Purpose: Drug delivery from topical delivery systems (TDS) can be influenced by external factors such as temperature. The extent of such influences may depend on the formulation design and drug load of the respective TDS. The purpose of this study was to evaluate the effect of transient heat exposure on 1) in vitro permeation of lidocaine across excised human skin and 2) in vivo bioavailability of lidocaine in healthy human volunteers, under harmonized study conditions, for two bioequivalent lidocaine TDS. A central consideration of the study design was to evaluate the influence of exposure to elevated heat early in the wear duration, before steady state is achieved, compared to exposure to elevated heat later in the wear duration, after steady state has been achieved for a TDS.
Methods: An open-label, six-way crossover pharmacokinetic (PK) study was conducted on healthy human subjects using two lidocaine TDS (Lidocaine topical patch, 5% from Mylan is the generic product and Lidoderm® (lidocaine) topical patch, 5% is the reference listed drug (RLD) product) in presence and absence of transient heat. The PK profiles in the absence of heat application was characterized first (sessions 1 and 2) then heat was applied for four successive sessions (sessions 3 – 6). During the transient heat application, a skin temperature of 42 ± 2°C was achieved by application of a heating pad over the TDS. Early heat was applied for 90 min, 4 hours post-TDS application (sessions 3-reference TDS and 4-generic TDS) and late heat was applied for 90 min, 8.5 hours after TDS application (sessions 5-reference TDS and 6-generic TDS). Serum samples were analyzed for lidocaine using a validated LC-MS/MS method. A study design harmonized to the clinical PK study was used for in vitro permeation tests (IVPT) performed using ex vivo human skin to investigate the dermal absorption from the two lidocaine TDS. A circulating water bath was used to modulate the heat. A 0.97-cm2 circular disc of the TDS was applied on the skin within the permeation area of the diffusion cell. Receptor solution was collected at predetermined time intervals and analyzed using a validated high performance liquid chromatography (HPLC) method. P values were calculated using Student’s t-test.
Results: For the reference TDS, a 5.0 ± 2.0 fold and a 2.0 ± 1.5 fold enhancement in mean Cmax was observed in vivo with early and late heat application, respectively. For the generic TDS, a 7.3 ± 1.8 fold and a 2.5 ± 1.5 fold enhancement in mean Cmax was observed in vivo with early and late heat application, respectively (n=5 subjects). For the reference TDS, 4.7 ± 1.3 fold and a 4.4 ± 1.1 fold enhancements (p<0.05) in Jmax were observed in vitro with early and late heat application, respectively. For the generic TDS, 1.9 ± 0.3 fold and 1.8 ± 0.1 fold enhancements (p<0.05) in Jmax were observed in vitro with early and late heat application, respectively. (n=4 donors, 4 replicates per donor).
Conclusion: Exposure to transient heat resulted in increased serum levels of lidocaine for both generic and reference lidocaine TDS, in human volunteers. When exposed to an elevated temperature in vitro, under conditions that closely matched the in vivo study conditions, lidocaine TDS exhibited an increase in the rate and extent of drug delivery relative to its baseline drug delivery under normal temperature conditions. The elevated rate of lidocaine delivery through the skin did not return to baseline levels immediately following the removal of the external heat source, both in vitro and in vivo, therefore the effect of heat on the bioavailability of lidocaine extends beyond the 1.5 hour heat application window. Overall, the limited interim in vivo dataset shows similar enhancement patterns in drug delivery as observed in vitro following exposure to transient heat. However, incorporation of data from additional volunteers may alter these results.
Acknowledgment: Funding for this project was made possible, in part, by the Food and Drug Administration through grant U01FD004955. The views expressed in this abstract do not reflect the official policies of the U.S. Food and Drug Administration or the U.S. Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.
Sagar Shukla– PhD Candidate, University of Maryland, Baltimore
Dana Hammell– Research Fellow, University of Maryland, Baltimore
Hassan Hazem– Clinical Pharmacologist, U S Food and Drug Adminstration
Audra Stinchcomb– Professor, University of Maryland Baltimore, Baltimore, Maryland