Patricia S. Walker

Pharmacokinetics of Tazarotene Cream 0.1% After a Single Dose and After Repeat Topical Applications at Clinical or Exaggerated Application Rates in Patients with Acne Vulgaris or Photodamaged Skin

AbstractObjective: To evaluate the safety and pharmacokinetics of tazarotene cream 0.1% under standard (face only) or exaggerated (15% body surface area, including the face) application conditions after a single dose and after repeat topical applications once daily to patients with acne vulgaris or photodamaged skin. Methods: Two separate, randomised, single-centre, nonblinded, parallel-group pharmacokinetic studies were conducted. In one study, tazarotene cream 0.1% was applied either to the face of eight female patients with moderate acne or to 15% body surface area of ten female patients with severe acne. In the other study, tazarotene cream 0.1% was applied either to the face (six females, two males) or to 15% body surface area (8 females, 8 males) of patients with photodamaged skin. In both studies, tazarotene cream 0.1% was applied once daily (except on days 1 and 2) for 30 days. Blood was drawn for measurement of plasma concentrations of tazarotenic acid at defined time intervals after application of the cream. Plasma tazarotenic acid concentrations were determined by a validated gas chromatography-tandem mass spectrometry method with a lower limit of quantification of 0.005 μg/L. Results: At exaggerated application rates in patients with acne vulgaris, the maximum average peak concentration (Cmax) and 24-hour area under the concentration-time curve (AUC) values of tazarotenic acid were (mean ± SD) 1.20 ± 0.41 μg/L (n = 10) and 17.0 ± 6.1 μg · h/L (n = 10), respectively, and occurred on day 15. The single highest Cmax was 1.91 μg/L. At standard application rates in patients with acne vulgaris, the maximum average Cmax and AUC values of tazarotenic acid were 0.10 ± 0.06 μg/L (n = 8) and 1.54 ± 1.01 μg · h/L (n = 8), respectively, and occurred on day 15. At exaggerated application rates in patients with photodamaged skin, the maximum average Cmax and AUC values of tazarotenic acid were (mean ± SD) 1.75 ± 0.53 μg/L (n = 16) and 23.8 ± 7.0 μg · h/L (n = 16), respectively, and occurred on day 22. The single highest Cmax was 3.43 μg/L on day 29. At standard application rates in patients with photodamaged skin, the maximum average Cmax and AUC values of tazarotenic acid were 0.236 ± 0.255 μg/L (n = 8) and 2.44 ± 1.38 μg · h/L (n = 8), respectively, and occurred on day 15. Gender had no influence on the systemic exposure of tazarotenic acid. The most common treatment-related adverse events were signs and symptoms of local irritation, of mild or moderate severity. Conclusion: The pharmacokinetics of tazarotene cream 0.1% in patients with acne vulgaris or photodamaged skin are similar. The maximum average plasma concentrations of tazarotenic acid after topical application of tazarotene cream 0.1% to the face were less than 0.25 μg/L. The maximum average plasma concentrations of tazarotenic acid following application to an exaggerated body surface area (15%) were less than 1.8 μg/L.

Tazarotene Does Not Affect the Pharmacokinetics and Efficacy of a Norethindrone/Ethinylestradiol Oral Contraceptive

ObjectiveTo determine the pharmacokinetic and pharmacodynamic interaction between oral tazarotene and an oral contraceptive containing norethindrone 1mg and ethinylestradiol 0.035mg (Ortho-Novum® 1/35).DesignTwo separate open-label, parallel-group, single-centre, pharmacokinetic and pharmacodynamic interaction studies.Participants and methodsTwenty-seven healthy women (age 20–55 years) completed Study I, with a duration of 64 days during three consecutive menstrual cycles. Ortho-Novum® 1/35 was taken once daily from study day 0 (first cycle day 1) to day 61 (third cycle day 6), and oral tazarotene 1.1mg was coadministered daily from study day 34 (second cycle day 7) to day 61. Twenty-nine healthy women (age 20–44 years) completed Study II, with a duration of 75 days during three consecutive menstrual cycles. Ortho-Novum® 1/35 was taken once daily from study day 0 (first cycle day 1) to day 74 (third cycle day 19), and oral tazarotene 6mg was coadministered daily from study day 48 (second cycle day 21) to day 74. In both studies, the pharmacokinetics of tazarotenic acid on study day 61 (third cycle day 6) were evaluated from plasma tazarotenic acid concentrations. Pharmacokinetic parameters of plasma norethindrone and ethinylestradiol were compared before and after tazarotene administration (cycle day 6 of the second and third cycles, respectively). Serum luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations were compared before and after tazarotene administration (cycle days 2, 4 and 6 of the second and third cycles, respectively). In Study II, serum progesterone concentrations were also determined on cycle days 18 and 20 of the second and third cycles. Tazarotenic acid was determined by liquid chromatography-tandem mass spectrometry. Ethinylestradiol and norethindrone were determined by gas chromatography-mass spectrometry. LH and FSH were assayed by microparticle enzyme immunoassay in Study I and by double-antibody radioimmunoassay in Study II. Progesterone was determined by solid-phase radioimmunoassay.ResultsIn Study I (tazarotene 1.1mg), the area under the plasma concentration-time curve from zero to 24 hours (AUC24) and the peak concentration in plasma (Cmax) for tazarotenic acid were 121 ± 27 μg • h/L and 28.9 ± 9.4 μg/L (mean ± SD), respectively. In Study II (tazarotene 6mg), AUC24 and Cmax for tazarotenic acid were 379 ± 78 μg • h/L and 111 ± 37 μg/L (mean ± SD), respectively. In both studies, for both norethindrone and ethinylestradiol, the 90% CIs of AUC24 and Cmax on cycle day 6 before and after tazarotene administration were within the 80–125% boundary. In Study I, the 90% CIs of serum FSH and LH concentrations on cycle day 4 were within the 80–125% boundary. FSH and LH concentrations on cycle day 6 were marginally/partially outside the 80–125% boundary as a result of high variability. However, the mean FSH and LH serum concentrations on cycle day 6 of the third cycle were lower than those of the second cycle. In Study II, the 90% CIs of serum FSH, LH and progesterone concentrations were all within the 80–125% boundary, except for LH on cycle day 2. LH concentrations on cycle day 2 were marginally/partially outside the 80–125% boundary as a result of high variability. However, the mean serum LH concentration on cycle day 2 of the third cycle was lower than that of the second cycle.ConclusionsOral tazarotene up to 6mg once daily does not affect the pharmacokinetics and efficacy of Ortho-Novum® 1/35.