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].