Chao Xu1,2, Patanjali Ravva1, Jun Steve Dang1, Johann Laurent3, Céline Adessi4, Christine McIntyre5, Georgina Meneses-Lorente5, François Mercier6. 1. Clinical Pharmacology, Pharmaceutical Sciences, Roche Innovation Center New York, New York, USA. 2. Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc, Rahway, USA. 3. Clinical Pharmacology, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland. 4. Pharma Drug Safety Licensing, Roche Innovation Center Basel, Basel, Switzerland. 5. Clinical Pharmacology, Pharmaceutical Sciences, Roche Innovation Center Welwyn, Welwyn, UK. 6. Clinical Pharmacology, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland. francois.mercier@roche.com.
Abstract
PURPOSE: To inform lumretuzumab and pertuzumab dose modifications in order to decrease the incidence, severity, and duration of the diarrhea events in metastatic breast cancer patients treated with a combination therapy of lumretuzumab (anti-HER3) in combination with pertuzumab (anti-HER2) and paclitaxel using quantitative clinical pharmacology modeling approaches. METHODS: The safety and pharmacokinetic (PK) data from three clinical trials (lumretuzumab monotherapy n = 47, pertuzumab monotherapy n = 78, and the combination therapy of lumretuzumab, pertuzumab and paclitaxel n = 35) were pooled together to develop a continuous-time discrete states Markov model describing the dynamics of the diarrhea events. RESULTS: The model was able to capture the time course of different severities of diarrhea reasonably well. The effect of lumretuzumab and pertuzumab was well described by an Emax function indicating an increased rate of transition from moderate to mild or more severe diarrhea with higher doses. The concentration needed to trigger or worsen diarrhea episodes was estimated to be 120-fold lower in combination therapy compared to monotherapy, suggesting strong synergy between the two monoclonal antibodies. The prophylactic effect of loperamide in a subset of patients was also well captured by the model with a clear tendency to reduce the occurrence of diarrhea events. CONCLUSIONS: This work shows that PK-toxicity modeling provides insight into how the severity of key adverse events evolves over time and highlights the potential use to support decision making in drug development.
PURPOSE: To inform lumretuzumab and pertuzumab dose modifications in order to decrease the incidence, severity, and duration of the diarrhea events in metastatic breast cancerpatients treated with a combination therapy of lumretuzumab (anti-HER3) in combination with pertuzumab (anti-HER2) and paclitaxel using quantitative clinical pharmacology modeling approaches. METHODS: The safety and pharmacokinetic (PK) data from three clinical trials (lumretuzumab monotherapy n = 47, pertuzumab monotherapy n = 78, and the combination therapy of lumretuzumab, pertuzumab and paclitaxel n = 35) were pooled together to develop a continuous-time discrete states Markov model describing the dynamics of the diarrhea events. RESULTS: The model was able to capture the time course of different severities of diarrhea reasonably well. The effect of lumretuzumab and pertuzumab was well described by an Emax function indicating an increased rate of transition from moderate to mild or more severe diarrhea with higher doses. The concentration needed to trigger or worsen diarrhea episodes was estimated to be 120-fold lower in combination therapy compared to monotherapy, suggesting strong synergy between the two monoclonal antibodies. The prophylactic effect of loperamide in a subset of patients was also well captured by the model with a clear tendency to reduce the occurrence of diarrhea events. CONCLUSIONS: This work shows that PK-toxicity modeling provides insight into how the severity of key adverse events evolves over time and highlights the potential use to support decision making in drug development.