Concerns regarding the effects of internal/external factors on
PK parameters
ICH E5 guideline summarizes the possible internal/external factors
(covariates) affecting PK parameters. This is also the focus of FDA and
EMA concerns in pharmacometric review. The common internal factors
include race, genetic polymorphisms, sex, age, body weight, body mass
index, and hepatic/renal functions. The frequently mentioned external
factors are diet, treatment compliance, treatment modality, and
infectious pathogen [9]. Correct selection of covariates is very
important, which should be based on the specific characteristics and
dosing regimen of a drug. Ceftazidime-avibactam (Avycaz), for example,
is eliminated through kidneys, so parameters of renal function like
augmented renal clearance and end-stage renal disease (ESRD) are among
the significant covariates [29]. Race is a significant covariate of
isavuconazole because the plasma level of isavuconazole is lower in
westerners than in Chinese descents [30]. In the case of mixed
infection caused by multiple pathogens, it is required to analyze the
effect of these pathogens on PK parameters.
The interaction between the active ingredients of a combination of
products is also a focus of concern. For instance, vabomere is a
combination of meropenem and vaborbactam. So, it is required to assess
the effect of vaborbactam on the PK profile of meropenem [31]. In
addition to ingredient interaction analysis, it is also of crucial
importance to investigate the possibility of drug-drug interactions
(DDIs). For example, the data from the in vitro and in
vivo studies of ceftazidime-avibactam combination were used to
investigate whether there was any significant interaction between drug
ingredients and the substrates, inhibitors, and inducers of cytochrome
P450 enzymes.
Covariates analysis may be affected by trial design and implementation.
For example, more than 60% of the administered dose of ceftaroline
fosamil is eliminated in urine in unchanged form. However, urinary
excretion data of ceftaroline were not available in phase 2/3 clinical
trials. It was impossible to assess the significant covariate (i.e.,
renal clearance) of ceftaroline simply based on population PK model
[32]. This is also the case of antibacterial agent dalbavancin
[33].
Concerns regardingexposure-response
relationship for efficacy evaluation
Exposure-response analysis a very useful method for evaluating the
efficacy of drugs and therefore a focus of FDA and EMA concern in
regulatory review. Except the topical agents lacking systemic exposure,
all antimicrobial agents are evaluated through exposure-response
analysis to determine whether the dosage and efficacy outcome data from
the completed clinical trials are adequate to support its efficacy in
the proposed indications. Vabomere (meropenem-vaborbactam) is an example
in this case. Population PK models, nonclinical PK-PD analysis and Monte
Carlo simulation are used to calculate the probability of achieving
PK-PD target. These results are combined with in vitrosusceptibility data to predict the clinical efficacy of the drug. All
the available efficacy endpoints of oritavancin in the patients with
acute skin and soft tissue infection caused by S. aureus were
used to establish PK-PD correlation for evaluating the efficacy of
oritavancin in patients with S. aureus infection [34].
When sufficient data of PK, PD and microbiology tests are available from
clinical trials, it is appropriate to conduct analyses of dose
exposure-response to determine the highest MIC permissible for clinical
efficacy of a dosing regimen, clinical PK-PD target value, and the PTA
at a specific MIC. If the results of clinical trials showed clinical
failure in very few cases or low prevalence of target pathogens, it is
impossible to establish the quantitative relationship between PK-PD
indices and clinical or microbiological efficacy. If clinical PK-PD
target value is not available, it is recommended to use the PK-PD target
value from animals or in vitro studies and Monte Carlo simulation
to evaluate the dosing regimen. It is very important to determine the
breakpoints of an antimicrobial agent in exposure-response analysis,
which involves multidisciplinary study covering in vitro andin vivo preclinical studies, clinical trials and microbiological
testing, and comprehensive analysis. In the example
of
ceftolozane-tazobactam, clinical efficacy data were not available for
the patients at higher MIC. FDA reviewers, therefore, selected a
relatively conservative target value (equivalent to
2-log10 kill effect) according to the clinical efficacy
of ceftolozane-tazobactam in the patients with complicated
intra-abdominal infections (cIAI). Accordingly, the susceptibility
breakpoint of this drug against Enterobacteriaceae andPseudomonas aeruginosa is 2 μg/mL and 4 μg/mL, respectively,
lower than the breakpoints (8 μg/mL for both Enterobacteriaceaeand P. aeruginosa ) proposed by the applicant [35]. The
exposure-response relationship is evaluated more reasonably by this
breakpoint modification [34].