Evaluation of dose linearity in the systemic availability and pharmacokinetics of topically administered diclofenac: A 14C-microdosing study in healthy volunteers.

Systemic absorption of a topically applied drug may not be dose-linear, limiting the usefulness of microdosing to predict therapeutic-dose exposure. In a crossover study of eight healthy participants, a topical microdose of diclofenac (62 μg) resulted in a higher fraction absorbed (0.48%) compared with a therapeutic dose (120 mg, 0.13%), a 3.79-fold difference. Intravenous dosing showed dose-linear disposition. Concentrations in subcutaneous tissue microdialysates were low and variable regardless of dose. The findings indicate that microdosing may not accurately predict the systemic availability of certain topical drugs at therapeutic doses.

Study at a glance

Abstract

An important safety consideration for topically administered drugs is the extent of systemic exposure they achieve. The aim of this study was to evaluate whether a topically administered microdose of the model drug diclofenac can predict the systemic availability, plasma, and tissue pharmacokinetics of a topical therapeutic dose. Eight healthy participants (6 men and 2 women) participated in a 4-period, crossover study. In period 1, a topical microdose (62 ± 6 μg) was administered; in period 2, a single intravenous microdose (0.95 ± 0.03 μg) was administered; in period 3, a topical therapeutic dose (120 mg) was administered; and in period 4, a single intravenous therapeutic dose (75 mg) of [14C]diclofenac was administered, with or without the addition of unlabeled diclofenac. Venous blood, urine, and microdialysis samples from subcutaneous adipose tissue beneath the dermal application site were collected for 24 h post-dosing. Total 14C-concentrations in plasma and microdialysates were quantified using accelerator mass spectrometry. The disposition of intravenously administered [14C]diclofenac was dose-linear. However, after topical administration, the fraction of total 14C absorbed (geometric mean and 95% confidence interval) was higher (P = .0019, 2-tailed, paired t test) for the microdose (0.48% and 0.34%-0.67%) compared with the therapeutic dose (0.13% and 0.07%-0.22%) (geometric mean ratio and 90% confidence interval: 3.79 and 2.41-5.98). Dose-normalized 14C-concentrations in microdialysates were low, variable, and did not differ between doses. Our study demonstrates the feasibility of quantifying 14C-concentrations in plasma and microdialysates following the topical administration of a microdose of [14C]diclofenac. The observed nonlinearity in systemic availability after topical dosing suggests that microdosing may not accurately predict the disposition of certain topical drugs at therapeutic doses. SIGNIFICANCE STATEMENT: We assessed whether a topically applied microdose of diclofenac could predict the systemic availability of a therapeutic dose. Results showed that systemic absorption was not dose-linear, indicating that microdosing may have limited use for predicting the pharmacokinetics of some topical drugs.