Pharmacometric review helps refine the wording of dosing regimen
and labeling
Exposure-response analysis is the key to analyzing the appropriateness
of dosing regimen (dosage, frequency, mode and duration of
administration) and so the focus of regulatory concern. FDA and EMA will
determine whether the proposed dosing regimen is reasonable; whether the
recommended dosage is acceptable in general adult population and special
populations (e.g., geriatric, pediatric or patients with impaired
renal/hepatic function) by examining the exposure-response relationship
in terms of drug efficacy and safety. If not, the Agency will decide how
to adjust the dosage or dosing regimen. The corresponding method and
wording of dose adjustment are also required to be reflected in the
package leaflet (labeling). For instance, the exposure-response analysis
in terms of efficacy and safety supports Vabomere 4 g (meropenem :
vaborbactam = 1:1) by intravenous infusion (IV) over 3 hours, every 8
hours (q8h), up to 14 days in adult patients (≥ 18 years old) with
adequate renal function evidenced by estimated glomerular filtration
rate (eGFR) ≥ 50 mL/min/1.73m2. However, for patients
with impaired renal function (eGFR < 50
mL/min/1.73m2), the dosing regimen should be adjusted.
Specifically, Vabomere 2 g, IV q8h if eGFR ranges from 30 to 49
mL/min/1.73m2; Vabomere 2 g IV q12h if eGFR ranges
from 15 to 29 mL/min/1.73m2; and Vabomere 1 g IV q12h
if eGFR is lower than 15 mL/min/1.73m2 [38].
Pharmacometric
review may trigger post-marketing clinical trial
Pharmacometric review also provides important evidence for justifying
the adequacy of the completed preclinical and clinical studies in
support of NDA. For example, ceftazidime is excreted through kidneys,
dose adjustment is required for ceftazidime-avibactam in the patients
with renal impairment. Based on pharmacometric review, FDA reviewers
advised the applicant to conduct a post-marketing study on
ceftazidime-avibactam in cIAI patients whose creatinine clearance ≤ 50
mL/min to assess the PK, efficacy, and safety after dose adjustment. The
PK results from the proposed post-marketing trial are used to analyze
whether it is necessary to further adjust the dosing regimen. Another
example is the antituberculosis drug delamanid. The relationship between
the exposure and antibacterial activity of delamanid was inconsistent.
So EMA reviewers request the applicant to perform a post-marketing study
to further examine the correlation between 2-month sputum conversion and
long-term efficacy following different dosing regimens.
From the relevant NMPA guidelines and the prescribing information of
some new antimicrobial agents approved in China, we can see that NMPA
has essentially the same focus of concerns as FDA and EMA in
pharmacometric review. NMPA approved the new antibacterial agent
nemonoxacin malate capsules in 2016. Various PK parameters of
nemonoxacin were evaluated thoroughly in the heathy subjects and the
patients with community-acquired pneumonia. Population PK analysis was
also provided to examine the effect of multiple covariates (sex, age,
the severity of renal impairment, and diet) on PK. These analyses
provide robust justification of the efficacy and safety of the drug in
patients and demonstrate whether it is necessary to adjust dosing
regimen [39].