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Pharmacokinetic interactions between alitretinoin and ketoconazole or simvastatin or ciclosporin A
Author(s) -
SchmittHoffmann A. H.,
Roos B.,
Sauer J.,
Spickermann J.,
Maares J.,
Schoetzau A.,
Meyer I
Publication year - 2011
Publication title -
clinical and experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.587
H-Index - 78
eISSN - 1365-2230
pISSN - 0307-6938
DOI - 10.1111/j.1365-2230.2011.04034.x
Subject(s) - ketoconazole , simvastatin , ciclosporin , cyp3a4 , pharmacokinetics , pharmacology , medicine , dermatology , chemotherapy , cytochrome p450 , antifungal , metabolism
Summary Background. Based on in vitro data with isolated cytochrome P450 (CYP) isoenzymes, alitretinoin interacts only with CYP3A4, and the potential for drug–drug interactions is considered negligible. Aim. To confirm in humans the lack of potential interactions between CYP3A4 and alitretinoin in vivo . Methods. This was a multiple‐dose, open‐label, parallel‐group, single‐centre study, which enrolled 54 healthy male volunteers aged 18–45 years. Subjects were divided into three groups, with 18 in each group: group 1 received either alitretinoin 30 mg and ketoconazole 200 mg, group 2 alitretinoin 30 mg and simvastatin 40 mg, and group 3 alitretinoin 30 mg and ciclosporin A 300‐mg. Results. At the highest therapeutic dose of 30 mg, alitretinoin had no significant effect on the pharmacokinetics (PK) of ketoconazole and ciclosporin A. There was a significant but not clinically relevant effect of simvastatin on the area under the curve (AUC) of plasma concentration vs. time and on maximum plasma concentration ( C max ) after repeated administration of alitretinoin. Exposure to simvastatin concomitantly with alitretinoin was decreased by 16% for AUC and 23% for C max . The CYP3A4 ± PgP substrates of simvastatin and ciclosporin A did not affect the single or repeated dose PK of alitretinoin. The strong CYP3A4/PgP inhibitor ketoconazole led to significant increases in both AUC and C max values for alitretinoin. Conclusions. Single and repeated doses of alitretinoin do not alter the PK of ciclosporin A and ketoconazole. Simvastatin levels were slightly but significantly reduced by co‐administration of alitretinoin. Substrates of CYP3A4 did not affect the PK of alitretinoin. However, ketoconazole significantly increased the plasma levels of alitretinoin, therefore, co‐administration with CYP3A4 inhibitors such as ketoconazole may require a dose reduction of alitretinoin.