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].

Model-Informed Drug Development for Everolimus Dosing Selection in Pediatric Infant Patients.

Everolimus is currently approved in Europe as an adjunctive therapy for patients aged ≥ 2 years with tuberous sclerosis complex (TSC)-associated treatment-refractory partial-onset seizures, based on the EXIST-3 study (NCT01713946) results. As TSC-associated seizures can also affect children aged between 6 months and 2 years, a modeling and simulation (M&S) approach was undertaken to extrapolate exposure (trough plasma concentration (Cmin )) after a dose of 6 mg/m2 and reduction in seizure frequency (RSF). A physiologically based pharmacokinetic model using Simcyp was developed to predict Cmin in adult and pediatric patients, which was then used by a population pharmacodynamic model and a linear mixed effect model to predict short-term and long-term efficacy in adults (for validation) and in children, respectively. Based on the results of the M&S study, everolimus at the dose of 6 mg/m2 is anticipated to be an efficacious treatment in children 6 months to 2 years of age (up to 77.8% RSF) with concentrations within the recommended target range.

Physiologically Based Pharmacokinetic Modeling to Supplement Nilotinib Pharmacokinetics and Confirm Dose Selection in Pediatric Patients.

In adult patients, nilotinib is indicated for chronic myeloid leukemia at an approved oral dose of 300 or 400 mg BID. Physiologically based pharmacokinetic (PBPK) model was developed to describe and supplement limited PK data in the pediatric population ranging from 2 to less than 6 years of age and ultimately inform dosing regimen. An adult Simcyp PBPK model was established and verified with clinical pharmacokinetic data after a single or multiple oral doses of 400 mg nilotinib (230 mg/m2). The model was then applied to a pediatric PBPK model, taking account of ontogeny profiles of metabolizing enzymes and pediatric physiological parameters. The model was further verified using observed pediatric PK data in 12- to <18-year-old and from 6- to <12-year-old patients. The PBPK models were able to recover, describe, and supplement the limited nilotinib concentration-time data profile in 2- to <6-year-old patients after a single dose and Cmin,ss after BID dosing. The exposure (Cmax,ss, Cmin,ss, and AUCtau,ss) was predicted to be similar across age groups. PBPK model simulations confirmed that body surface area-normalized dosing regimen of 230 mg/m2 is considered appropriate for pediatric patients >2 to <18 years of age.

Population pharmacokinetics-pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex.

Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5-15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustments. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure mean was implemented as an asymptotic exponential function of time leading to a new steady-state seizure mean. The everolimus effect was implemented as an inhibitory Emax function of Cmin on the seizure mean, where Emax exhibited an asymptotic exponential increase over time to a higher steady-state value. Increasing age was found to decrease the baseline seizure mean and to prolong the half-life of the increase in Emax. The dependence of seizure frequencies on Cmin was explored by simulation. The responder rate increased with increasing Cmin. As Cmin decreased below 5 ng/mL, variability in response became larger and responder rates decreased more rapidly. The results supported the recommended target concentration range for everolimus of 5-15 ng/mL to ensure treatment efficacy.

Prediction of shrinkage of individual parameters using the bayesian information matrix in non-linear mixed effect models with evaluation in pharmacokinetics.

PURPOSE: When information is sparse, individual parameters derived from a non-linear mixed effects model analysis can shrink to the mean. The objective of this work was to predict individual parameter shrinkage from the Bayesian information matrix (M BF ). We 1) Propose and evaluate an approximation of M BF by First-Order linearization (FO), 2) Explore by simulations the relationship between shrinkage and precision of estimates and 3) Evaluate prediction of shrinkage and individual parameter precision. METHODS: We approximated M BF using FO. From the shrinkage formula in linear mixed effects models, we derived the predicted shrinkage from M BF . Shrinkage values were generated for parameters of two pharmacokinetic models by varying the structure and the magnitude of the random effect and residual error models as well as the design. We then evaluated the approximation of M BF FO and compared it to Monte-Carlo (MC) simulations. We finally compared expected and observed shrinkage as well as the predicted and estimated Standard Errors (SE) of individual parameters. RESULTS: M BF FO was similar to M BF MC. Predicted and observed shrinkages were close . Predicted and estimated SE were similar. CONCLUSIONS: M BF FO enables prediction of shrinkage and SE of individual parameters. It can be used for design optimization.