International society of Pharmacometrics Mentorship Program (IMP): feedback survey from the first cohort of mentor-mentee pairs.

The International Society of Pharmacometrics (ISoP) Mentorship Program (IMP) aims to help professionals at all career stages to transition into the pharmacometrics field, move to a different role/area within pharmacometrics, or expand their skillsets. The program connects mentees at various stages of their careers with mentors based on established criteria for mentor-mentee matching. Pairing mentees with appropriate mentors ensures strong alignment between mentees' interests and mentors' expertise as this is critical to the success and continuation of the relationship between the mentor and mentee. Once mentors and mentees are connected, they are strongly encouraged to meet at least once per month for an hour. The mentor and mentee have the freedom to tailor their sessions to their liking, including frequency, duration, and topics they choose to focus on. Mentees are encouraged to clearly define their goals to help direct their mentor-mentee relationship and conversations. Mentees and mentors alike are given the opportunity to provide feedback about the program to the ISoP Education Committee through surveys and testimonials. Due to the program's infancy, structured guidelines for mentor-mentee sessions are still being developed and instituted using the program evaluation described in this paper.

A population pharmacokinetic model of polymyxin B based on prospective clinical data to inform dosing in hospitalized patients.

OBJECTIVES: To develop a population pharmacokinetic (PK) model with data from the largest polymyxin B-treated patient population studied to date to optimize its dosing in hospitalized patients. METHODS: Hospitalized patients receiving intravenous polymyxin B for ≥48 hours were enrolled. Blood samples were collected at steady state and drug concentrations were analysed by liquid chromotography tandem mass spectrometry (LC-MS/MS). Population PK analysis and Monte Carlo simulations were performed to determine the probability of target attainment (PTA). RESULTS: One hundred and forty-two patients received intravenous polymyxin B (1.33-6 mg/kg/day), providing 681 plasma samples. Twenty-four patients were on renal replacement therapy, including 13 on continuous veno-venous hemodiafiltration (CVVHDF). A 2-compartment model adequately described the PK with body weight as a covariate on the volume of distribution that affected Cmax, but it did not impact clearance or exposure. Creatinine clearance was a statistically significant covariate on clearance, although clinically relevant variations of dose-normalized drug exposure were not observed across a wide creatinine clearance range. The model described higher clearance in CVVHDF patients than in non-CVVHDF patients. Maintenance doses of ≥2.5 mg/kg/day or ≥150 mg/day had a PTA ≥90% (for non-pulmonary infections target) at a steady state for minimum inhibitory concentrations ≤2 mg/L. The PTA at a steady state for CVVHDF patients was lower. DISCUSSION: Fixed loading and maintenance doses of polymyxin B seemed to be more appropriate than weight-based dosing regimens in patients weighing 45-90 kg. Higher doses may be needed in patients on CVVHDF. Substantial variability in polymyxin B clearance and volume of distribution was found, suggesting that therapeutic drug monitoring may be indicated.

Proof-of-concept for incorporating mechanistic insights from multi-omics analyses of polymyxin B in combination with chloramphenicol against Klebsiella pneumoniae.

Carbapenemase-resistant Klebsiella pneumoniae (KP) resistant to multiple antibiotic classes necessitates optimized combination therapy. Our objective is to build a workflow leveraging omics and bacterial count data to identify antibiotic mechanisms that can be used to design and optimize combination regimens. For pharmacodynamic (PD) analysis, previously published static time-kill studies (J Antimicrob Chemother 70, 2015, 2589) were used with polymyxin B (PMB) and chloramphenicol (CHL) mono and combination therapy against three KP clinical isolates over 24 h. A mechanism-based model (MBM) was developed using time-kill data in S-ADAPT describing PMB-CHL PD activity against each isolate. Previously published results of PMB (1 mg/L continuous infusion) and CHL (Cmax : 8 mg/L; bolus q6h) mono and combination regimens were evaluated using an in vitro one-compartment dynamic infection model against a KP clinical isolate (108 CFU/ml inoculum) over 24 h to obtain bacterial samples for multi-omics analyses. The differentially expressed genes and metabolites in these bacterial samples served as input to develop a partial least squares regression (PLSR) in R that links PD responses with the multi-omics responses via a multi-omics pathway analysis. PMB efficacy was increased when combined with CHL, and the MBM described the observed PD well for all strains. The PLSR consisted of 29 omics inputs and predicted MBM PD response (R2  = 0.946). Our analysis found that CHL downregulated metabolites and genes pertinent to lipid A, hence limiting the emergence of PMB resistance. Our workflow linked insights from analysis of multi-omics data with MBM to identify biological mechanisms explaining observed PD activity in combination therapy.

A Systems-Based Analysis of Mono- and Combination Therapy for Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections.

Antimicrobial resistance is a global threat. As "proof-of-concept," we employed a system-based approach to identify patient, bacterial, and drug variables contributing to mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKp) bloodstream infections exposed to colistin (COL) and ceftazidime-avibactam (CAZ/AVI) as mono- or combination therapies. Patients (n = 49) and CRKp isolates (n = 22) were part of the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-1), a multicenter, observational, prospective study of patients with carbapenem-resistant Enterobacterales (CRE) conducted between 2011 and 2016. Pharmacodynamic activity of mono- and combination drug concentrations was evaluated over 24 h using in vitro static time-kill assays. Bacterial growth and killing dynamics were estimated with a mechanism-based model. Random Forest was used to rank variables important for predicting 30-day mortality. Isolates exposed to COL+CAZ/AVI had enhanced early bacterial killing compared to CAZ/AVI alone and fewer incidences of regrowth compared to COL and CAZ/AVI. The mean coefficient of determination (R2) for the observed versus predicted bacterial counts was 0.86 (range: 0.75 - 0.95). Bacterial subpopulation susceptibilities and drug mechanistic synergy were essential to describe bacterial killing and growth dynamics. The combination of clinical (hypotension), bacterial (IncR plasmid, aadA2, and sul3) and drug (KC50) variables were most predictive of 30-day mortality. This proof-of-concept study combined clinical, bacterial, and drug variables in a unified model to evaluate clinical outcomes.

Assessing the predictive performance of population pharmacokinetic models for intravenous polymyxin B in critically ill patients.

Polymyxin B (PMB) has reemerged as a last-line therapy for infections caused by multidrug-resistant gram-negative pathogens, but dosing is challenging because of its narrow therapeutic window and pharmacokinetic (PK) variability. Population PK (POPPK) models based on suitably powered clinical studies with appropriate sampling strategies that take variability into consideration can inform PMB dosing to maximize efficacy and minimize toxicity and resistance. Here we reviewed published PMB POPPK models and evaluated them using an external validation data set (EVD) of patients who are critically ill and enrolled in an ongoing clinical study to assess their utility. Seven published POPPK models were employed using the reported model equations, parameter values, covariate relationships, interpatient variability, parameter covariance, and unexplained residual variability in NONMEM (Version 7.4.3). The predictive ability of the models was assessed using prediction-based and simulation-based diagnostics. Patient characteristics and treatment information were comparable across studies and with the EVD (n = 40), but the sampling strategy was a main source of PK variability across studies. All models visually and statistically underpredicted EVD plasma concentrations, but the two-compartment models more accurately described the external data set. As current POPPK models were inadequately predictive of the EVD, creation of a new POPPK model based on an appropriately powered clinical study with an informed PK sampling strategy would be expected to improve characterization of PMB PK and identify covariates to explain interpatient variability. Such a model would support model-informed precision dosing frameworks, which are urgently needed to improve PMB treatment efficacy, limit resistance, and reduce toxicity in patients who are critically ill.

Insights Into Patient Variability During Ivacaftor-Lumacaftor Therapy in Cystic Fibrosis.

Background: The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). However, due to the plethora of variances in disease manifestations in CF, there are inherent challenges in unified responses under CFTR modulator treatment arising from variability in patient outcomes. The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited. Methods: Secondary objectives were to identify (1) patient characteristics and (2) the interactions between ivacaftor-lumacaftor responsible for interindividual variability (IIV). Results: Peak plasma concentrations (Cmax) of ivacaftor - lumacaftor were >10 fold lower than expected compared to label information. The one-way ANOVA indicated that the patient site had an effect on Cmax values of ivacaftor metabolites ivacaftor-M1, ivacaftor-M6, and lumacaftor (p < 0.001, p < 0.001, and p < 0.001, respectively). The Spearman's rho test indicated that patient weight and age have an effect on the Cmax of lumacaftor (p = 0.003 and p < 0.001, respectively) and ivacaftor metabolite M1 (p = 0.020 and p < 0.001, respectively). Age (p < 0.001) was found to effect on Cmax of ivacaftor M6 and on Tmax of ivacaftor M1 (p = 0.026). A large impact of patient characteristics on the IIV of PK parameters Cmax and Tmax, was observed among the CF patients. Conclusion: Understanding the many sources of variability can help reduce this individual patient variability and ensure consistent patient outcomes.

Evaluation Strategies for Triple-Drug Combinations against Carbapenemase-Producing Klebsiella Pneumoniae in an In Vitro Hollow-Fiber Infection Model

Mounting antimicrobial resistance to carbapenemase-producing Klebsiella pneumoniae (CPKP) highlights the need to optimize currently available treatment options. The objective of this study was to explore alternative dosing strategies that limit the emergence of resistance to preserve the utility of last-line antibiotics by: (i) evaluating the pharmacodynamic (PD) killing activity of simulated humanized exposures to monotherapy and two-drug and three-drug combinations against CPKP bacterial isolates with different resistance mechanisms; and (ii) optimizing polymyxin B (PMB) exposure simulated in the three-drug combination regimens to maximize the killing activity. Two CPKP clinical isolates (BAA2146 (NDM-1) and BRKP76 (KPC-2)) were evaluated over 168 hours using a hollow-fiber infection model simulating clinically relevant PMB, fosfomycin, and meropenem dosing regimens. PMB-based three-drug combinations were further optimized by varying the initial exposure (0­24 hours) or maintenance dose received over the duration of treatment. The area under the bacterial load-versus-time curve (AUCFU) was used to determine PD activity. Overall reductions in PMB exposure ranged from 2 to 84%. BAA2146 and BRKP76 had median (range) AUCFUs of 11.0 (10.6­11.6) log10 CFU hour/mL and 7.08 (7.04­11.9) log10 CFU hour/mL, respectively. The PMB "front loaded" 2.5 mg/ kg/day + 0.5 mg/kg maintenance dose in combination with meropenem and fosfomycin was a promising regimen against BRKP76, with an overall reduction in PMB exposure of 56% while still eradicating the bacteria. Tailored triple combination therapy allows for the optimization of dose and treatment duration of last-line agents like PMB to achieve adequate drug exposure and appropriate PD activity while minimizing the emergence of resistance.

Reapproaching Old Treatments: Considerations for PK/PD Studies on Phage Therapy for Bacterial Respiratory Infections.

Antibiotic resistant bacterial respiratory infections are a significant global health burden, and new therapeutic strategies are needed to control the problem. For bacterial respiratory infections, this need is emphasized by the rise in antibiotic resistance and a lean drug development pipeline. Bacteriophage (phage) therapy is a promising alternative to antibiotics. Phage are viruses that infect and kill bacteria. Because phage and antibiotics differ in their bactericidal mechanisms, phage are a treatment option for antibiotic-resistant bacteria. Here, we review the history of phage therapy and highlight recent preclinical and clinical case reports of its use for treating antibiotic-resistant respiratory infections. The ability of phage to replicate while killing the bacteria is both a benefit for treatment and a challenge for pharmacokinetic (PK) and pharmacodynamic (PD) studies. In this review, we will discuss how the phage lifecycle and associated bidirectional interactions between phage and bacteria can impact treatment. We will also highlight PK/PD considerations for designing studies of phage therapy to optimize the efficacy and feasibility of the approach.

Evaluation Strategies for Triple-Drug Combinations against Carbapenemase-Producing Klebsiella Pneumoniae in an In Vitro Hollow-Fiber Infection Model.

Mounting antimicrobial resistance to carbapenemase-producing Klebsiella pneumoniae (CPKP) highlights the need to optimize currently available treatment options. The objective of this study was to explore alternative dosing strategies that limit the emergence of resistance to preserve the utility of last-line antibiotics by: (i) evaluating the pharmacodynamic (PD) killing activity of simulated humanized exposures to monotherapy and two-drug and three-drug combinations against CPKP bacterial isolates with different resistance mechanisms; and (ii) optimizing polymyxin B (PMB) exposure simulated in the three-drug combination regimens to maximize the killing activity. Two CPKP clinical isolates (BAA2146 (NDM-1) and BRKP76 (KPC-2)) were evaluated over 168 hours using a hollow-fiber infection model simulating clinically relevant PMB, fosfomycin, and meropenem dosing regimens. PMB-based three-drug combinations were further optimized by varying the initial exposure (0-24 hours) or maintenance dose received over the duration of treatment. The area under the bacterial load-versus-time curve (AUCFU) was used to determine PD activity. Overall reductions in PMB exposure ranged from 2 to 84%. BAA2146 and BRKP76 had median (range) AUCFUs of 11.0 (10.6-11.6) log10  CFU hour/mL and 7.08 (7.04-11.9) log10 CFU hour/mL, respectively. The PMB "front loaded" 2.5 mg/kg/day + 0.5 mg/kg maintenance dose in combination with meropenem and fosfomycin was a promising regimen against BRKP76, with an overall reduction in PMB exposure of 56% while still eradicating the bacteria. Tailored triple-combination therapy allows for the optimization of dose and treatment duration of last-line agents like PMB to achieve adequate drug exposure and appropriate PD activity while minimizing the emergence of resistance.

A mechanism-based pharmacokinetic model of remdesivir leveraging interspecies scaling to simulate COVID-19 treatment in humans.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak initiated the global coronavirus disease 2019 (COVID-19) pandemic resulting in 42.9 million confirmed infections and > 1.1 million deaths worldwide as of October 26, 2020. Remdesivir is a broad-spectrum nucleotide prodrug shown to be effective against enzootic coronaviruses. The pharmacokinetics (PKs) of remdesivir in plasma have recently been described. However, the distribution of its active metabolite nucleoside triphosphate (NTP) to the site of pulmonary infection is unknown in humans. Our objective was to use existing in vivo mouse PK data for remdesivir and its metabolites to develop a mechanism-based model to allometrically scale and simulate the human PK of remdesivir in plasma and NTP in lung homogenate. Remdesivir and GS-441524 concentrations in plasma and total phosphorylated nucleoside concentrations in lung homogenate from Ces1c-/- mice administered 25 or 50 mg/kg of remdesivir subcutaneously were simultaneously fit to estimate PK parameters. The mouse PK model was allometrically scaled to predict human PK parameters to simulate the clinically recommended 200 mg loading dose followed by 100 mg daily maintenance doses administered as 30-minute intravenous infusions. Simulations of unbound remdesivir concentrations in human plasma were below 2.48 µM, the 90% maximal inhibitory concentration for SARS-CoV-2 inhibition in vitro. Simulations of NTP in the lungs were below high efficacy in vitro thresholds. We have identified a need for alternative dosing strategies to achieve more efficacious concentrations of NTP in human lungs, perhaps by reformulating remdesivir for direct pulmonary delivery.

Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing.

SARS-CoV-2 utilizes the IMPα/ß1 heterodimer to enter host cell nuclei after gaining cellular access through the ACE2 receptor. Ivermectin has shown antiviral activity by inhibiting the formation of the importin-α (IMPα) and IMPß1 subunits as well as dissociating the IMPα/ß1 heterodimer and has in vitro efficacy against SARS-CoV-2. Plasma and lung ivermectin concentrations vs. time profiles in cattle were used to determine the apparent plasma to lung tissue partition coefficient of ivermectin. This coefficient, together with a simulated geometric mean plasma profile of ivermectin from a published population pharmacokinetic model, was utilized to develop a minimal physiologically-based pharmacokinetic (mPBPK) model. The mPBPK model accurately described the simulated ivermectin plasma concentration profile in humans. The mPBPK model was also used to simulate human lung exposure to ivermectin after 12, 30, and 120 mg oral doses. The simulated ivermectin lung exposures reached a maximum concentration of 772 ng/mL, far less than the estimated 1750 ng/mL IC50 reported for ivermectin against SARS-CoV-2 in vitro. Further studies of ivermectin either reformulated for inhaled delivery or in combination with other antivirals with differing mechanisms of action is needed to assess its therapeutic potential.