In Response.

Abstract

We thank Dr Dennis M. Fisher and Dr Steven L. Shafer,1 for their careful critique of our article. The criticisms raised in their letter to the editor1 will be discussed in this response point by point. First, in this study, we investigated the pharmacokinetics and pharmacodynamics of 3 doses of oral-mucosal dexmedetomidine (DEX) gel (0.5, 0.75, and 1 μg/kg) for sedative premedication in women undergoing modified radical mastectomy for breast cancer.2 The gel formula of DEX was formulated in our local pharmaceutical laboratory. Then pharmacokinetic assessments were performed using noncompartmental approach. As mentioned in our article, the use of buccal DEX as a gel decreases the oral loses of the drug, improves its absorption, and attenuates the unwanted adverse effects. To our knowledge, this is the first study that investigated such issue. Second, the primary outcome parameter of this study was to measure the plasma concentrations of Dex and to determine the degree of exposure following buccal Dex administration using the area under the curve (AUC) and the other pharmacokinetic parameters including clearance. A noncompartmental pharmacokinetic analysis was performed using 7 whole venous blood samples (3 mL for each) collected from each patient at 15, 30, 45 minutes and 1, 2, 4, and 6 hours after drug administration. The rationale for measuring DEX plasma concentrations out to 6 hours was based on previous study exploring the duration of action and the clearance of intravenous, intramuscular, peroral, and buccal administration of DEX.3 As this formula was novel, our primary aim was focused on determining the maximum plasma concentration (Cmax), time to peak plasma concentration (Tmax). Thus, most of our samples were distributed in the first 6 hours following DEX administration. In our results, some of the measured DEX plasma concentrations were similar, especially at the 4- and 6-hour samples producing flat concentration versus time curves. As Drs Fisher and Shafer1 point out, when extrapolating to infinity from these flat curves, the AUC from the last measured plasma concentration to infinity may be higher than anticipated. Experts recommend that the extrapolated area from the last plasma concentration to infinity should be as small as possible and not exceed 25% of the total AUC. In our analysis, the contribution of the extrapolated AUC from the last plasma concentration to infinity contributed substantially more than 25% to the total AUC. Thus, our estimates of the total AUC are likely excessively large, should be considered preliminary, and confirmed with additional investigation.4 To calculate the apparent clearance, an AUC extrapolated to infinity is required.5 As such, our estimates of apparent clearance are likely too small and should also be considered preliminary. To solve the flat plasma concentration over time curve problem observed in some of our patients, additional blood samples out to 8 or 12 hours after buccal DEX gel administration would likely improve the accuracy of the total AUC and apparent clearance. This will be taken into consideration in future studies.However, it worth mentioning that patients enrolled in our study were cancer patients. They were subjected to frequent blood sampling for investigations and adjuvant therapy. Aspiration of more than 7 blood samples from such patients may be excessive. Indeed, most pharmacokinetic analyses use a maximum of 6 to 8 blood samples in high-risk patients like ours. Third, in the Figure, thank you for pointing out the axis labeling error and the curved lines between data points. As suggested, the vertical axis is linear, not logarithmic. The text in the “Pharmacokinetic Results” segment should be revised to read: “The plasma concentrations of DEX versus time (minutes) in the 3 studied groups are shown in the Figure.” instead of “The plasma concentrations of DEX in the 3 studied groups are shown on a logarithmic scale versus time (minutes) in the Figure.” Also, the lines drawn between plasma concentration points in the figure were replaced with straight lines instead of smooth curves as recommended. Sahar Abdel-Baky Mohamed, MDDepartment of Anesthesia, Intensive Care and PainManagementSouth Egypt Cancer InstituteAssiut UniversityAssiut, Egypt Hala Saad Abdel-Ghaffar, MDDepartment of Anesthesia and Intensive CareFaculty of MedicineAssiut UniversityAssiut, Egypt[email protected] Nivin Abdel-Azim Hassan, MDDepartment of Cancer Biology (Pharmacology and Experimental Oncology)South Egypt Cancer InstituteAssiut UniversityAssiut, Egypt Fatma Adel El Sherif, MDDepartment of Anesthesia, Intensive Care and Pain ManagementSouth Egypt Cancer InstituteAssiut UniversityAssiut, Egypt Samia Abdelsamie Shouman, PhDDepartment of Cancer BiologyNational Cancer InstituteCairo UniversityCairo, Egypt Mervat Mostafa Omran, MDDepartment of Cancer Biology (Pharmacology and Experimental Oncology)National Cancer InstituteCairo UniversityCairo, Egypt Sahar Badr Hassan, PhDDepartment of Clinical PharmacyFaculty of PharmacyAssiut UniversityAssiut, Egypt Ayat Ahmed Abd EL-Monsef Allam, PhDDepartment of PharmaceuticsFaculty of PharmacyAssiut UniversityAssiut, EgyptDepartment of PharmaceuticsFaculty of PharmacySphinx UniversityNew Assiut CityAssiut, EgyptAssiut International Center of NanomedicineAL-Rajhy Liver HospitalAssiut UniversityAssiut, Egypt