Model‐Informed Evaluation of Drug–Drug Interaction Recommendations for Amlodipine and Nirmatrelvir‐Ritonavir: A Hypothesis‐Generating Analysis

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While nirmatrelvir‐ritonavir effectively prevents severe COVID‐19, its ritonavir component causes significant drug–drug interactions (DDIs). Current guidelines suggest mitigating this interaction by halving the amlodipine dose or moving to every‐other‐day (EOD) dosing, then resuming the standard regimen 3–5 days post‐antiviral treatment. We applied physiologically based pharmacokinetic/pharmacodynamic (PBPK‐PD) modeling to evaluate the effects of these recommendations on systolic blood pressure (SBP) control. SARS‐CoV‐2 inpatients who received nirmatrelvir‐ritonavir (October–December 2022) and were exposed to potential DDIs were identified. An amlodipine PBPK‐PD model incorporating the diurnal variation of SBP was developed. The model was validated using amlodipine PK studies, including in DDI scenarios, while the PD model was validated against SBP data collected during amlodipine treatment. Simulations were performed in representative virtual populations, comprising various amlodipine doses and regimens, during and after nirmatrelvir‐ritonavir therapy. 362/1729 (20.9%) drugs from 166/217 (76.5%) patients were identified to have potential DDIs implicating nirmatrelvir‐ritonavir. Amlodipine was a common interacting drug (64/362, 17.7%) and often prescribed without dose adjustment (63%). Our simulations supported that continuing amlodipine during therapy may lead to SBP ≤100 mmHg at daily doses of ≥5 mg, while discontinuation may lead to SBP >130–150 mmHg. Halving the amlodipine dose during nirmatrelvir‐ritonavir treatment could provide more stable SBP control than EOD dosing. Resuming usual doses 3 days after nirmatrelvir‐ritonavir could be more important in those receiving 7.5 and 10 mg of amlodipine. DDIs between nirmatrelvir‐ritonavir and amlodipine were common. Our simulations evaluated current dose adjustment recommendations for amlodipine with mechanistic quantitative reasoning.