RAPID CLEARANCE OF METHYLPREDNISOLONE AFTER INTRATYMPANIC APPLICATION IN HUMANS. COMMENT ON: BIRD PA, BEGG EJ, ZHANG M, ET AL. INTRATYMPANIC VERSUS INTRAVENOUS DELIVERY OF METHYLPREDNISOLONE TO COCHLEAR PERILYMPH. OTOL NEUROTOL 2007;28:1124-30
2008-08-01

To the Editor: The study by Bird et al. (1) is extremely important to the field of drug delivery to the inner ear because it provides the first measurements of human perilymph levels of a glucocorticoid (methylprednisolone [MP]) after local intratympanic application. Perilymph samples were taken at various times (20 min to 3 h) after application, and the measurements were tabulated. However, because of the variability they observed, the authors chose to pool their data and they were presented as a simple scatterplot. We reanalyzed the raw data, taking into account the timing of the samples, from which we have been able to derive important pharmacokinetic parameters for MP entry into the inner ear. The symbols in Figure 1 show the data by Bird et al. replotted based on the sample timing information. It is apparent that samples taken at 1 hour show consistently higher levels than samples taken at longer times (2 and 3 h) that are uniformly low. We have used computer simulation methods (2) to calculate expected sample concentration time courses as kinetic parameters were varied. The most important variable affecting the time course is the rate of drug clearance from the system. The rate of clearance was varied while calculating the sum of squares of deviations between calculated sample values and those obtained experimentally. The lowest sum of squares, indicating best fit, was found with a clearance halftime of 27 minutes. This estimated rate of clearance for MP was somewhat faster than that calculated for prednisolone based on prior experiments in guinea pigs, which occurred with a halftime of 130 minutes (2,3).FIG. 1: Measured MP concentrations reported by Bird et al. (1) plotted as a function of the time between drug application and sampling (solid symbols); predicted time courses derived by simulating the drug application and perilymph sampling protocols (lines). The heavy line shows the best fit to the data, derived by minimizing the sum of squares of differences between measured and calculated values (inset graph). Lighter lines show curves calculated for 0.5× (13.3 min) and 2× (54 min) clearance values and scaled to the same peak amplitude to demonstrate the expected time course as clearance rates were varied. The inset graph shows the sum of squares of deviations (an index of how well the curve fits the data) as the rate of clearance was varied. (Details of simulation parameters: The simulation program [available at: http://oto.wustl.edu/cochlea/] was set with cochlear dimensions appropriate to the human and with a diffusion coefficient for MP of 0.784 × 10−9 m2/s. Simulation of the drug application to the RW niche used an applied volume of 1 ml at a concentration of 40 mg/ml. It was assumed that the 20-μL sample volume taken experimentally originated from the most basal 12 mm of scala tympani which, based on the scala cross-sectional area data, makes up this volume. Because the sites of clearance cannot be definitively established, the same rates were used to define clearance from the middle ear and the cochlear fluids. An RW permeability of 7.8 × 10−9 m/s and clearance halftime of 27 minutes generated the best fit curve.)The data by Bird et al. show that MP is rapidly eliminated after a single intratympanic application in humans. We think that the time course results from 2 competing processes. Initially, MP perilymph concentration increases as a function of application time. As time progresses, clearance of drug from the middle ear and perilymph counteracts the increase and results in declining concentration with time. Because of this rapid rate of clearance, to maximize glucocorticoid levels in the inner fluids and tissues, the drug concentration in the round window (RW) niche needs to be maintained. Even considering the likely time course followed, the variation of sample values is large, as correctly pointed out by the authors. However, the degree of variation is comparable to that observed with RW delivery of another glucocorticoid (dexamethasone) in animals (3-5). Our calculations show that the perilymph drug level achieved is highly dependent on the time of contact of drug with the RW membrane. In contrast, the applied drug volume plays a lesser role. Based on the RW membrane permeability, the amount of drug entering the cochlea is a small proportion of that applied. Loss of drug from the RW niche to regions other than the cochlea is of far greater significance. This can occur either by the loss of volume from the middle ear, such as loss through the eustachian tube, or as absorption by the mucosa, which can cause drug concentration to decrease without an associated volume change. The important conclusion is that in order to maximize drug entry into perilymph a high concentration on the RW membrane must be maintained either by replacing the drug solution at intervals or by using a sustained delivery vehicle. *Stefan K. Plontke, M.D. †Anthony A. Mikulec, M.D. ‡Alec N. Salt, Ph.D. *Department of Otorhinolaryngology Head and Neck Surgery Tübingen Hearing Research Center University of Tübingen Tübingen, Germany †Department of Otolaryngology Saint Louis University School of Medicine and ‡Department of Otolaryngology Washington University School of Medicine St. Louis, Missouri, U.S.A.