Overview of Oritavancin
than vancomycin, although this result was not repeated in the larger study H4Q-MC-ARRI (ARRI). In regards to safety, there was a theoretical concern about oritavancin’s long half-life and accumulation in macrophages potentially leading to immunosuppression, an effect which has not been seen in any clinical trials to date.
The rate and extent of bacterial killing increase with higher oritavancin concentrations. In addition, the post-antibiotic effect of oritavancin is long, both in vitro9
and in vivo,10 such that
oritavancin inhibits regrowth of bacteria even after its concentration in the blood has fallen beneath the minimum inhibitory concentration (MIC) against the infecting strain. In vivo efficacy of antimicrobial agents that display long-lived, concentration-dependent bactericidal activity is usually predicted by the area under the plasma concentration–time curve (AUC) to minimum inhibitory concentration (MIC) ratio (AUC:MIC)
and/or the maximum plasma concentration (Cmax) to minimum inhibitory concentration (MIC) ratio (Cmax:MIC).11,12
Based on a population PK analysis of 360 patients in Phase 2 and 3 studies, oritavancin exhibits slow clearance (0.601 L/h) and marked accumulation over time.5
The long half-life is likely a result of
drug accumulation within macrophages and other cells as observed both in vitro13
and in Phase 1 clinical studies.14 In addition, its 85 %
albumin binding probably also plays a role, serving as a reservoir for maintaining serum concentration as drug is used up at the infection site. Steady-state oritavancin concentrations with daily dosing are not attained within the first five days of therapy.15
Front-loaded regimens,
therefore, provide a basis for achieving effective exposures early in the course of therapy.
Efficacy testing in animal models of infection demonstrates that front loading of oritavancin exposure is the most effective way to administer the drug.16–19
As measured by the burden of S. aureus in
With dosing that mimics exposures seen in humans at various human dosing schedules, experiments using the well-studied neutropenic murine thigh model of infection with S. aureus and S. pyogenes, were undertaken to evaluate the impact of ‘shape’ of oritavancin exposure on efficacy. These data were integrated with human PK parameter estimates and various oritavancin dosing regimens were simulated for patients with ABSSSI (see Figure 1).16,21
mouse thighs up to 72 hours after infection, a human equivalent single dose of 1,200 mg oritavancin provided more substantial bacterial killing relative to both human equivalent 200 mg once-daily dosing and a matched total human equivalent dose (400 mg daily for three days).18,20
A re-evaluation of oritavancin’s PK and pharmacodynamic (PD) properties indicated that a single, 1,200 mg front-loaded, intravenous dose might improve oritavancin’s efficacy for the treatment of ABSSSI. Oritavancin displays a concentration-dependent pattern of bactericidal activity in vitro.7,8
Figure 1: Predicted Daily Oritavancin Area Under the Plasma Concentration–Time Curve Profiles for Daily and Front-Loaded Dosing Regimens
A
1,000 1,500 2,000 2,500 3,000
500 0 B
1,000 1,500 2,000 2,500 3,000
500 0 C
1,000 1,500 2,000 2,500 3,000
500 0
0 1234567 8 9 10 11 12 13 14 Day
200 mg daily (A) 800 mg on day one plus 400 mg on day five (B) and 1,200 mg single-dose (C) regimens.20,23
AUC = area under the plasma concentration–time curve.
Presented in Figure 1 is the predicted daily oritavancin AUC in plasma following 200 mg daily dosing in comparison with the predicted exposures from front-loaded dosing regimens (that is, most of AUC delivered up front: 1,200 mg single dose on day one or 800 mg on day one plus 400 mg on day five).15
AUC was chosen as the measure of
comparison since non-clinical models of infection demonstrated that oritavancin AUC:MIC is predictive of in vivo efficacy for Gram-positive bacteria.17,22
Oritavancin 1,200 mg single dose and 800 mg on day
one with 400 mg on day five each provided mean cumulative AUC values that exceeded exposure targets for efficacy23
as demonstrated in the neutropenic murine thigh infection model for a similar duration to EUROPEAN INFECTIOUS DISEASE
the 200 mg IV daily regimen dosed for a minimum of three days. The more rapid, predictable and profound bacterial killing that is achieved by the front-loaded dosing regimen of oritavancin, whether the infecting strain is methicillin-susceptible Staphylococcus aureus (MSSA), MRSA, or vancomycin-resistant Staphylococcus aureus (VRSA), is consistent with its concentration-dependent bactericidal activity in vitro.18,20
Based upon these analyses, a Phase 2 study, SIMPLIFI,21 was conducted
to evaluate the safety and efficacy of a daily dosing regimen of intravenous oritavancin compared to two front-loaded dosing regimens; a single, 1,200 mg dose and an 800 mg dose of oritavancin on day one followed by an optional 400 mg dose on day five. In this study, the efficacy of a single dose of 1,200 mg was not significantly different from the drug being dosed on the 200 mg daily basis or the infrequent
99
0 1234567 8 9 10 11 12 13 14 Day
0 1234567 8 9 10 11 12 13 14 Day
Daily AUCplasma
Daily AUCplasma
Daily AUCplasma
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