A population PK model using pooled data from phase 1 healthy subjects and phase 2 and 3 patients with cSSSI or S. aureus bacteremia was developed to characterize the disposition of oritavancin. A robust data set with 6,290 oritavancin PK samples obtained from 560 subjects was created along with various subject descriptors and disease characteristics to assess its influence. Overall, excellent fits to the data were obtained using a three-compartment model with linear elimination and separate RV models for phase 1 subjects and phase 2 and 3 patients. Exploration of subject factors that explain the interindividual variability in oritavancin CL and Vc demonstrated relationships between both body weight and study phase and CL and both BSA and age and Vc. No other relationships were identified between CL and Vc and gender, age, or renal and hepatic dysfunction.
For CL, the most statistically significant relationship was observed in subjects of >80 kg of total body weight, with CL increasing in a linear fashion above 80 kg. The magnitude of this relationship was such that the population predicted CL would be expected to rise by approximately 53% over a total body weight range of 80 to 200 kg. There was no relationship between total body weight and CL in subjects of ≤80 kg. For Vc, the most statistically significant body size measure was BSA. The magnitude of this relationship was such that, assuming age is constant, the population predicted Vc would be expected to rise by approximately 85% over the BSA range of 1.3 to 3.5 m2. Vc was also found to decrease in a linear fashion as age increased. The magnitude of this relationship was such that, assuming BSA is constant, the population predicted Vc would fall by approximately 35% over the age range of 20 to 85 years.
The relationship between CL and study phase is notable given that, for many drugs, CL decreases in sick patients due to compromised organ function. However, our results show CL to be increased in phase 2 and 3 patients by an average of 30% after accounting for differences in body weight. The exact mechanism for this observation is not clear but may be related to differences in oritavancin tissue distribution between subjects and patients. However, the clinical impact of higher CL in healthy subjects is somewhat irrelevant, as the drug will be used only in infected patients, and the other covariate relationships were similar in patients and subjects.
Although the covariate relationships for CL and Vc were statistically significant, they were not necessarily clinically significant, as evidenced by the small amount of the interindividual variability explained by the covariates retained in the final model. The interindividual variability in CL decreased from 40.7% using the base structural model to 33.7% using the final covariate model; these same values were 36.2% and 35.2% for Vc, respectively. The clinical insignificance of the relationship between Vc and age is clearly illustrated in Fig. , given that dose-normalized Cmax is not increased in elderly subjects. In contrast, those subjects with very high total body weight (>110 kg) had clearances high enough that they would be expected to have oritavancin AUC0-24 values lower than those for subjects of ≤110 kg for fixed 200-mg daily doses (Fig. , left panel). Thus, a dosage adjustment for patients of >110 kg may be warranted to maintain similar steady-state AUC0-24 values. As shown in Fig. , right panel, when administering a 50% increased dose to these patients (i.e., 300 mg daily instead of 200 mg daily), the distribution of AUC0-24 values for these patients is predicted to fall closer to the center of the distribution for patients with a total body weight of ≤110 kg.
It is important to note that the dosage recommendation described above is based solely on maintaining a consistent distribution of AUC0-24
values for a fixed 200-mg daily dosing regimen, regardless of body size. This is reasonable given that the PK-PD measure most closely associated with efficacy for oritavancin is the ratio of the AUC0-24
to the MIC of oritavancin for the microorganism (AUC0-24
:MIC ratio) (11
). Based on the goodness of fit of the population PK model and the richness of the sampling scheme in the phase 2 and 3 studies, confidence for the model-derived individual PK estimates of oritavancin clearance is high. As CL is the sole determinant of AUC0-24
, individual estimates of AUC0-24
among patients with cSSSI or S. aureus
bacteremia should be accurate and precise. Thus, future PK-PD analyses may allow for the opportunity to identify critical threshold AUC0-24
:MIC ratios associated with efficacy and will also help to further refine the importance of the above-described dosing recommendation in patients with a total body weight of >110 kg.
The results of this analysis illustrate the value of pooling data across the continuum of clinical drug development to confirm key PK concepts regarding a drug. Through this process, we were able to confirm that oritavancin exhibits linear PKs and that the only demographic factor of clinical importance in relation to dose adjustment may be body weight. Through these analyses, we were also able to evaluate appropriate dosage regimens for heavier patients in order to achieve exposures similar to those in lighter patients.