Theodoros Papathanasiou

Quantitative modeling can guide drug development and regulatory decisions by providing insights into pharmacokinetics, pharmacodynamics, efficacy, and safety. Integrating models allows simulations that support dosing considerations. A simulation framework for belantamab mafodotin (B) in relapsed/refractory multiple myeloma was developed using data from monotherapy studies and combination studies with bortezomib/dexamethasone (BVd) and pomalidomide/dexamethasone (BPd). Individual changes from baseline in serum M‐protein concentrations were modeled using a tumor growth inhibition model. Changes in ophthalmic exam findings (OEFs) grades per the Keratopathy and Visual Acuity (KVA) scale were modeled using a continuous‐time Markov model. Belantamab mafodotin concentrations were modeled with a population pharmacokinetic model. All final models adequately described the clinical data. The M‐protein/KVA/pharmacokinetic models were integrated in a simulation framework, and simulations of treatment outcomes were performed. Simulated regimens included dose modifications (holds/reductions) for OEFs. Simulations of protocol dosing and dose modifications from the phase 3 DREAMM‐7 (BVd) and DREAMM‐8 (BPd) trials predicted similar results to the respective trials (for BVd simulations/DREAMM‐7 data: very good partial response rates [VGPR+] 62.0%/62.0%, median progression‐free survival [mPFS] 39.4/36.6 months, and grade ≥ 3 OEFs 87.5%/76.5%; for BPd simulations/DREAMM‐8 data: VGPR+ rates 60.2%/68.0%, mPFS not reached/not reached, and grade ≥ 3 OEFs 77.2%/82.5%). Simulations of alternative BVd regimens indicated that a 2.5 mg/kg starting dose produces the highest efficacy, and schedule extensions after the first BVd dose can improve tolerability while continuing to demonstrate efficacy. This framework adequately predicted outcomes from DREAMM‐7/DREAMM‐8, supporting its use to predict benefit–risk profiles of alternate belantamab mafodotin dosing strategies.

Background: Belantamab mafodotin, bortezomib and dexamethasone (BVd) demonstrated clinical activity in the phase I/II DREAMM-6 (Arm B) study and significant clinical benefit in the phase III DREAMM-7 study for patients with relapsed/refractory multiple myeloma (RRMM) and ≥1 prior line of therapy. Methods: Population pharmacokinetic-derived Cycle 1 (C1) belantamab mafodotin exposures were used to evaluate exposure-efficacy/exposure-safety relationships across multiple doses and schedules for benefit-risk assessment. Results: Belantamab mafodotin C1 exposure was positively associated with response endpoints and grade ≥2/ ≥3 ophthalmic exam findings (OEFs), but not grade ≥2/ ≥3 ocular adverse events (oAEs) or best-corrected visual acuity (BCVA) worsening to 20/50 or worse in both eyes. Probability of very good partial response or better (≥VGPR) was higher than grade ≥3 oAEs/BCVA worsening in both eyes across C1 exposures; efficacy improved at higher C1 exposures without increased OEF risk. Model-based benefit-risk assessment showed a belantamab mafodotin starting dose of 1.9 mg/kg instead of 2.5 mg/kg would result in lower probability of ≥VGPR without reduction in BCVA worsening in both eyes/grade ≥3 oAEs. Conclusions: An initial belantamab mafodotin dose of 2.5 mg/kg for BVd yields deeper responses with minimal change in safety outcomes versus 1.9 mg/kg for patients with RRMM.

Background In the phase 3 DREAMM-8 study (NCT04484623), belantamab mafodotin (anti-B-cell maturation antigen [BCMA] antibody-drug conjugate with a monomethyl auristatin F payload) with pomalidomide and dexamethasone (BPd) showed significant progression-free survival benefit in second-line or later relapsed/refractory multiple myeloma (RRMM). Objective This exposure-response analysis explored the relationship between belantamab mafodotin cycle 1 exposure and efficacy/safety and predicted the benefit-risk profile of belantamab mafodotin at an initial dose of 1.9 versus 2.5 mg/kg using DREAMM-8 data. Patients and Methods In the BPd arm of DREAMM-8, belantamab mafodotin was dosed at 2.5 mg/kg intravenously in cycle 1, then at 1.9 mg/kg every 4 weeks from cycle 2 onward. Cycle 1 belantamab mafodotin and free payload exposures derived from population pharmacokinetic analysis were used to perform exposure-efficacy/exposure-safety analyses for probability of/time to first event. Selected covariate effects were evaluated. Results Higher belantamab mafodotin cycle 1 exposure was associated with deeper response (higher probabilities of complete response or better [≥ CR] and minimal residual disease negativity), but not with grade ≥ 3 ocular adverse events (oAEs)/ophthalmic exam findings. Benefit-risk assessment showed that an initial belantamab mafodotin dose of 1.9 mg/kg instead of 2.5 mg/kg would result in reduction in probability of ≥ CR without reduction in oAEs/ophthalmic exam findings. Conclusions An initial belantamab mafodotin dose of 2.5 mg/kg for BPd yields deeper responses versus 1.9 mg/kg with minimal change in safety outcomes in RRMM. DREAMM-8 (NCT04484623) was registered at clinicaltrials.gov (21 July 2020)

Aims: To investigate the impact on weight loss of the treatment changes in overweight or obese people that may be needed in case of gastrointestinal (GI) tolerability issues during escalation of the glucagon‐like peptide‐1 analogue liraglutide. Materials and methods: The individual longitudinal body weight data from the main trial periods of three phase II/III trials in overweight or obese patients (56‐week treatment with once‐daily liraglutide 1.2, 1.8, 2.4 or 3.0 mg or placebo, n = 4952) were analysed using a non‐linear mixed‐effect modelling approach. Individual pharmacokinetic profiles were derived based on published pharmacokinetic models. Baseline body weight, baseline glycated haemoglobin (HbA1c), age, gender, diabetes status (no diabetes, prediabetes or type 2 diabetes), race and trial region were investigated as covariates. As a form of external validation, the model was used to predict the weight regain after treatment cessation at week 56 (data not included in model development). Results: A pharmacokinetic/pharmacodynamic model provided an adequate description of the weight loss trajectories for all studied doses. Gender and diabetes status were identified as the most influential covariates, and an underlying seasonal weight fluctuation was identified. Slower than that recommended, one‐week dose‐escalation algorithms led up to 2 weeks slower initial weight loss but similar long‐term weight loss trajectories. Conclusions: The relationship between liraglutide systemic exposure and weight loss was successfully established in overweight or obese people. The model could predict the time course of weight regain after treatment cessation and suggests that GI tolerability can be mitigated by slower escalation with only minor impact on the weight loss trajectory.

Combinations of pharmacological treatments are increasingly being investigated for potentially higher clinical benefit, especially when the combined drugs are expected to act via synergistic interactions. The clinical development of combination treatments is particularly challenging, particularly during the dose-selection phase, where a vast range of possible combination doses exists. The purpose of this work was to evaluate the added value of using optimal design for guiding the dose allocation in drug combination dose-finding studies as compared with a typical drug-combination trial. Optimizations were performed using local [D(s)-optimality] and global [ED(s)-optimality] optimal designs to maximize the precision of model parameters in a number of potential exposure-response (E-R) surfaces. A compound criterion [D(s)/V-optimality] was used to optimize the precision of model predictions in specific parts of the E-R surfaces. Optimal designs provided unbiased estimates and significantly improved the accuracy of results relative to the typical design. It was possible to improve the efficiency and overall parameter precision up to 7832% and 96.6% respectively. When the compound criterion was used, the probability to accurately identify the optimal dose-combination increased from 71% for the typical design up to 91%. These results indicate that optimal design methodology in tandem with E-R analyses is a beneficial tool that can be used for appropriate dose allocation in dose-finding studies for drug combinations.

Aim: High-dose administration of the -opioid receptor inverse agonist naloxone (NX), has previously been demonstrated to reinstate nocifensive behavior in the late phase of inflammatory injuries. However, no current analytical methods can provide pharmacokinetic insight into the pharmacodynamic response of high-dose administration of NX. Materials & methods:Based on protein precipitation using 50l human plasma, NX and naloxone--d-glucuronide (NXG) was analysed by UHPLC-MS/MS with 6 min cycle time.Results: A method for quantification of high-dose administered NX and NXG was developed and validated with intra- and interday precision and accuracy within 8.5% relative standard deviation (RSD)and -1.2-5.5% relative error (RE) for NX and 9.6% RSD and 0.6-6.5% RE for NXG. The method show excellent internal standard corrected matrix effects. Conclusion: A rapid UHPLC-MS/MS method was developed for quantification of NX and NXG in human plasma within 10-4000ng/ml.

The exposure-response relationship of combinatory drug effects can be quantitatively described using pharmacodynamic interaction models, which can be used for the selection of optimal dose...