De la dose à l'effet clinique (utilisation de la modélisation dans les différentes étapes du processus de prédiction du critère clinique)

Les données épidémiologiques montrent une association inverse entre les taux de HDL-cholestérol (HDL-C) et le risque d'évènements cardiovasculaires. Des traitements ayant montré une augmentation significative du HDL-C, comme les inhibiteurs de la protéine de transfert des esters de cholestérol, devraient donc permettre de réduire le risque cardio-vasculaire. En utilisant différentes techniques de modélisation, nous avons tenté de quantifier l'efficacité attendue sur les événements cardiovasculaires de l'un d'entre eux, le dalcétrapib, ne disposant que de données pharmacocinétiques et pharmacodynamiques. Tout d abord, afin d'établir la relation pharmacocinétique / pharmacodynamique entre les concentrations et la modification de HDL-C, nous avons analysé les données individuelles des patients dyslipidémiques par une approche de population. Une hausse moyenne de HDL-C de 26.4 % par rapport au placebo était alors anticipée. Nous avons ensuite tenté de corréler l'effet observé sur l'HDL-C et l'effet clinique à partir de données d'autres études par méta-régression des essais évaluant l'effet des principaux hypolipémiants en prévention secondaire. Cette modélisation n'a pas permis de montrer de corrélation entre le changement de l HDL-C (P5 P95 :-3.0 et 36 %) et la réduction du risque cardiovasculaire. Une analyse de sensibilité par type de traitement suggère qu'une même hausse de HDL-C entre deux classes thérapeutiques pourrait se traduire par un effet clinique dissemblable, indiquant que HDL-C ne peut pas être utilisé comme critère intermédiaire puisqu'il ne serait pas un prédicteur indépendant du risque cardiovasculaireEpidemiological data demonstrate an inverse correlation between HDL-cholesterol (HDL-C) levels and cardiovascular risk. Therefore, drugs as cholesteryl ester transfer protein (CETP) inhibitors that lead to a significant HDL-C increase are believed to reduce the occurrence of coronary events. We aimed to evaluate the clinical efficacy of one CETP inhibitor, dalcetrapib, by using various modeling techniques while only pharmacokinetic (PK) and pharmacodynamlc (PD) data were available. First, we analyzed individual data from dyslipidemic patients using a population approach in order to establish the PK/PD relationship between dalcetrapib concentrations and HDL-C change. The results show that an average raise of 26.4 % is expected in comparison to placebo with the 5th (P5) and 95th (P95) percentile of the mean average at 20.7 % and 31.9 % respectively. The increase in HDL-C is explained by a delayed catabolism following the transfer inhibition of cholesterol ester from HDL to Apo-B rich lipoproteins. We endeavored then to correlate HDL-C increase to coronary events by using a meta-regression analysis on randomized trials that evaluated the clinical efficacy of main dyslipidemic drugs on coronary events in secondary prevention. The modeling did not show a statistical association between HDL-C change (P5-P95:-3.0 and 36 %) and coronary risk reduction. A sensitivity analysis by drug class suggests that the same HDL-C increase resulting from different mechanisms of action may not impact the cardiovascular risk in the same way. This would indicate that HDL-C could not be used as a risk marker since it might not be an independent predictor of cardiovascular riskST ETIENNE-Bib. électronique (422189901) / SudocSudocFranceF

De la dose à l'effet clinique : utilisation de la modélisation dans les différentes étapes du processus de prédiction du critère clinique : Exemple avec un nouveau médicament en prévention secondaire de la morbidité-mortalité cardiovasculaire

Epidemiological data demonstrate an inverse correlation between HDL-cholesterol (HDL-C) levels and cardiovascular risk. Therefore, drugs as cholesteryl ester transfer protein (CETP) inhibitors that lead to a significant HDL-C increase are believed to reduce the occurrence of coronary events. We aimed to evaluate the clinical efficacy of one CETP inhibitor, dalcetrapib, by using various modeling techniques while only pharmacokinetic (PK) and pharmacodynamlc (PD) data were available. First, we analyzed individual data from dyslipidemic patients using a population approach in order to establish the PK/PD relationship between dalcetrapib concentrations and HDL-C change. The results show that an average raise of 26.4 % is expected in comparison to placebo with the 5th (P5) and 95th (P95) percentile of the mean average at 20.7 % and 31.9 % respectively. The increase in HDL-C is explained by a delayed catabolism following the transfer inhibition of cholesterol ester from HDL to Apo-B rich lipoproteins. We endeavored then to correlate HDL-C increase to coronary events by using a meta-regression analysis on randomized trials that evaluated the clinical efficacy of main dyslipidemic drugs on coronary events in secondary prevention. The modeling did not show a statistical association between HDL-C change (P5-P95:-3.0 and 36 %) and coronary risk reduction. A sensitivity analysis by drug class suggests that the same HDL-C increase resulting from different mechanisms of action may not impact the cardiovascular risk in the same way. This would indicate that HDL-C could not be used as a risk marker since it might not be an independent predictor of cardiovascular riskLes données épidémiologiques montrent une association inverse entre les taux de HDL-cholestérol (HDL-C) et le risque d'évènements cardiovasculaires. Des traitements ayant montré une augmentation significative du HDL-C, comme les inhibiteurs de la protéine de transfert des esters de cholestérol, devraient donc permettre de réduire le risque cardio-vasculaire. En utilisant différentes techniques de modélisation, nous avons tenté de quantifier l'efficacité attendue sur les événements cardiovasculaires de l'un d'entre eux, le dalcétrapib, ne disposant que de données pharmacocinétiques et pharmacodynamiques. Tout d’abord, afin d'établir la relation pharmacocinétique / pharmacodynamique entre les concentrations et la modification de HDL-C, nous avons analysé les données individuelles des patients dyslipidémiques par une approche de population. Une hausse moyenne de HDL-C de 26.4 % par rapport au placebo était alors anticipée. Nous avons ensuite tenté de corréler l'effet observé sur l'HDL-C et l'effet clinique à partir de données d'autres études par méta-régression des essais évaluant l'effet des principaux hypolipémiants en prévention secondaire. Cette modélisation n'a pas permis de montrer de corrélation entre le changement de l’HDL-C (P5 P95 :-3.0 et 36 %) et la réduction du risque cardiovasculaire. Une analyse de sensibilité par type de traitement suggère qu'une même hausse de HDL-C entre deux classes thérapeutiques pourrait se traduire par un effet clinique dissemblable, indiquant que HDL-C ne peut pas être utilisé comme critère intermédiaire puisqu'il ne serait pas un prédicteur indépendant du risque cardiovasculair

From dose to clinical effect : use of modeling through drug development to predict clinical benefit : Example of a new drug in secondary prevention of coronary heart disease

Les données épidémiologiques montrent une association inverse entre les taux de HDL-cholestérol (HDL-C) et le risque d'évènements cardiovasculaires. Des traitements ayant montré une augmentation significative du HDL-C, comme les inhibiteurs de la protéine de transfert des esters de cholestérol, devraient donc permettre de réduire le risque cardio-vasculaire. En utilisant différentes techniques de modélisation, nous avons tenté de quantifier l'efficacité attendue sur les événements cardiovasculaires de l'un d'entre eux, le dalcétrapib, ne disposant que de données pharmacocinétiques et pharmacodynamiques. Tout d’abord, afin d'établir la relation pharmacocinétique / pharmacodynamique entre les concentrations et la modification de HDL-C, nous avons analysé les données individuelles des patients dyslipidémiques par une approche de population. Une hausse moyenne de HDL-C de 26.4 % par rapport au placebo était alors anticipée. Nous avons ensuite tenté de corréler l'effet observé sur l'HDL-C et l'effet clinique à partir de données d'autres études par méta-régression des essais évaluant l'effet des principaux hypolipémiants en prévention secondaire. Cette modélisation n'a pas permis de montrer de corrélation entre le changement de l’HDL-C (P5 P95 :-3.0 et 36 %) et la réduction du risque cardiovasculaire. Une analyse de sensibilité par type de traitement suggère qu'une même hausse de HDL-C entre deux classes thérapeutiques pourrait se traduire par un effet clinique dissemblable, indiquant que HDL-C ne peut pas être utilisé comme critère intermédiaire puisqu'il ne serait pas un prédicteur indépendant du risque cardiovasculaireEpidemiological data demonstrate an inverse correlation between HDL-cholesterol (HDL-C) levels and cardiovascular risk. Therefore, drugs as cholesteryl ester transfer protein (CETP) inhibitors that lead to a significant HDL-C increase are believed to reduce the occurrence of coronary events. We aimed to evaluate the clinical efficacy of one CETP inhibitor, dalcetrapib, by using various modeling techniques while only pharmacokinetic (PK) and pharmacodynamlc (PD) data were available. First, we analyzed individual data from dyslipidemic patients using a population approach in order to establish the PK/PD relationship between dalcetrapib concentrations and HDL-C change. The results show that an average raise of 26.4 % is expected in comparison to placebo with the 5th (P5) and 95th (P95) percentile of the mean average at 20.7 % and 31.9 % respectively. The increase in HDL-C is explained by a delayed catabolism following the transfer inhibition of cholesterol ester from HDL to Apo-B rich lipoproteins. We endeavored then to correlate HDL-C increase to coronary events by using a meta-regression analysis on randomized trials that evaluated the clinical efficacy of main dyslipidemic drugs on coronary events in secondary prevention. The modeling did not show a statistical association between HDL-C change (P5-P95:-3.0 and 36 %) and coronary risk reduction. A sensitivity analysis by drug class suggests that the same HDL-C increase resulting from different mechanisms of action may not impact the cardiovascular risk in the same way. This would indicate that HDL-C could not be used as a risk marker since it might not be an independent predictor of cardiovascular ris

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

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 (CML). This was a randomized, single dose, open-label, four-period cross-over study in healthy adult participants (N=24) which evaluated the relative bioavailability of a single 40 mg dose of asciminib pediatric formulation (1 mg mini-tablets) compared with the reference adult tablet, under fasting conditions. In addition, the effect of food on the bioavailability of the mini-tablet formulation was evaluated. Under fasting conditions, asciminib exposure was similar for both formulations (geometric mean [Gmean] area under the concentration-time curve from time 0 to infinity [AUCinf] 5970 ng·h/mL 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 (CI)]: 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). Both formulations were well tolerated. The mini-tablets were assessed to be easy to ingest with good palatability. Results gained from this study will be utilized in physiologically-based pharmacokinetic (PBPK) modelling to define asciminib starting doses in a pivotal pediatric clinical trial

The effects of imatinib and food on the pharmacokinetics of asciminib

Asciminib, a first-in-class, Specifically Targeting the ABL Myristoyl Pocket (STAMP) inhibitor of BCR-ABL1 with the potential to overcome resistance to ATP-competitive tyrosine kinase inhibitors (TKIs), is being investigated in leukemias as monotherapy and in combination with TKIs including imatinib. This Phase 1 study in healthy volunteers assessed the effect of imatinib (steady-state; 400 mg once daily, with a low-fat meal) or food (to improve tolerability of imatinib) on the pharmacokinetics (PK) of asciminib (40 mg single dose; final market formulation). Asciminib + imatinib resulted in a 2-fold increase in asciminib exposure (area under the curve, AUC) and a 1.6-fold increase in asciminib Cmax compared with single-agent asciminib. The PK of imatinib was not substantially impacted by asciminib. Compared with fasted conditions, asciminib administered with food decreased asciminib AUC by 30-60%, depending on the meal’s fat content. Asciminib + imatinib was well tolerated with no new safety signals. Overall, co-administration of imatinib 400 mg once daily with asciminib 40 mg once daily under low-fat meal conditions resulted in increased asciminib exposure, similar to that provided with the recommended asciminib single-agent dose (40 mg twice daily) under fasted conditions. Single-agent asciminib should be administered in the fasted state to avoid suboptimal exposure

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

Pharmacokinetics and safety of subcutaneous rituximab plus fludarabine and cyclophosphamide for patients with chronic lymphocytic leukaemia

The aim of the phase Ib, two part SAWYER study (BO25341; NCT01292603) was to investigate the pharmacokinetics and safety of subcutaneous (s.c.) rituximab compared with intravenous (i.v.) rituximab, both in combination with fludarabine and cyclophosphamide (FC), as first line treatment for patients with chronic lymphocytic leukaemia (CLL)