Retapamulin clinical pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Clinical Pharmacology
Mechanism of Action
ALTABAX is an antibacterial agent [see Clinical Pharmacology (12.4)].
Pharmacodynamics
In post-hoc analyses of manually over-read 12-lead ECGs from healthy subjects (N = 103), no significant effects on QT/QTc intervals were observed after topical application of retapamulin ointment on intact and abraded skin. Due to the low systemic exposure to retapamulin with topical application, QT prolongation in patients is unlikely [see Clinical Pharmacology (12.3)].
Pharmacokinetics
Absorption
In a trial of healthy adult subjects, retapamulin ointment, 1% was applied once daily to intact skin (800 cm2 surface area) and to abraded skin (200 cm2 surface area) under occlusion for up to 7 days. Systemic exposure following topical application of retapamulin through intact and abraded skin was low. Three percent of blood samples obtained on Day 1 after topical application to intact skin had measurable retapamulin concentrations (lower limit of quantitation 0.5 ng/mL); thus Cmax values on Day 1 could not be determined.
Eighty-two percent of blood samples obtained on Day 7 after topical application to intact skin and 97% and 100% of blood samples obtained after topical application to abraded skin on Days 1 and 7, respectively, had measurable retapamulin concentrations. The median Cmax value in plasma after application to 800 cm2 of intact skin was 3.5 ng/mL on Day 7 (range: 1.2 to 7.8 ng/mL). The median Cmax value in plasma after application to 200 cm2 of abraded skin was 11.7 ng/mL on Day 1 (range: 5.6 to 22.1 ng/mL) and 9.0 ng/mL on Day 7 (range: 6.7 to 12.8 ng/mL).
Plasma samples were obtained from 380 adult subjects and 136 pediatric subjects (aged 2 to 17 years) who were receiving topical treatment with ALTABAX topically twice daily. Eleven percent had measurable retapamulin concentrations (lower limit of quantitation 0.5 ng/mL), of which the median concentration was 0.8 ng/mL. The maximum measured retapamulin concentration in adults was 10.7 ng/mL and in pediatric subjects (aged 2 to 17 years) was 18.5 ng/mL.
A single plasma sample was obtained from 79 pediatric subjects (aged 2 to 24 months) who were receiving topical treatment with ALTABAX twice daily. Forty-six percent had measurable retapamulin concentrations (>0.5 ng/mL) compared with 7% in pediatric subjects aged 2 to 17 years. A higher proportion (69%) of pediatric subjects aged 2 to 9 months had measurable concentrations of retapamulin compared with subjects aged 9 to 24 months (32%). Among pediatric subjects aged 2 to 9 months (n = 29), 4 subjects had retapamulin concentrations that were higher (≥26.9 ng/mL) than the maximum concentration observed in pediatric subjects aged 2 to 17 years (18.5 ng/mL). Among pediatric subjects aged 9 to 24 months (n = 50), 1 subject had a retapamulin concentration that was higher (95.1 ng/mL) than the maximum level observed in pediatric subjects aged 2 to 17 years.
Distribution
Retapamulin is approximately 94% bound to human plasma proteins, and the protein binding is independent of concentration. The apparent volume of distribution of retapamulin has not been determined in humans.
Metabolism
In vitro studies with human hepatocytes showed that the main routes of metabolism were mono-oxygenation and di-oxygenation. In vitro studies with human liver microsomes demonstrated that retapamulin is extensively metabolized to numerous metabolites, of which the predominant routes of metabolism were mono-oxygenation and N-demethylation. The major enzyme responsible for metabolism of retapamulin in human liver microsomes was cytochrome P450 3A4 (CYP3A4).
Elimination
Retapamulin elimination in humans has not been investigated due to low systemic exposure after topical application.[1]
References
Adapted from the FDA Package Insert.