Flux Matters: IVIVC-Based Prediction of Occlusion Effects on Transdermal Oxybutynin

Oxybutynin (OXB), an antimuscarinic agent used to treat overactive bladder, is available as oral tablets, transdermal patches, and transdermal gels. In a recent clinical study involving the transdermal products, ~ 15-fold higher OXB exposures were observed during and following occlusion (i.e., creating a significant barrier to transepidermal water loss) potentially elevating the risk of adverse events. To better understand and predict these occlusion effects, a transdermal in vitro-in vivo correlation (IVIVC) model was developed. In vitro OXB permeation from a transdermal gel was characterized based on in vitro permeation tests using excised human skin without occlusion or with occlusion application from 7 to 10 h. OXB disposition was characterized by using digitized data from literature following intravenous administration. In vivo OXB absorption was characterized by using deconvolution techniques on data from a clinical study under similar occlusion conditions. In vitro and in vivo flux and occlusion-related parameters were correlated in an IVIVC model. While the in vitro flux showed a mean lag time of 3.5 h (21% variability), in vivo flux had no lag. The skin exit rate constant was similar in vitro (0.17 h^-1, 61% variability) and in vivo (0.16 h^-1, 79% variability). In vivo occlusion effects increased on average by 18-fold and 30-fold during occlusion and after occlusion removal, respectively. The IVIVC model predictions adequately described the observed data with precisely estimated parameters. This work establishes a new framework for developing transdermal IVIVCs and demonstrates the feasibility of predicting in vivo OXB concentrations while accounting for occlusion effects.