Systemic concentrations of halobetasol propionate (lower limit of quantification (LLOQ) = 50 pg/mL) and tazarotene (LLOQ = 5pg/mL) on Day 28 were quantifiable in 13 and 18 out of a total number of 22 subjects, respectively. Tazarotenic acid (LLOQ = 5pg/mL) was quantifiable in all subjects. Systemic exposure of the three moieties was at or near steady state by Day 28. The mean(standard deviation) of PK parameters on Day 28 is shown in Table 2.
Table 2: PK Parameters of Halobetasol Propionate, Tazarotene, and Tazarotenic Acid following Once Daily Administration ofDUOBRII Lotion for 28 Days in Subjects with Moderate to Severe Plaque Psoriasis
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to eva luate the carcinogenic potential of halobetasol propionate.
A long-term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications ofincreased carcinogenic risks. Based on pharmacokinetic data from a shorter term study in rats, the highest dose of 0.125 mg/kg/daywas anticipated to give systemic exposure in the rat equivalent to 1.4 times the MRHD (based on AUC comparison).
A long-term study with topical application of up to 0.1% of tazarotene in a gel formulation in mice terminated at 88 weeks showedthat dose levels of 0.05, 0.125, 0.25, and 1 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermalirritation) revealed no apparent carcinogenic effects when compared to vehicle control animals. Tazarotenic acid systemic exposuresat the highest dose was 35 times the MRHD (based on AUC comparison).
Halobetasol propionate was not genotoxic in the Ames assay, in the sister chromatid exchange test in Chinese hamster somatic cells,in chromosome aberration studies of germinal and somatic cells of rodents, and in a mammalian spot test. Positive mutagenicityeffects were observed in a mouse lymphoma gene mutation assay in vitro and in a Chinese hamster micronucleus test.
Tazarotene was non-mutagenic in the Ames assay and did not produce structural chromosomal aberrations in human lymphocytes.
Tazarotene was non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in an invivo mouse micronucleus test.
Studies in rats following oral administration of halobetasol propionate at dose levels up to 0.05 mg/kg/day, approximately 0.53 timesthe MRHD based on BSA comparisons, indicated no impairment of fertility or general reproductive performance.
No impairment of fertility occurred in rats when male animals were treated for 70 days prior to mating and female animals weretreated for 14 days prior to mating and continuing through gestation and lactation with topical doses of a tazarotene gel formulation up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat at the highest dose was 5 times theMRHD (based on AUC comparison).
No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of upto 1 mg/kg/day tazarotene, which produced a systemic exposure 17 times the MRHD (based on AUC comparison).
No impairment of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuingthrough gestation day 7 with oral doses of tazarotene up to 2 mg/kg/day. However, there was a significant decrease in the number ofestrous sta |
