Scientific article

Assessment and prediction of the cutaneous bioavailability of topical terbinafine, in vivo, in man

Published inPharmaceutical research, vol. 18, no. 10, p. 1472-1475
Publication date2001

OBJECTIVE : The in vivo effectiveness of a topical, dermatological formulation depends on the bioa-vailability of the drug within the skin at the site of action. Unlike oral drugs, or those delivered trans-dermally for systemic effect, the amount of active agent reaching the general circulation after topical application is a measurement of questionable relevance with respect to its local bioavailability. In ad-dition, the level of a dermatological drug, which can be found in the blood is invariably very small and difficult, if not impossible, to quantify easily. While local, ‘skin' concentrations of topical drugs can be obtained from biopsies of the site of application, this approach is very invasive and is unacceptable for routine use. Other practical alternatives have not been abundantly proposed, and the vasoconstriction assay for corticosteroids remains the only method (albeit imperfect itself) with significant credibility. Recently, the U.S. Food and Drug Administration has suggested a new, so-called dermatopharma-cokinetic (DPK), approach. METHODS: The idea is to evaluate topically applied drug levels in the stratum corneum (SC) in vivo as a function of time post-application and post-removal of the formulation, and to generate a SC con-centration versus time profile from which such “classical” measures as maximum drug level, time to reach this maximum, and the area under the curve can be obtained (i.e., in an analogous fashion to blood level measurements for an orally administered drug). The DPK method assumes that: (a) in normal circumstances, the SC is the rate-determining barrier to percutaneous absorption, (b) the SC concentration of drug is directly related to that which diffuses into the underlying viable epidermis, and (c) SC drug levels are more useful and relevant for assessing local, dermatological efficacy than plasma concentrations. Whereas methodological and validation issues for the DPK technique remain to be answered, it is clear that there is an attractive logic behind this idea. However, examination of the draft guidance reveals that this methodology will be labor-intensive even for relatively simple evaluations of bioequivalence. Our objective, therefore, is to begin an examination of whether experiments (following, in general, a DPK methodology) of relatively short duration can be analyzed to produce physicochemical parame-ters that describe drug transport in the SC and which can therefore be used to predict drug uptake as a function of time. RESULTS : Using the antimycotic drug, terbinafine (molecular weight = 291 Da; log(octanol/water partition coefficient) = 3.3), we have measured, in vivo, in man, the SC concentration versus depth profile following a 0.5-h exposure to a simple formulation. The data have been analyzed mathematicaly to yield the SC/vehicle partition coefficient (K)of the drug and its characteristic diffu-sion parameter (D/L2, where D is the drug's diffusivity across the SC of thickness L). CONCLUSION: With these values, the mathematical model has been used to predict the integrated quantity of drug in the SC following treatment periods of 2 and 4 h, and the predictions have then been compared to experiment. In addition, the longer-time data have been evaluated independently to determine whether K and D/L2 are sensitive to the duration of drug treatment.

  • Administration, Topical
  • Adult
  • Algorithms
  • Antifungal Agents/administration & dosage/pharmacokinetics
  • Area Under Curve
  • Biological Availability
  • Diffusion
  • Female
  • Humans
  • Male
  • Models, Biological
  • Naphthalenes/administration & dosage/pharmacokinetics
  • Pharmaceutical Vehicles
  • Predictive Value of Tests
  • Skin Absorption
Citation (ISO format)
ALBERTI, Ingo et al. Assessment and prediction of the cutaneous bioavailability of topical terbinafine, in vivo, in man. In: Pharmaceutical research, 2001, vol. 18, n° 10, p. 1472–1475. doi: 10.1023/A:1012217209228
Main files (1)
Article (Published version)
ISSN of the journal0724-8741

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