Application of Population Pharmacokinetic Modeling, Exposure-Response Analysis, and Classification and Regression Tree Analysis to Support Dosage Regimen and Therapeutic Drug Monitoring of Plazomicin in Complicated Urinary Tract Infection Patients with Renal Impairment.

In 2018, the FDA approved plazomicin for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult patients with limited or no alternative treatment options. The objective of this article is to provide the scientific rationales behind the recommended dosage regimen and therapeutic drug monitoring (TDM) of plazomicin in cUTI patients with renal impairment. A previous population pharmacokinetic (PK) model was used to evaluate the dosage regimen in cUTI patients with different degrees of renal impairment. The exposure-response analysis was conducted to identify the relationship between plazomicin exposure and nephrotoxicity incidence in cUTI patients with renal impairment. Classification and regression tree (CART) analysis was utilized to assess the TDM strategy. The receiver operating characteristics curve was plotted to compare two TDM thresholds in cUTI patients with renal impairment. The analyses suggested that dose reduction is necessary for cUTI patients with moderate or severe renal impairment. TDM should be implemented for cUTI patients with mild, moderate, or severe renal impairment to reduce the risk of nephrotoxicity. The trough concentration of 3 µg/mL is a reasonable TDM threshold to reduce the nephrotoxicity incidence while maintaining efficacy in cUTI patients with renal impairment. The application of population PK modeling, exposure-response analysis, and CART analysis allowed for the evaluation of a dosage regimen and TDM strategy for plazomicin in cUTI patients with renal impairment. Our study demonstrates the utility of pharmacometrics and statistical approaches to inform a dosage regimen and TDM strategy for drugs with narrow therapeutic windows.

US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®).

In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice. Clinical Trials Registration: NCT02321800.

Variations in pharmacokinetic-pharmacodynamic target values across MICs and their potential impact on determination of susceptibility test interpretive criteria.

BACKGROUND: An antibacterial drug's susceptibility test interpretive criteria (STIC) are determined by integrating clinical, microbiological and pharmacokinetic-pharmacodynamic (PK-PD) data. PTA analysis plays a pivotal or supportive role in STIC determination and is heavily dependent on the PK-PD target values determined from animal PK-PD studies. Therefore, variations in PK-PD target values may impact STIC determination. Factors contributing to variation in the PK-PD target values include the number of and MICs for bacterial isolates used in animal PK-PD studies. OBJECTIVES: To analyse the relationship between PK-PD target values and MICs, describe the variations in PK-PD target values of isolates and evaluate whether the proposed/target STICs were within the ranges of the MICs for isolates used in animal PK-PD studies. METHODS: A database was compiled for this research by screening animal PK-PD study reports submitted to the FDA from 10 new drug applications (NDAs). RESULTS: A relationship evaluation between PK-PD target values and MICs for tested isolates for seven drugs (that used AUC/MIC ratio as the PK-PD index) showed that, generally, the AUC/MIC values decreased with an increase in MIC. These target values were highly variable, with the percentage coefficient of variation ranging between 1% and 132% for isolates having the same MIC. For 16/27 (59%) drug/bacteria combinations from all 10 drugs, the proposed/target STICs were higher than the highest MIC for bacteria isolates evaluated, while 6/27 (22.5%) were lower. CONCLUSIONS: This research suggests that careful considerations related to selection of bacterial isolates for animal PK-PD studies could strengthen the STIC determination process.

Cefiderocol Dosing for Patients Receiving Continuous Renal Replacement Therapy.

In this report, we describe our scientific approach for including effluent flow rate (QE )-based dosing recommendations of cefiderocol for patients receiving continuous renal replacement therapy (CRRT) in the product labeling. The total clearance (CL) of cefiderocol in patients receiving CRRT was estimated as the sum of patients' nonrenal clearance (CLnonrenal ) and extracorporeal clearance by CRRT (CLCRRT ), based on the following rationale: (a) The renal clearance (CLrenal ) of cefiderocol is assumed to be negligible in patients receiving CRRT, (b) CLnonrenal represents the CRRT patients' own remaining systemic clearance and is estimated from the observed clearance in participants with creatinine clearance (CLcr) < 15 mL/minute without undergoing hemodialysis, and (c) CLCRRT was estimated by the product of unbound (free) fraction of plasma drug concentration (fu ) and QE because the free fraction of low-molecular-weight compounds like cefiderocol (752 Da) can be completely filtered by CRRT, regardless of CRRT modality. Hence, cefiderocol CL in CRRT patients was calculated by the equation of CL = CLnonrenal + fu × QE . Accordingly, the cefiderocol dosing regimens for patients receiving CRRT in clinically relevant ranges of QE were determined with the goal of achieving an average daily area under the concentration-time curve (AUC) observed in patients not receiving CRRT. Subsequently, pharmacokinetic (PK) simulations demonstrated that cefiderocol PK profiles following the QE -based dosing in patients receiving CRRT would be similar to those in patients not receiving CRRT.

Evaluation of Hemodialysis Effect on Pharmacokinetics of Meropenem/Vaborbactam in End-Stage Renal Disease Patients Using Modeling and Simulation.

The objectives of this study were to evaluate the effect of hemodialysis (HD) on the pharmacokinetics (PK) of meropenem/vaborbactam, an approved beta-lactam/beta-lactamase inhibitor combination, and provide the rationale for the recommended timing of meropenem/vaborbactam administration relative to HD in end-stage renal disease (ESRD) patients. Population PK models were developed separately for meropenem and vaborbactam in subjects with normal renal function and different degrees of renal impairment, including those receiving HD. Simulations were performed to evaluate the exposure of meropenem and vaborbactam in ESRD patients who received a fixed dose of 0.5 g/0.5 g meropenem/vaborbactam every 12 hours as a 3-hour intravenous infusion under various drug administration schedules relative to HD. The probability of target attainment (PTA) analyses were conducted with pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem and vaborbactam. Simulations showed that HD reduces the accumulation of vaborbactam, but the exposure of vaborbactam is still above the PK/PD target regardless of whether meropenem/vaborbactam is administered predialysis or postdialysis. For meropenem, drug infusion completed right prior to initiation of HD may substantially reduce exposure leading to poor PTA results. In contrast, drug infusion completed at least 2 hours prior to initiation of HD is not predicted to result in efficacy loss based on PTA analysis. The results of simulation indicate that meropenem/vaborbactam infusion completed at least 2 hours prior to initiation of HD or administered immediately after the end of HD can avoid potential efficacy loss in ESRD patients.

Clinical aspects of drug delivery to tumors.

This report describes our experience on enhancement of drug delivery to solid tumors. Results of our preclinical and clinical studies including a randomized prospective phase III trial have validated the concept that enhanced drug delivery can significantly improve the treatment efficacy of intravesical mitomycin C therapy of superficial bladder cancer. The report further describes the roles of interstitial space, drug removal by capillaries, tissue structure and tissue composition on drug distribution. In general, drug distribution favors interstitial space and vasculature, with little penetration in muscles. The transport of highly protein-bound drugs such as paclitaxel and doxorubicin in a solid tumor is retarded by a high tumor cell density and enhanced by drug-induced apoptosis. Results of in vitro studies using solid tumor histocultures and in vivo studies using tumor-bearing animals demonstrate that the delivery of highly protein-bound drugs to tumor can be enhanced using a pretreatment that induces apoptosis and reduces cell density, and by using treatment schedules designed to take advantage of these drug-induced changes in tumor tissue composition.

Enhanced drug-induced apoptosis associated with P-glycoprotein overexpression is specific to antimicrotubule agents.

PURPOSE: We have reported that overexpression of mdr1 P-glycoprotein (Pgp) is associated with a higher sensitivity to paclitaxel-induced apoptosis (1,2). The present study examined the substrate specificity of this phenomenon. METHODS: Two Pgp substrates (vincristine and doxorubicin) and three nonsubstrates (cisplatin, camptothecin. and 5-fluorouracil) were studied. Serum deprivation, known to induce apoptosis, was used as a comparison. RESULTS: The Pgp nonsubstrates and serum deprivation showed similar overall cytotoxicity and apoptosis in human breast MCF7 cells (with negligible Pgp expression) and its mdr1-transfected subline BC19 cells (with nine-fold higher Pgp expression). In contrast, the overall cytotoxicity and apoptosis of the two Pgp substrates was higher in MCF7 cells. Cotreatment with a Pgp inhibitor, verapamil, abolished the difference in intracellular accumulation of doxorubicin as well as the differences in apoptosis between MCF7 and BC19 cells. This finding confirms that the lower apoptosis of doxorubicin in BC19 cells, in the absence of verapamil, was a result of lower intracellular drug accumulation secondary to high Pgp expression in BC19 cells. In contrast, abolishing the difference in intracellular vincristine concentration by verapamil cotreatment resulted in significantly higher apoptosis in BC19 cells. This finding is identical to our previous finding with paclitaxel, where equal intracellular drug concentration resulted in greater apoptosis in the Pgp-rich BC19 cells. CONCLUSIONS: These data, together with the opposite effects of paclitaxel and vincristine on microtubules (i.e., polymerization versus depolymerization), indicate that the enhanced apoptosis in Pgp-rich cells is specific for antimicrotubule agents but is not related to the polymerization of microtubules.