S3.7
Dermal pharmacokinetic profile of topical formulations using microdialysis in the göttingen minipig.
Charbel Azar, Severine Collet, Cathy Berthaud, Adeline Maximilien, Thierry Alvarez,
André Jomard. GALDERMA R&D, SOPHIA ANTIPOLIS, FRANCE
In a previous PK/PD study (unpublished results), we observed that 2 different galenic forms (formulation A=solubilized form and formulation B=encapsulated form) containing the same active at the same concentration presented the same level of skin exposure to the active but very different levels of pharmacodynamic activity after repeated topical application in the minipig model. Indeed, when dosages of the active were performed from crunched skin biopsies, formulation A and formulation B led to the same level of skin exposure. But surprisingly when measuring the pharmacodynamic activity of the 2 galenic forms using modulation of biomarkers we observed that the activity of formulation B was much less important than the activity of formulation A.
In order to explain that discrepancy, we designed a skin PK study using the dermal microdialysis method to evaluate the amount of the free fraction of the active in the dermis after topical application of formulation A and formulation B in the minipig model.
Two formulations; A and B containing both 0.01% of the active (CDX) were evaluated in 2 minipigs.
Topical applications were performed once daily during fourteen days. On Day 14, six microdialysis probes per area (CMA 30 linear, 6 kDa with a membrane of 10 mm) were used. A microdialysis pump provides the perfusate flow of 1.5 µL/minute. Due to the physico-chemical properties of CDX (highly lipophilic LogD 7.2 = 5), 20% intralipid was used as perfusion liquid. Following equilibrium period, at t=0 the formulation was applied in a dose of 6 mg/cm² on a treated area of 35 cm². Samples of 90 µL were collected every 60 minutes over a 8-hour period from animals maintained under volatile anesthesia.
CDX content in samples was analyzed by UHPLC-mass spectrometry. The concentration of dialysates for each tested formulation was expressed in ng/mL.
The results show that formulation B (AUC0-8h = 0.041 ± 0.007 ng.h/mL) exposed less (≈3 - fold) the dermis to free fraction of CDX after repeated application than the formulation A (AUC0-8h = 0.128 ± 0.035 ng.h/mL)
The relative low level of free fraction concentration in the dermis with the formulation B is related to a lack of bioavailable drug in the dermis due to the galenic form. Those results were consistent with results previously obtained which showed «poor» pharmacological activity of formulation B when compared to formulation A.
Overall, those results demonstrate that cutaneous microdialysis is a relevant and accurate method to evaluate the skin PK profile of an active in different galenic forms, and suggest that false positive results can occur within some types of galenic forms when using dosage of the active from crunched skin biopsies.