Intra-individual Dose Escalation of Abiraterone According to Its Plasma Exposure in Patients with Progressive Metastatic Castration-Resistant Prostate Cancer: Results of the OPTIMABI Trial.

BACKGROUND AND OBJECTIVE: Trough abiraterone concentration (ABI Cmin) of 8.4 ng/mL has been identified as an appropriate efficacy threshold in patients treated for metastatic castration-resistant prostate cancer (mCRPC). The aim of the phase II OPTIMABI study was to evaluate the efficacy of pharmacokinetics (PK)-guided dose escalation of abiraterone acetate (AA) in underexposed patients with mCRPC with early tumour progression. METHODS: This multicentre, non-randomised study consisted of two sequential steps. In step 1, all patients started treatment with 1000 mg of AA once daily. Abiraterone Cmin was measured 22-26 h after the last dose intake each month during the first 12 weeks of treatment. In step 2, underexposed patients (Cmin < 8.4 ng/mL) with tumour progression within the first 6 months of treatment were enrolled and received AA 1000 mg twice daily. The primary endpoint was the rate of non-progression at 12 weeks after the dose doubling. During step 1, adherence to ABI treatment was assessed using the Girerd self-reported questionnaire. A post-hoc analysis of pharmacokinetic (PK) data was conducted using Bayesian estimation of Cmin from samples collected outside the sampling guidelines (22-26 h). RESULTS: In the intention-to-treat analysis (ITT), 81 patients were included in step 1. In all, 21 (26%) patients were underexposed in step 1, and 8 of them (38%) experienced tumour progression within the first 6 months. A total of 71 patients (88%) completed the Girerd self-reported questionnaire. Of the patients, 62% had a score of 0, and 38% had a score of 1 or 2 (minimal compliance failure), without a significant difference in mean ABI Cmin in the two groups. Four patients were enrolled in step 2, and all reached the exposure target (Cmin > 8.4 ng/mL) after doubling the dose, but none met the primary endpoint. In the post-hoc analysis of PK data, 32 patients (39%) were underexposed, and ABI Cmin was independently associated with worse progression-free survival [hazard ratio (HR) 2.50, 95% confidence interval (CI) 1.07-5.81; p = 0.03], in contrast to the ITT analysis. CONCLUSION: The ITT and per-protocol analyses showed no statistical association between ABI underexposure and an increased risk of early tumour progression in patients with mCRPC, while the Bayesian estimator showed an association. However, other strategies than dose escalation at the time of progression need to be evaluated. Treatment adherence appeared to be uniformly good in the present study. Finally, the use of a Bayesian approach to recover samples collected outside the predefined blood collection time window could benefit the conduct of clinical trials based on drug monitoring. OPTIMABI trial is registered as National Clinical Trial number NCT03458247, with the EudraCT number 2017-000560-15).

Extending the dosing intervals of nivolumab: model-based simulations in unselected cancer patients.

BACKGROUND: Reducing nivolumab dose intensity could increase patients' life quality and decrease the financial burden while maintaining efficacy. The aims of this study were to develop a population PK model of nivolumab based on data from unselected metastatic cancer patients and to simulate extended-interval regimens allowing to maintain minimal effective plasma concentrations (MEPC). METHODS: Concentration-time data (992 plasma nivolumab concentrations, 364 patients) were modeled using a two-compartment model with linear elimination clearance in Monolix software. Extended-interval regimens allowing to maintain steady-state trough concentrations (Cmin,ss) above the MEPC of 2.5 mg/L or 1.5 mg/L in >90% of patients were simulated. RESULTS: Increasing 3-times the dosing interval from 240 mg every two weeks (Q2W) to Q6W and 2-times from 480 mg Q4W to Q8W resulted in Cmin,ss above 2.5 mg/L in 95.8% and 95.4% of patients, respectively. 240 mg Q8W and 480 mg Q10W resulted in Cmin,ss above 1.5 mg/L in 91.0% and 91.8% of patients, respectively. Selection of a 240 mg Q6W regimen would decrease by 3-fold the annual treatment costs compared to standard regimen of 240 mg Q2W (from 78,744€ to 26,248€ in France). CONCLUSIONS: Clinical trials are warranted to confirm the non-inferiority of extended-interval compared to standard regimen.

Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab.

Interspecies translation of monoclonal antibodies (mAbs) pharmacokinetics (PK) in presence of target-mediated drug disposition (TMDD) is particularly challenging. Incorporation of TMDD in physiologically based PK (PBPK) modeling is recent and needs to be consolidated and generalized to provide better prediction of TMDD regarding inter-species translation during preclinical and clinical development steps of mAbs. The objective of this study was to develop a generic PBPK translational approach for mAbs using the open-source software (PK-Sim® and Mobi®). The translation of bevacizumab based on data in non-human primates (NHP), healthy volunteers (HV), and cancer patients was used as a case example for model demonstration purpose. A PBPK model for bevacizumab concentration-time data was developed using data from literature and the Open Systems Pharmacology (OSP) Suite version 10. PK-sim® was used to build the linear part of bevacizumab PK (mainly FcRn-mediated), whereas MoBi® was used to develop the target-mediated part. The model was first developed for NHP and used for a priori PK prediction in HV. Then, the refined model obtained in HV was used for a priori prediction in cancer patients. A priori predictions were within 2-fold prediction error (predicted/observed) for both area under the concentration-time curve (AUC) and maximum concentration (Cmax) and all the predicted concentrations were within 2-fold average fold error (AFE) and average absolute fold error (AAFE). Sensitivity analysis showed that FcRn-mediated distribution and elimination processes must be accounted for at all mAb concentration levels, whereas the lower the mAb concentration, the more significant the target-mediated elimination. This project is the first step to generalize the full PBPK translational approach in Model-Informed Drug Development (MIDD) of mAbs using OSP Suite.

Review of the Existing Translational Pharmacokinetics Modeling Approaches Specific to Monoclonal Antibodies (mAbs) to Support the First-In-Human (FIH) Dose Selection.

The interest in therapeutic monoclonal antibodies (mAbs) has continuously growing in several diseases. However, their pharmacokinetics (PK) is complex due to their target-mediated drug disposition (TMDD) profiles which can induce a non-linear PK. This point is particularly challenging during the pre-clinical and translational development of a new mAb. This article reviews and describes the existing PK modeling approaches used to translate the mAbs PK from animal to human for intravenous (IV) and subcutaneous (SC) administration routes. Several approaches are presented, from the most empirical models to full physiologically based pharmacokinetic (PBPK) models, with a focus on the population PK methods (compartmental and minimal PBPK models). They include the translational approaches for the linear part of the PK and the TMDD mechanism of mAbs. The objective of this article is to provide an up-to-date overview and future perspectives of the translational PK approaches for mAbs during a model-informed drug development (MIDD), since the field of PK modeling has gained recently significant interest for guiding mAbs drug development.

Pharmacokinetics, Safety, and Efficacy of Gadopiclenol in Pediatric Patients Aged 2 to 17 Years.

OBJECTIVES: The aim of this study was to evaluate the pharmacokinetic (PK) profile, safety, and efficacy of gadopiclenol, a new high-relaxivity gadolinium-based contrast agent, in children aged 2 to 17 years. MATERIALS AND METHODS: Children scheduled to undergo contrast-enhanced magnetic resonance imaging of the central nervous system (CNS cohort) or other organs (body cohort) were included sequentially into 3 age groups (12-17, 7-11, and 2-6 years). Gadopiclenol was administered at the dose of 0.05 mmol/kg. A sparse sampling approach was applied, with 4 blood samples per child collected up to 8 hours postinjection. Population PK modeling was used for the analysis, including the CNS cohort and adult subjects from a previous study. Adverse events were recorded, and efficacy was assessed for all children. RESULTS: Eighty children were included, 60 in the CNS cohort and 20 in the body cohort. The 2-compartment model with linear elimination from the central compartment developed in adults was also suitable for children. Pharmacokinetic parameters were very similar between adults and children. Terminal elimination half-life was 1.82 hours for adults and 1.77 to 1.29 hours for age groups 12-17 to 2-6 years. The median clearance ranged from 0.08 L/h/kg in adults and 12-17 years to 0.12 L/h/kg in 2-6 years. The median central and peripheral volumes of distribution were 0.11 to 0.12 L/kg and 0.06 L/kg, respectively, for both adults and children. Simulations of plasma concentrations showed minor differences, and median area under the curve was 590 mg·h/L for adults and 582 to 403 mg·h/L for children. Two patients (2.5%) experienced nonserious adverse events considered related to gadopiclenol: a mild QT interval prolongation and a moderate maculopapular rash. Despite the limited number of patients, this study showed that gadopiclenol improved lesion detection, visualization, and diagnostic confidence. CONCLUSIONS: The PK profile of gadopiclenol in children aged 2 to 17 years was similar to that observed in adults. Thus, there is no indication for age-based dose adaptation, and comparable plasma gadopiclenol concentrations are predicted to be achieved with body weight-based dosing in this population. Gadopiclenol at 0.05 mmol/kg seems to have a good safety profile in these patients and could improve lesion detection and visualization, therefore providing better diagnostic confidence.

OBJECTIVES: The aim of this study was to evaluate the pharmacokinetic (PK) profile, safety, and efficacy of gadopiclenol, a new high-relaxivity gadolinium-based contrast agent, in children aged 2 to 17 years. MATERIALS AND METHODS: Children scheduled to undergo contrast-enhanced magnetic resonance imaging of the central nervous system (CNS cohort) or other organs (body cohort) were included sequentially into 3 age groups (12­17, 7­11, and 2­6 years). Gadopiclenol was administered at the dose of 0.05 mmol/kg. A sparse sampling approach was applied, with 4 blood samples per child collected up to 8 hours postinjection. Population PK modeling was used for the analysis, including the CNS cohort and adult subjects from a previous study. Adverse events were recorded, and efficacy was assessed for all children. RESULTS: Eighty children were included, 60 in the CNS cohort and 20 in the body cohort. The 2-compartment model with linear elimination from the central compartment developed in adults was also suitable for children. Pharmacokinetic parameters were very similar between adults and children. Terminal elimination half-life was 1.82 hours for adults and 1.77 to 1.29 hours for age groups 12­17 to 2­6 years. The median clearance ranged from 0.08 L/h/kg in adults and 12­17 years to 0.12 L/h/kg in 2­6 years. The median central and peripheral volumes of distribution were 0.11 to 0.12 L/kg and 0.06 L/kg, respectively, for both adults and children. Simulations of plasma concentrations showed minor differences, and median area under the curve was 590 mg·h/L for adults and 582 to 403 mg·h/L for children. Two patients (2.5%) experienced nonserious adverse events considered related to gadopiclenol: a mild QT interval prolongation and a moderate maculopapular rash. Despite the limited number of patients, this study showed that gadopiclenol improved lesion detection, visualization, and diagnostic confidence. CONCLUSIONS: The PK profile of gadopiclenol in children aged 2 to 17 years was similar to that observed in adults. Thus, there is no indication for age-based dose adaptation, and comparable plasma gadopiclenol concentrations are predicted to be achieved with body weight­based dosing in this population. Gadopiclenol at 0.05 mmol/kg seems to have a good safety profile in these patients and could improve lesion detection and visualization, therefore providing better diagnostic confidence.