Mechanism of Action

ALTABAX is an antibacterial agent [see CLINICAL PHARMACOLOGY].

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].

Pharmacokinetics

Absorption: In a study 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 patients and 136 pediatric patients (aged 2-17 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 patients was 18.5 ng/mL. 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.

Microbiology

Retapamulin is a semisynthetic derivative of the compound pleuromutilin, which is isolated through fermentation from Clitopilus passeckerianus (formerly Pleurotus passeckerianus). In vitro activity of retapamulin against isolates of Staphylococcus aureus as well as Streptococcus pyogenes has been demonstrated.

Antimicrobial Mechanism of Action: Retapamulin selectively inhibits bacterial protein synthesis by interacting at a site on the 50S subunit of the bacterial ribosome through an interaction that is different from that of other antibiotics. This binding site involves ribosomal protein L3 and is in the region of the ribosomal P site and peptidyl transferase center. By virtue of binding to this site, pleuromutilins inhibit peptidyl transfer, block P-site interactions, and prevent the normal formation of active 50S ribosomal subunits. Retapamulin is bacteriostatic against Staphylococcus aureus and Streptococcus pyogenes at the retapamulin in vitro minimum inhibitory concentration (MIC) for these organisms. At concentrations 1,000x the in vitro MIC, retapamulin is bactericidal against these same organisms. Retapamulin demonstrates no in vitro target-specific cross-resistance with other classes of antibiotics.

Mechanisms of Decreased Susceptibility to Retapamulin: In vitro, 2 mechanisms that cause reduced susceptibility to retapamulin have been identified, specifically, mutations in ribosomal protein L3 or the presence of an efflux mechanism. Decreased susceptibility of S. aureus to retapamulin (highest retapamulin MIC was 2 mcg/mL) develops slowly in vitro via multistep mutations in L3 after serial passage in sub-inhibitory concentrations of retapamulin. There was no apparent treatment-associated reduction in susceptibility to retapamulin in the Phase 3 clinical program. The clinical significance of these findings is not known.

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