Biomedical Engineering Reference
In-Depth Information
motavizumab lots with AUCs no less than 80% of motavizumab drug product. The 80%
lower limit is based on FDA guidance Statistical Approaches to Establishing Bioequiv-
alence [25] to ensure no adverse impact on PK. The risk of an adverse impact on safety
due to increased AUC is considered minimal for the following reasons: (1) nonclinical
studies performed in cynomolgus monkeys found no safety signals at a dose 6.8 times
higher than the human dose when given weekly for 26 weeks; (2) specificity of activity is
directed against a nonhost target, that is, RSV; and (3) clinical trials conducted to date
with motavizumab and palivizumab suggest a comparable safety profile. Therefore, an
upper limit was deemed irrelevant.
The risk to efficacy is low based on the analysis because all the AUC values were
80% of the motavizumab values and therefore are considered bioequivalent exposure.
The analysis supports the conclusion that any combination of oligosaccharide composi-
tion within the range of 0-100% for all three glycoforms (G0, G1
Man-5, and G2)
would result in a lot with an AUC no less than 80% of motavizumab drug product.
Palivizumab PK profiles were modeled for a typical multiple injection regimen for
prophylactic administration covering the RSV season. The modeling was performed by
using the derived half-life parameters for the palivizumab drug product and the
hypothetical case of palivizumab consisting of 100% G2 glycoform. Figure 4.18 shows
that the model predicts that 100%G2 formwould display a PK profile that is well within
the 95% confidence interval for palivizumab drug product on the basis of interpatient
variability observed in clinical trials. Any difference in the PK of the extreme case of
100%G2 form is insignificant as compared to the natural variation in PKbehavior among
patients.
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P ROCESS C APABILITY . The clinical lots that were tested had oligosaccharide profiles
that were consistent with each other and the reference standard (Fig. 4.15). The results
Figure 4.18. Seasonalmodelingof palivizumabandG2 glycoformPKprofiles. (See the insert for
color representation of this figure.)
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