Reply to: Comment: Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients

Abstract

To the editor,

We appreciate the interest of Drs. Du and Chen in our recent manuscript describing a pharmacokinetic model for intermittent intrathecal nicardipine administration.¹ The authors mentioned a few details that were omitted from our manuscript. These omissions were primarily due to prioritizing critical details in a limited space. We are happy to use the current space to further shed light on our clinical investigation.

First, with regard to sample storage, the hourly cerebrospinal fluid (CSF) (or plasma) samples were collected and initially stored on ice while protected from light. After completing the of sample collection for each dose tested, the entire set of samples was aliquoted and kept in a −80°C freezer. All the samples from all subjects in this cohort were measured as a single batch.

Second, the Du and Chen mention that we did not report certain patient outcomes. However, we clearly stated that the purpose of our study was to determine the pharmacokinetics of nicardipine in the CSF of a limited number of patients with subarachnoid hemorrhage. Many of the clinical aspects of intrathecal (IT) nicardipine administration were reported previously in a larger, better powered cohort.² Reporting patient outcomes in an underpowered small cohort may lead to the misinterpretation of efficacy. Therefore, despite the encouraging clinical outcomes observed in the current cohort, we chose not to publish them herein. As noted in our manuscript, we agree that larger and more rigorously designed studies are needed in the future to develop an optimal dosing strategy for IT nicardipine based on integrative pharmacokinetic/pharmacodynamic (PK/PD) assessment of patient outcome data.

Third, Du and Chen mentioned a single center small cohort study that reported an alternative IT nicardipine administration approach using a cisternal drain.³ Per this report, cisternal drain placement occurred during microsurgical clipping rather than during endovascular repair of the aneurysm as Du and Chen mistakenly stated. Since the endovascular approach is associated with improved patient outcomes (see International Subarachnoid Aneurysmal Trial [ISAT] ⁴), it is unclear to us how mentioning the work of Vandenbulcke et al. in relationship to ours is relevant.

Furthermore, Du and Chen incorrectly claimed that q12hr dosing is the most common frequency for intrathecal nicardipine. This might be true at their center. Indeed, in a new clinical trial originated from The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China (FAST-IT trial, NCT06329635) this was the regimen chosen. However, prior to our report, a dose range of 2–10 mg q8hr or q6hr dosing was reported in 6 different papers involving 548 patients,^{2, 5-9} while a dosing regimen of 4 mg q12hr was reported in 4 papers involving 192 patients.^10-13

By choosing a 4 mg q12hr regimen for their clinical trial, we believe that the researchers at The Affiliated Hospital of Guizhou Medical University have taken a significant risk. Without defining a clear pharmacokinetic model, and a dose-finding phase to identify the optimal dose prior to a phase III clinical trial, FAST-IT may fail to demonstrate efficacy of IT nicardipine due to underdosing.

The authors declare no conflicts of interest.

The data presented herein will be shared upon reasonable request.