Pharmacokinetic Drug Interactions of Asciminib With the Sensitive Cytochrome P450 Probe Substrates Midazolam, Warfarin and Repaglinide in Healthy Volunteers

Asciminib, a novel agent being investigated in chronic myeloid leukemia, is a first-in-class BCR-ABL1 inhibitor that works by STAMP (Specifically Targeting the ABL Myristoyl Pocket) and therefore differs from approved ATP-competitive tyrosine kinase inhibitors. In vitro, asciminib has shown reversible inhibition of cytochrome P450 (CYP) 3A4/5, CYP2C9 and CYP2C8. This phase 1, open-label, 2-stage study in healthy volunteers evaluated the effect of asciminib (40 mg twice daily at steady-state) as a potential perpetrator on single-dose pharmacokinetics of a 2-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 vs midazolam, geometric mean (Gmean) ratios (90% confidence interval) for midazolam AUCinf and Cmax were 1.28 (1.15, 1.43) and 1.11 (0.96-1.28), respectively. For warfarin plus asciminib vs warfarin, Gmean ratios for S-warfarin AUCinf and Cmax were 1.41 (1.37, 1.45) and 1.08 (1.04, 1.13). Results for R-warfarin were in line with those for S-warfarin. For repaglinide plus asciminib vs 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 reports with asciminib monotherapy. Overall, the results indicate that asciminib (40 mg twice daily) is a weak inhibitor of CYP3A and CYP2C9 and has no effect on CYP2C8

Effect of progesterone supplementation on post-coital unilaterally ovariectomized superovulated mice in relation to implantation and pregnancy

Unilateral ovariectomy (ULO) and its consequences with endocrine replacement in pregnant mice are important to examine both follicular dynamics as well as the outcome of implantation and pregnancy. In mice, ovariectomy on fourth day morning (D4), before pre-implantation estrogen secretion induces delayed implantation and embryonic diapauses, i.e. a state of suspended animation of embryos. The present study has been undertaken to evaluate the effect of progesterone supplementation on rate of implantation in unilaterally ovariectomized superovulated mice. Our study reveals that progesterone (P4) may help to protect the loss of embryo before and after the implantation if ULO is done during pre-implantation period (D4). The present study also shows if ovary is present in one side of the animal, it secretes estrogen (E2) in circulation which acts systematically on the uterus rather than locally. The findings of the present study show that progesterone may help to avoid the loss of embryo before and after the implantation, if ULO is done during pre-implantation period (D4) and the serum estrogen (E2) acts systematically on the uterus. Thus, it can be concluded that implantation in the uterine horn where ovary is not there

Physiologically Based Pharmacokinetic Modeling of Oral Absorption, pH, and Food Effect in Healthy Volunteers to Drive Alpelisib Formulation Selection

A physiologically based pharmacokinetic (PBPK) human model for alpelisib, an oral α-specific class I phosphatidylinositol-3-kinase (PI3K) inhibitor, was established to simulate oral absorption and plasma pharmacokinetics of healthy subjects to allow model-informed drug development. The GastroPlus™ model consisted of an advanced absorption gut model, which was linked to a 2-compartmental model. Systemic clearance and volume of distribution were estimated using population pharmacokinetics (popPK). Various food effect and pH-mediated absorption drug–drug interaction (DDI) scenarios were modeled. In fasted healthy subjects, simulated absorption was lower (ca. 70% for a 300-mg dose) due to pH and bile acid concentration-dependent solubility. Ranitidine showed a significant pH-mediated DDI effect only in the fasted but not fed state. The PBPK model identified that more drug is absorbed in the fed state, and alpelisib intestinal permeability is rate limiting to systemic exposure. Simulations for healthy subject showed a positive food effect with ca. 2-fold increase in plasma Cmax and 1.5-fold increase in AUC0-inf with a meal compared with fasted conditions. The PBPK model was verified using clinical food effect data with pivotal clinical formulation (PCF) and then applied to predict the performance of a commercial formulation (CF) in healthy volunteers. The model successfully predicted the outcome of a clinical bioequivalence study for PCF and CF with included in vitro dissolution data, both fasted and fed state. Estimated predictive errors (based on plasma Cmax, AUC0-t) were equal or below 30%. The alpelisib model for healthy subjects enables future bioequivalence formulation assessments, in fasted, fed, or altered pH conditions. [Figure not available: see fulltext.

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

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 findings from two Phase 1 studies assessing the pharmacokinetics (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 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 one 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 have 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

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 findings from two Phase 1 studies assessing the pharmacokinetics (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 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 one 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 have 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

Evaluation of hepatoprotective and antioxidant activity of Ichnocarpus frutescens (Linn.) R.Br. on paracetamol-induced hepatotoxicity in rats

Purpose: The entire plant including the flowers, of Ichnocarpus frutescens R.Br. (Apocynaceae) has been used for the treatment of cancer, skin infections, diabetes and liver disorder. The present study is aimed at evaluating the hepatoprotective effect of chloroform and methanol extract (CEIF and MEIF) of whole plant of I. frutescens (Linn.) by paracetamol-induced liver damage in rats. Methods: The chloroform and methanolic extracts of I. frutescens (CEIF and MEIF) were studied for their hepatoprotective and antioxidant effects on paracetamol (750mg/kg) induced acute liver damage on Wistar albino rats. The degree of protection was measured by using biochemical parameters such as serum glutamate oxalate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), bilirubin and total protein. Further, the effects of both extracts on lipid peroxidation (LPO), glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were estimated. Results: CEIF and MEIF at a dose level of 250mg/kg and 500mg/kg produce significant (P<0.05) hepatoprotection by decreasing the activity of serum enzymes, bilirubin, and lipid peroxidation, while they significantly increased the levels of Glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in a dose dependent manner. The effects of CEIF and MEIF were comparable to that of standard drug, Silymarin. Conclusion: From this study, it can be concluded that the chloroform and methanol extract of I. frutescens is not only an effective hepatoprotective agent, but also possesses significant (p<0.05) antioxidant activity

Efficacy and safety of MAS825 (anti-IL-1ꞵ/IL-18) in COVID-19 patients with pneumonia and impaired respiratory function.

MAS825, a bispecific IL-1⍰/IL-18 monoclonal antibody, could improve clinical outcomes in COVID19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized nonventilated patients with COVID-19 pneumonia (n=138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo in addition to standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 or on day of discharge (whichever was earlier) with worst case imputation for death. Other study endpoints included safety, Creactive protein (CRP), SARS-CoV2 presence and inflammatory markers. On Day 15, the APACHE II score was 14.5±1.87 and 13.5±1.8 in the MAS825 and placebo groups, respectively (P=0.33). MAS825 + SoC led to 33% relative reduction in intensive care unit (ICU) admissions, ~1 day reduction in ICU stay, reduction in mean duration of oxygen support (13.5 versus 14.3 days) and earlier clearance of virus on Day 15 versus placebo + SoC group. On Day 15, compared with placebo group, patients treated with MAS825 + SoC showed a 51% decrease in CRP levels, 42% lower IL-6 levels, 19% decrease in neutrophil levels and 16% lower interferon-γ levels, indicative of IL-1β and IL-18 pathway engagement. MAS825 + SoC did not improve APACHE II score in hospitalized patients with severe COVID19 pneumonia; however, it inhibited relevant clinical and inflammatory pathway biomarkers and resulted in faster virus clearance versus placebo + SoC. MAS825 used in conjunction with SoC was well tolerated. None of the adverse events (AEs) or serious AEs were treatment-related