Devendra Pade, Jan Wahlstrom
Terbinafine (TBNF), a lipophilic anti-fungal agent prescribed for onychomycosis distributes extensively into adipose, skin and peripheral tissues. TBNF and metabolite desmethyl terbinafine (DMT) are potent inhibitors of CYP2D6. A combination of prolonged half-life and CYP2D6 inhibition causes clinically significant interactions with drugs involving CYP2D6 metabolism that may persist for weeks after dosing cessation. A physiologically based pharmacokinetic (PBPK) model for TBNF and DMT incorporating in vitro and clinical information was developed and verified to predict their steady state pharmacokinetics. Experimentally determined Kiu,CYP2D6 for TBNF and DMT enabled to predict the interaction with CYP2D6 substrates Desipramine, Amitriptyline and Nortriptyline. The PBPK model predicted steady-state plasma concentration-time profiles of TBNF and DMT after daily administration of 250 mg and 125 mg TBNF were in agreement with the observed data, including sustained plasma concentrations after dosing cessation. This enabled prediction of drug interactions with the CYP2D6 substrates during and after termination of TBNF dosing. The distribution of TBNF into adipose and skin acts as a depot leading to its slow re-distribution back into plasma, followed by sequential metabolism to DMT and CYP2D6 inhibition. The model was validated against data from three independent drug interaction reports. This PBPK framework can be applied in different clinical pharmacology settings for drugs characterized by extensive distribution, formation rate limited metabolism and enzyme inhibition. The framework provides applicability in informing the rational design of clinical trials where sustained plasma drug levels warrant patient monitoring long after termination of dosing.