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].