Percutaneous lidocaine administration via a new iontophoresis system in children: tolerability and absence of systemic bioavailability
Gregory L. Kearns
Venipuncture is a routine and necessary medical procedure that is performed to facilitate the care of patients and also the conduct of pediatric clinical trials that require either multiple venipunctures or the insertion of an indwelling venous cannula. The psychosocial and practical importance of relieving pain associated with skin puncture and the techniques to accomplish this goal were reviewed recently. (1) Although topical application of cream-based local anesthetic mixtures (eg, eutectic mixture of local anesthetics or EMLA cream; lidocaine 2.5% and prilocaine 2.5%; AstraZeneca, Wayne, PA) have been associated with efficacy, their use can be somewhat inefficient because of the need to apply the preparation 1 hour before a minor dermal procedure (eg, venipuncture). (2)
Lidocaine, a small molecular weight amide local anesthetic, has extremely poor bioavailability when applied passively (ie, without devices to enhance penetration) to intact skin as a solution or semisolid (eg, ointment) formulation (3) and therefore is virtually devoid of clinical efficacy. Iontophoresis allows for the transdermal delivery of small molecular weight, charged drugs using a low-level electrical current that facilitates migration of a drug ion from a percutaneous contact site (eg, drug delivery patch or reservoir) through the skin in response to the influence of an electrical potential. (4) The safety, tolerability, and efficacy of lidocaine iontophoresis in pediatric patients has been demonstrated in opens (5,6) comparatorbased (eg, versus EMLA) (7-9) and placebo-controlled (10) clinical trials. Although iontophoresis has been demonstrated by Wallace et al (11) to produce the greatest depth of dermal anesthesia relative to other current-based techniques (eg, electroporation, electroincorporation), none of the previously published (assessed from a computer-based search of the indexed holdings of the US National Library of Medicine from 1978 through 2003) investigations of lidocaine iontophoresis in pediatric patients (5-10) has systematically evaluated the bioavailability of the drug after single or repeated application.
Recently, a new iontophoresis system was developed (Northstar Iontophoretic Patch; Becton Dickinson Transdermal Systems, Fair Lawn, NJ) for transdermal lidocaine delivery to pediatric patients who require regional, dermal anesthesia for venipuncture. Unlike other iontophoresis devices, this system uses a hydrogel reservoir that is prefilled with lidocaine (10%) and epinephrine (0.1%) and is designed to deliver an effective dose over a 10-minute period. (12) The clinical safety and efficacy of this particular device was recently demonstrated in a study of 272 pediatric patients that did not include an assessment of systemic lidocaine exposure. (13) We report the results from a tolerance study of this novel iontophoresis system conducted in a population of children and adolescents that had as a primary goal the assessment of systemic lidocaine exposure.
This was a single-center, open-label phase I trial designed to assess the tolerance and short-term safety of the Northstar Iontophoresis System in healthy children and adolescents between 5 and 15 years of age after randomized repeated applications of the study device. The primary and secondary study endpoints were the assessment of lidocaine bioavailability and device tolerability, respectively. The protocol was conducted under applicable Good Clinical Practice regulations in compliance with all regulatory requirements under the US Food and Drug Administration IND #48365. The study protocol and consent form were also reviewed and approved by the University of Missouri–Kansas City Pediatric Health Services Institutional Review Board and the Network Steering Committee of the Pediatric Pharmacology Research Unit Network (National Institute of Child Health and Human Development, Bethesda, MD). Children and adolescents of either sex and all racial/ethnic groups were considered for enrollment. All study participants were enrolled by informed parental consent (ie, permission) and for children [greater than or equal to] 7 years of age by subject assent.
After informed consent was obtained, all subjects underwent a comprehensive screening evaluation to determine their eligibility for study participation. Subjects were required to be between 5 and 15 years of age; to have no evidence of (by biochemical and historical assessment) hepatic, renal, hematologic, vasculitic, cardiovascular, neurologic, respiratory, endocrine, and/or dermatologic disease; to be of normal height and weight for age (ie, 5th-95th percentile); and to be capable of completing all required study procedures. Subjects who had a history of intolerance and/or hypersensitivity reactions to lidocaine or other amide anesthetic agents, epinephrine, and/or medical adhesives were excluded, as were those who had any dermatologic abnormality or had previously demonstrated (by history) an intolerance to venipuncture.
On the day of study, subjects reported to the Pediatric Clinical Research Unit at approximately 7 AM after a 6-hour fast that was maintained for an additional 2 hours. A brief intake history and physical examination, including visual examination of the skin, were completed, and all subjects were reweighed. An indwelling venous cannula (22 gauge, 1.0 inch, 0.9 x 25 mm BD Insyte Autoguard; Becton Dickinson Medical Systems Inc, Sandy, UT) was then inserted into a large vein located either on the dorsum of the hand or on the forearm of the extremity that was contralateral to the one used for placement of the study device. Topical anesthetic agents were not used for this procedure consequent to the potential for interference/interaction with the assessment of the study device. The patency of this cannula was maintained using a sterile solution of 0.9% sodium chloride for injection (Syrex, Neptune, NJ).
At 15 minutes before application of the study device, a venous blood sample (2.0 mL) was obtained as a “baseline” measurement for lidocaine concentration. For each subject, the study device was applied for 10 minutes at 3 defined time intervals: 0 (initiation of study), 3.0, and 3.5 hours. Each application of the study device (Fig 1) used the Northstar iontophoretic patch that contains aqueous anode and cathode hydrogel reservoirs. The anode reservoir contained 10% lidocaine hydrochloride (100.0 mg) and 0.1% epinephrine free base (1.0 mg) from L-epinephrine bitartrate (as active ingredients) and the following excipients: sodium chloride, sodium metabisulfite, edetate disodium, citric acid, glycerin, and a phenol-based preservative. The cathode hydrogel reservoir contained sodium chloride, monobasic sodium phosphate, glycerin, and phenol-based preservative. All ingredients were United States Pharmacopeia or National Formulary grade. Both electrodes and interconnect traces used Ag/AgCl to facilitate conductance. The study device also included a controller (heart-shaped chamber; Fig 1) that used a maximum voltage that was limited to 35 volts and a current of 1.78 mA. The duration of the period for each application of the study device in the subjects was 10 minutes.
[FIGURE 1 OMITTED]
The site for application of the study device was selected at random using a Latin square technique to 3 of 4 possible anatomic sites that consisted of the antecubital fossa, the anterior chest wall, the upper back, and the dorsum of the hand. Within a given subject, the device was not applied to the same site twice. Repeated venous blood samples (2.0 mL each) were obtained at the following times after the first application of the study device: 0.25, 0.5, 1, 2, 2.9, 3.4, 3.75, 4, 4.5, 6.67, and 9.67 hours. The sampling schedule was chosen so as not to interfere with the times of application for the study device (0, 3, and 3.5 hours) and in an attempt to capture both apparent peak plasma lidocaine concentrations associated with each application and the elimination of the drug after the last application. During this time, subjects were permitted to ambulate but were prohibited from engaging in vigorous aerobic exercise or related activities that could potentially influence dermal or hepatic blood flow. They were provided with age-appropriate (ie, content and composition) meals, snacks, and beverages in accordance with menus established by the hospital Department of Nutritional Services.
At the conclusion of the repeated blood sampling, a single research nurse trained by a pediatrician evaluated all application and intravenous access sites for erythema and edema using the Draize scoring method as described by Singh et al. (14) A single rater was used to facilitate accuracy in the interpretation of dermal findings and eliminate bias associated with interrater reliability. Subjects were asked to return to the study unit in 24 hours after the onset of the study for a subsequent evaluation of all application sites.
Pharmacokinetic and Statistical Analyses
Repeated blood samples for determination of plasma lidocaine concentrations were collected into glass tubes containing anticoagulant (5.4 mg [K.sub.2]EDTA; Vacutainer, Becton Dickinson, Franklin Lakes, NJ), immediately mixed by inversion, and centrifuged (2500 x g for 10 minutes at 4[degrees]C) to separate plasma, which was then removed by manual aspiration and placed at -70[degrees]C within 30 minutes of sample collection. Lidocaine was quantified in triplicate from all plasma samples in accordance with Good Laboratory Practice guidelines using a validated high-performance liquid chromatography method with mass spectrophotometric detection. (15) The method had a lower limit of quantification of 5 ng/mL and appropriate inter- and intra-assay variability (ie, <10%) over the range of linearity of 5 to 1000 ng/mL. Lidocaine plasma concentrations as a function of time were evaluated for each subject using graphical techniques to determine whether a pharmacokinetic "pattern" of behavior was evident, and, if so, standard pharmacokinetic and statistical approaches (eg, curve fitting, analysis of variance with log transformation of concentration data if appropriate) to assess time and/or application dependent changes in plasma concentration were to be used.
Sample size determination was based on the lower limit of detection for the plasma lidocaine assay (5 ng/mL) and the hypothesis that “no plasma lidocaine concentration above the lower limit of detection” would be observed. Assuming that an interval of 0 to 5 ng/mL represented a 6[sigma] interval in the distribution of plasma lidocaine concentrations in subjects with assay results below the limit of detection and that the midpoint concentration was 2.5 ng/mL, the hypothetical standard deviation is 6/5 or 0.833 ng/mL. The sample size of 12 subjects with 6 observation (plasma concentration) points was therefore predicted to provide approximately 95% power to reject the null hypothesis of no change in plasma lidocaine level if there was a change of 1 standard deviation ([approximately equal to] 0.833 ng/mL) in plasma lidocaine levels.
Standard descriptive statistics (eg, mean, standard deviation, range) were used to examine demographic variables. Results of the Draize scores from each of the application sites for both the anode and cathode were expressed as the percentage of total subjects evaluated who had evidence of either no (Draize score = 0), very slight (Draize score = 1), well-defined (Draize score = 2), moderate (Draize score = 3), or severe (Draize score = 4) erythema and/or edema at the conclusion of the blood sampling period and at the 24-hour poststudy evaluation interval. All statistical analyses were conducted using a commercially available software package (SAS Version 8.0 for Windows; SAS, Inc, Cary, NC) and assumed a significance limit of [alpha] = 0.05.
All 12 subjects who were enrolled into the clinical trial completed virtually 100% of study procedures (the 580-minute blood sample was not obtained in subject 11 consequent to technical difficulties) and hence had assessable data. The subjects (8 boys/4 girls; 10 white and 2 black) ranged in age from 5 to 15 years (10.4 [+ or -] 3.8 years) and had age-appropriate body composition (mean [+ or -] standard deviation [range] height and weight: 144.4 [+ or -] 20.8 cm [116-176 cm] and 44.3 [+ or -] 21.7 kg [19-79 kg], respectively). With the possible exception of 1 subject (subject 02, who was receiving carbamazepine, 400 mg/d for seizure control), none of the other study participants was receiving concomitant treatment with drugs and/or natural/complimentary medications known either to interact with lidocaine (3) or to have an impact on the activity of cytochrome P450 3A4 (the enzyme primarily responsible for lidocaine biotransformation).
Examination of lidocaine concentrations from plasma samples (n = 12 per subject over 580 minutes) revealed values that were below the lower limit of detection (<5 ng/mL) for the analytical method in 11 of 12 subjects at all observation points. The 1 exception was observed with data from subject 07, who had a single, isolated plasma lidocaine concentration of 8.9 ng/mL at the 225th minute, approximately 5 minutes after the third and final application of the study device. In this particular subject, all plasma lidocaine concentrations before and after the 225-minute time point were reported to be <5 ng/ mL. Thus, a pharmacokinetic "pattern" (ie, discernible absorption and elimination phase) for plasma lidocaine concentrations was not seen in any subject; consequently, additional statistical examination of these data was not warranted.
All 12 subjects had 3 applications each of the study device (36 applications total for the study) to 3 of 4 possible anatomic sites (antecubital fossa, anterior chest, back, and dorsum of hand; 9 applications per site). During applications of the study device, no subject complained of frank pain or discomfort. Subjects did uniformly report a definite “sensation” (eg, mild tingling) on the skin during the respective 10minute periods of iontophoresis. Transient and virtual complete (>90%) blanching of the skin under the anode was noted immediately after the first application of the study device. After the subsequent 2 applications at the 205- and 225-minute evaluation periods, transient blanching of the skin under the anode was again seen, albeit to a slightly reduced degree (approximately 75%) as compared with the initial application. Blanching of the anode site and any sensations associated with active iontophoresis seemed (by visual inspection) to be resolved completely in all subjects within approximately 15 minutes of removal of the study device.
The results of the Draize scoring from each of the application sites are summarized in Table 1. Subjects experienced only “very slight” erythema and/or edema (Draize score = 1) at the application sites. As well, with the possible exception of very slight erythema associated primarily with the anode at each of the 4 application sites, relatively few of the subjects (0%-28%) experienced any discernible dermal abnormalities during the first day of the study. These findings were maintained at the 24-hour follow-up evaluation with virtually all of the subjects having no evidence of erythema or edema irrespective of application site. Although there were also no appreciable differences in dermal response as a function of anatomic site (Table 1), erythema associated with the anode seemed to be more prominent when the study device was applied to either the chest or the back as compared with the antecubital fossa or the dorsum of the hand. Furthermore, it is important to note that no subject had a Draize score of 2 or greater for any anatomic site at any of the 2 evaluation periods, which collectively represented 72 separate evaluations over a 24-hour period.
Finally, global evaluation of spontaneous reports from all subjects demonstrated that repeated applications of the study device and the performance of all study-associated procedures were generally well tolerated. Only 4 subjects reported minor adverse events ranging from reports of “redness” associated with the anode or cathode patch (n = 3 subjects; data captured as erythema in the Draize scoring) and “raised bumps” associated with the cathode patch (n = 3 subjects). No severe adverse events were reported in association with this clinical trial.
The Northstar iontophoresis system was specifically designed to administer an effective intradermal dose of lidocaine, supplemented by the addition of a minute amount of epinephrine to maintain regionalization of the anesthetic and thus to prevent its systemic bioavailability. (12) This particular iontophoresis system uses a patented form of hydrogel technology that controls the release kinetics of small molecules and physicochemically facilitates their penetration into the stratum corneum. (16) Implicit in the development of any such device is the requirement to assess completely its tolerability and, ultimately, its safety in the target population by demonstrating objectively that significant systemic absorption of the anesthetic agent does not occur.
As denoted above, none of repeated blood samples from any of the 12 subjects obtained during the study period (Fig 1) had a plasma concentration of lidocaine >10 ng/mL, with 131 of 132 total postadministration specimens (99.2%) having concentrations below the limit of detection (5 ng/mL) for the analytical method. All lidocaine plasma concentrations in the subjects were well below those associated with either systemic therapeutic effect (1500-5500 ng/ mL) or toxic effects ([greater than or equal] 6000 ng/mL). (3) The absence of a discernible absorption or elimination phase for plasma lidocaine concentrations in each subject precluded the application of pharmacokinetic modeling to describe apparent rates of drug appearance/disappearance. Although epinephrine plasma concentrations were not specifically assessed in this investigation, previous data from studies of the Northstar iontophoresis system in animals suggest that clinically significant systemic bioavailability of epinephrine does not occur (ie, consistently <0.25% of the [sup.3]H-epinephrine dose contained in the patch). (15)
An equally important focus of this investigation was to assess the tolerance and short-term safety of this iontophoresis system. Although the intended use of the product entails single administration 10 minutes before venipuncture, anticipation of clinical scenarios in pediatrics where intentional repeated applications may occur (eg, unsuccessful venipuncture attempts) prompted us to use a multiple administration study paradigm. As reflected by the data from the repeated assessments (72 total) of 4 different anatomic sites (Table 1), only very slight erythema and/or edema was associated with any of the applications of the study device. Other than the expected reports of a “sensation,” which occurred in all subjects during active iontophoresis, transient blanching of the skin associated with the anode site, and sporadic reports (n = 3) of small papules (ie, raised bumps) occurring immediately after iontophoresis, all subjects tolerated the application of the study device well. No subject experienced a frank burn or any other objective finding that would have supported clinically significant dermal irritation. These findings have been corroborated by a recent randomized, double-blind, placebo-controlled, clinical trial conducted in 272 pediatric patients that demonstrated both the safety and the efficacy of this device used to reduce pain associated with venipuncture. (13) Given that the primary objective of our study was to assess lidocaine bioavailability, ethical constraints associated with the study requirement for repeated blood sampling precluded our use of a placebo-control group. Despite that the power associated with our bioavailability evaluation permits generalization of the bioavailability results to a larger population of pediatric patients of similar age, the extrapolation of tolerance data is statistically constrained by the relatively small number of subjects in our trial. However, the assertion of tolerance/safety and efficacy of this particular iontophoresis device in pediatric patients seems to be supported by results from a recent controlled trial. (13) Finally, it should be noted that neither our data nor those from previously published clinical trials examining lidocaine iontophoresis in pediatric patients (7,10,13) provide any information that would support or accurately predict the safety of the technique and/or a specific device with long-term, regular (eg, daily) use.
This iontophoresis system seems to provide a well-tolerated method for providing dermal anesthesia with lidocaine in children that is not associated with the systemic delivery of this drug. Therefore, its proper use in pediatric patients should be devoid of systemic toxicity produced by lidocaine.
TABLE 1. Summary of Tolerance Data
None (10 Very None (24 Very
Hours) Slight Hours) Slight
% of (10 Hours) % of (24 Hours)
Subjects % of Subjects % of
Anode edema 100 0 100 0
Anode erythema 90 11 90 11
Cathode edema 100 0 100 0
Cathode erythema 90 11 90 0
Anode edema 100 0 90 11
Anode erythema 55 44 77 28
Cathode edema 100 0 100 0
Cathode erythema 100 0 90 11
Anode edema 100 0 100 0
Anode erythema 55 44 100 0
Cathode edema 100 0 100 0
Cathode erythema 90 11 100 0
Dorsum of hand
Anode edema 100 0 100 0
Anode erythema 90 11 90 11
Cathode edema 100 0 100 0
Cathode erythema 90 11 100 0
N = 9 evaluations per site. Percentage figures rounded to whole number.
It was supported in part by a clinical trial grant from Becton Dickinson Medical Systems. Partial salary support for Drs Kearns and Alander was provided through grant 5 U01 HD 31313-09 from the Network of Pediatric Pharmacology Research Units, National Institute of Child Health and Human Development, Bethesda, MD.
We gratefully acknowledge the support and assistance provided by Jami Penny, LPN; Michael Venneman, BSN, RN; Jennifer A. Lowry, MD; and Amy J. Nopper, MD, in the evaluation of the study protocol and subjects and in the conduct of this clinical trial.
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Gregory L. Kearns, PharmD, PhD * ([double dagger]) ([section]); Jeanellen Heacook, BS, CCRA ([parallel]); Sally Ann J. Daly, BA, CCRA ([paragraph]); Hena Singh, MS ([paragraph]); Sarah W. Alander, MD * ([double dagger]) ([parallel]); and Shankang Qu, PhD ([paragraph])
From the Departments of * Pediatrics and ([double dagger]) Pharmacology, University of Missouri-Kansas City, Kansas City, Missouri; the Divisions of ([section]) Pediatric Clinical Pharmacology and Medical Toxicology and ([parallel]) Pediatric Emergency Medicine, Children’s Mercy Hospitals and Clinics, Kansas City, Missouri; and ([paragraph]) Becton Dickinson Medical Systems, Franklin Lakes, New Jersey. This work was presented in part at the 103rd Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics; March 25, 2002; Atlanta, GA.
Received for publication Mar 3, 2002; accepted Feb 20, 2003.
Reprint requests to (G.L.K.) Division of Pediatric Pharmacology and Medical Toxicology, Department of Pediatrics, Children’s Mercy Hospitals and Clinics, 2401 Gillham Rd, Kansas City, MO 64108. E-mail: email@example.com
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