrations (C(max)) were reached at approximately 1.0 h in both ethnic groups. C(max) was 13% lower (ratio of geometric means [90% CI]: 0.87 [0.53, 1.43]), and the total exposure (AUC(0-)∞) was 15% lower (0.85 [0.54, 1.35]) in the Japanese subjects. There was no difference in the geometric mean ratio for t(1/2) between the two ethnic groups (1.03 [0.84, 1.25]). Almorexant was well tolerated in both ethnic groups. CONCLUSION: The pharmacokinetics and tolerability profiles of almorexant in Japanese and Caucasian healthy male subjects are similar. No dose adjustments for clinical studies with almorexant in Japanese subjects appear to be needed.

Pharmacokinetics of Asciminib in Individuals With Hepatic or Renal Impairment.

Asciminib is an investigational, first-in-class, specifically targeting the ABL myristoyl pocket (STAMP) inhibitor of BCR-ABL1 with a new mechanism of action compared with approved ATP-competitive tyrosine kinase inhibitors. This report describes the findings from 2 phase 1 studies assessing the pharmacokinetic (PK) profile of a single dose of asciminib (40 mg) in individuals with impaired renal function (based on absolute glomerular filtration rate; NCT03605277) or impaired hepatic function (based on Child-Pugh classification; NCT02857868). Individuals with severe renal impairment exhibited 49%-56% higher exposure (area under the curve [AUC]), with similar maximum plasma concentration (Cmax ), than matched healthy controls. Based on these findings, as per the protocol, the PK of asciminib in individuals with mild or moderate renal impairment was not assessed. In individuals with mild and severe hepatic impairment, asciminib AUC was 21%-22% and 55%-66% higher, respectively, and Cmax was 26% and 29% higher, respectively, compared with individuals with normal hepatic function. Individuals with moderate hepatic impairment had similar asciminib AUC and Cmax than matched healthy controls. The increase in asciminib AUC and Cmax in the mild hepatic impairment cohort was mainly driven by 1 participant with particularly high exposure. Asciminib was generally well tolerated, and the safety data were consistent with its known safety profile. In summary, these findings indicate that renal or hepatic impairment has no clinically meaningful effect on the exposure or safety profile of asciminib, and support its use in patients with varying degrees of renal or hepatic dysfunction.