Population Pharmacokinetic (PPK) Analysis for Lefamulin Using Phase 1 Data and Assessment of Optimal PK Sampling Strategies (OSS) for a Phase 3 Community-Acquired Bacterial Pneumonia (CABP) Study

Introduction Concizumab is a high-affinity anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical investigation for the subcutaneous (SC) treatment of patients with hemophilia. The data generated from phase 1 and 2 concizumab trials have been used to develop a population pharmacokinetic (PK) model with the aim of supporting dose selection for phase 3 trials. WMethods The objective of this study was to develop a model to describe the PK of concizumab across administration routes in various groups of patients with hemophilia to generate a generally applicable population PK model of concizumab. The model was developed based on available PK data from four phase 1 trials (for both intravenous [IV] and SC concizumab administration) and two phase 2 trials (for SC concizumab administration). Trial populations in the phase 1 trials included both healthy subjects and patients with hemophilia, whilst the phase 2 trials enrolled patients with hemophilia A or B with inhibitors and patients with hemophilia A without inhibitors. A structural population PK model was first developed based on phase 1 data and the final population PK model was then estimated using data from both phase 1 and phase 2 trials. Simulations were performed for phase 3 concizumab exposure using a full parametric simulation (n=10,000), including both inter-individual and intra-individual variability for the selected population. Randomly sampled body weights from a normal distribution with mean and variance corresponding to body weight distribution from phase 2 trials were used to simulate patient profiles. WResults The population PK dataset used for the model comprised 1,504 observations from 119 subjects (89 patients and 30 healthy individuals), with a mean age of 35 years (range: 18-65 years) and mean body weight of 74.4 kg (range: 47.1-130 kg). The PK model parameters were first estimated based on phase 1 data alone, and after fixing the majority in order to ensure robustness of the model only a few parameters were re-estimated based on phase 1 and 2 data combined. The PK model (Figure 1) was evaluated by standard goodness-of-fit plots and qualification assessments. Using visual predictive checks, it was shown that the model was able to reproduce the median and the 5th and 95th percentiles of the observed concizumab concentrations from phase 1 and 2 trials, and so it was deemed suitable for simulation purposes. The PK model suggested a target-mediated drug disposition following concizumab binding to TFPI at the endothelium, and subsequent elimination of the complex to account for the non-linear elimination. WConclusions The developed model accurately described the PK of concizumab delivered at a wide dose range by either SC or IV administration to both healthy subjects and patients with hemophilia A or B with and without inhibitors. The model was used for simulations to select the dosing regimen for subsequent phase 3 studies. Figure 1. Concizumab pharmacokinetic model. Structure of the final concizumab PK model for SC and IV dosing with target-mediated drug disposition via the endothelial TFPI. CL, clearance; doseiv, intravenous dose; dosesc, subcutaneous dose; IV, intravenous; ka, absorption rate constant; kcom, elimination rate constant of the concizumab-TFPI complex; kon and koff, rate constants for binding of concizumab to the endothelial TFPI; ktr, rate constant from the transit compartment; Q, inter-compartmental clearance; Rtot, amount of endothelial TFPI available for concizumab binding; SC, subcutaneous; TFPI, tissue factor pathway inhibitor; V, volume. Figure Disclosures Høyer Rose: Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Hollensen:Novo Nordisk: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Agersø:Novo Nordisk A/S: Current Employment. Viig Overgaard:Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company.

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Population Pharmacokinetics of Doravirine and Exposure-Response Analysis in Individuals with HIV-1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02502-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 8

Author(s):

Ka Lai Yee ◽

Aziz Ouerdani ◽

Anetta Claussen ◽

Rik de Greef ◽

Larissa Wenning

Keyword(s):

Virologic Failure ◽

Phase 1 ◽

Fixed Dose ◽

Response Analysis ◽

Population Pharmacokinetic ◽

Phase 3 ◽

Once Daily ◽

Intrinsic Factors ◽

Exposure Response ◽

Hiv 1

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1) infection. A population pharmacokinetic (PK) model was developed for doravirine using pooled data from densely sampled phase 1 trials and from sparsely sampled phase 2b and phase 3 trials evaluating doravirine administered orally as a single entity or as part of a fixed-dose combination of doravirine-lamivudine-tenofovir disoproxil fumarate. A one-compartment model with linear clearance from the central compartment adequately described the clinical PK of doravirine. While weight, age, and healthy versus HIV-1 status were identified as statistically significant covariates affecting doravirine PK, the magnitude of their effects was not clinically meaningful. Other intrinsic factors (gender, body mass index, race, ethnicity, and renal function) did not have statistically significant or clinically meaningful effects on doravirine PK. Individual exposure estimates for individuals in the phase 2b and 3 trials obtained from the final model were used for subsequent exposure-response analyses for virologic response (proportion of individuals achieving <50 copies/ml) and virologic failure. The exposure-response relationships between these efficacy endpoints and doravirine PK were generally flat over the range of exposures achieved for the 100 mg once-daily regimen in the phase 3 trials, with a minimal decrease in efficacy in individuals in the lowest 10th percentile of steady-state doravirine concentration at 24 h values. These findings support 100 mg once daily as the selected dose of doravirine, with no dose adjustment warranted for the studied intrinsic factors.

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Population Pharmacokinetics of Isavuconazole from Phase 1 and Phase 3 (SECURE) Trials in Adults and Target Attainment in Patients with Invasive Infections Due to Aspergillus and Other Filamentous Fungi

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02819-15 ◽

2016 ◽

Vol 60 (9) ◽

pp. 5483-5491 ◽

Cited By ~ 47

Author(s):

Amit Desai ◽

Laura Kovanda ◽

Donna Kowalski ◽

Qiaoyang Lu ◽

Robert Townsend ◽

...

Keyword(s):

Invasive Aspergillosis ◽

Fungal Infections ◽

Phase 1 ◽

Water Soluble ◽

Simulated Patients ◽

Population Pharmacokinetic ◽

Target Attainment ◽

Phase 3 ◽

Absorption Function ◽

The Mean

ABSTRACTIsavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent used for the treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model to identify covariates that affect isavuconazole pharmacokinetics and to determine the probability of target attainment (PTA) for invasive aspergillosis patients. Data from nine phase 1 studies and one phase 3 clinical trial (SECURE) were pooled to develop the PPK model (NONMEM, version 7.2). Stepwise covariate modeling was performed in Perl-speaks-NONMEM, version 3.7.6. The area under the curve (AUC) at steady state was calculated for 5,000 patients by using Monte Carlo simulations. The PTA using the estimated pharmacodynamic (PD) target value (total AUC/MIC ratio) estimated fromin vivoPD studies of invasive aspergillosis over a range of MIC values was calculated using simulated patient AUC values. A two-compartment model with a Weibull absorption function and a first-order elimination process adequately described plasma isavuconazole concentrations. The mean estimate for isavuconazole clearance was 2.360 liters/h (percent coefficient of variation [%CV], 34%), and the mean AUC from 0 to 24 h (AUC0–24) was ∼100 mg·h/liter. Clearance was approximately 36% lower in Asians than in Caucasians. The PTA calculated over a range of MIC values by use of the nonneutropenic murine efficacy index corresponding to 90% survival indicated that adequate isavuconazole exposures were achieved in >90% of simulated patients to treat infections with MICs up to and including 1 mg/liter according to European Committee on Antimicrobial Susceptibility Testing methodology and in >90% of simulated patients for infections with MICs up to and including 0.5 mg/liter according to Clinical and Laboratory Standards Institute methodology. The highest MIC result for PTA was the same for Caucasian and Asian patients.

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Population Pharmacokinetic Analyses for Arbekacin after Administration of ME1100 Inhalation Solution

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00267-19 ◽

2019 ◽

Vol 63 (8) ◽

Cited By ~ 2

Author(s):

Elizabeth A. Lakota ◽

Nobuo Sato ◽

Tomokazu Koresawa ◽

Kenichiro Kondo ◽

Sujata M. Bhavnani ◽

...

Keyword(s):

Bacterial Pneumonia ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Phase 1 ◽

Time Profile ◽

Population Pharmacokinetic ◽

Dose Selection ◽

Mechanically Ventilated ◽

Model Following ◽

Hospital Acquired

ABSTRACT ME1100, an inhalation solution of arbekacin, an aminoglycoside, is being developed for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. The objective of these analyses was to develop a population pharmacokinetic model to describe the arbekacin concentration-time profile in plasma and epithelial lining fluid (ELF) following ME1100 administration. Data were obtained from a postmarketing study for an intravenous (i.v.) formulation of arbekacin, a phase 1 study of ME1100 in healthy volunteers, and a phase 1b study of ME1100 in mechanically ventilated subjects with bacterial pneumonia. Data from the postmarketing study were utilized to develop a population pharmacokinetic model following i.v. administration, and this model was subsequently utilized as the foundation for development of the model characterizing arbekacin disposition following inhalation of ME1100. The final model utilized two compartments for both plasma and ELF disposition, with movement of arbekacin between the ELF and plasma parameterized using linear first-order rate constants. A bioavailability term was included for the inhalational route of administration, which was estimated to be 19.5% for a typical subject. The model included normalized creatinine clearance (CLcrn) and weight as covariates on arbekacin clearance: CL = (weight/52.2)0.855·[(CLcrn–77)·0.0289 + 2.32]. The model simultaneously described arbekacin concentrations following both i.v. and inhaled administration and provided acceptable fits to the plasma and ELF data (r2 of 0.922 and 0.557 for observed versus fitted concentrations, respectively). The developed model will be useful for conducting future analyses to support ME1100 dose selection.

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Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02263-19 ◽

2020 ◽

Vol 64 (7) ◽

Cited By ~ 2

Author(s):

Elizabeth A. Lakota ◽

Scott A. Van Wart ◽

Michael Trang ◽

Evan Tzanis ◽

Sujata M. Bhavnani ◽

...

Keyword(s):

Goodness Of Fit ◽

Phase 1 ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Uncomplicated Urinary Tract Infection ◽

Phase 3 ◽

Data Set ◽

First Order ◽

Final Population ◽

Population Pk

ABSTRACT Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously developed population pharmacokinetic (PK) model based on phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 phase 1 studies used to develop the previous model were pooled with data from three additional phase 1 studies, a phase 1b uncomplicated urinary tract infection study, one phase 3 CABP study, and two phase 3 ABSSSI studies. The final population PK model was a three-compartment model with first-order absorption using transit compartments to account for absorption delay following oral dosing and first-order elimination. Epithelial lining fluid (ELF) concentrations were modeled as a subcompartment of the first peripheral compartment. A food effect on oral bioavailability was included in the model. Sex was the only significant covariate identified, with 15.6% lower clearance for females than males. Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. The final model, which was robust in its ability to predict plasma and ELF exposures following omadacycline administration, was also able to predict the central tendency and variability in concentration-time profiles using an external phase 3 ABSSSI data set. A population PK model, which described omadacycline PK in healthy subjects and infected patients, was developed and subsequently used to support pharmacokinetic-pharmacodynamic (PK-PD) and PK-PD target attainment assessments.

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Population Pharmacokinetics of Meropenem and Vaborbactam Based on Data from Non-Infected Subjects and Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02606-20 ◽

2021 ◽

Author(s):

M. Trang ◽

D.C. Griffith ◽

S.M. Bhavnani ◽

J.S. Loutit ◽

M.N. Dudley ◽

...

Keyword(s):

Bacterial Infections ◽

Time Course ◽

Phase 1 ◽

Type Equation ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Phase 3 ◽

Two Phase ◽

Tract Infections

Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the USA and Europe to treat patients with complicated urinary tract infections and in Europe, other serious bacterial infections, including hospital- acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time-course of meropenem and vaborbactam using pooled data from two Phase 1 and two Phase 3 studies. Multi-compartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment (Vc) increased with increasing body surface area, and CL, Vc, and volume of the peripheral compartment were systematically different in Phase 1 non-infected subjects relative to Phase 3 infected patients, respectively. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.

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Monte Carlo Simulations Based on Phase 1 Studies Predict Target Attainment of Ceftobiprole in Nosocomial Pneumonia Patients: a Validation Study

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02292-12 ◽

2013 ◽

Vol 57 (5) ◽

pp. 2047-2053 ◽

Cited By ~ 18

Author(s):

Anouk E. Muller ◽

Anne H. Schmitt-Hoffmann ◽

Nieko Punt ◽

Johan W. Mouton

Keyword(s):

Monte Carlo ◽

Healthy Volunteers ◽

Nosocomial Pneumonia ◽

Extreme Values ◽

Phase 1 ◽

Optimal Dose ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Target Attainment ◽

Phase 3

ABSTRACTMonte Carlo simulation (MCS) of antimicrobial dosage regimens during drug development to derive predicted target attainment values is frequently used to choose the optimal dose for the treatment of patients in phase 2 and 3 studies. A criticism is that pharmacokinetic (PK) parameter estimates and variability in healthy volunteers are smaller than those in patients. In this study, the initial estimates of exposure from MCS were compared with actual exposure data in patients treated with ceftobiprole in a phase 3 nosocomial-pneumonia (NP) study (NTC00210964). Results of MCS using population PK data from ceftobiprole derived from 12 healthy volunteers were used (J. W. Mouton, A. Schmitt-Hoffmann, S. Shapiro, N. Nashed, N. C. Punt, Antimicrob. Agents Chemother. 48:1713–1718, 2004). Actual individual exposures in patients were derived after building a population pharmacokinetic model and were used to calculate the individual exposure to ceftobiprole (the percentage of time the unbound concentration exceeds the MIC [percentfT> MIC]) for a range of MIC values. For the ranges of percentfT> MIC used to determine the dosage schedule in the phase 3 NP study, the MCS using data from a single phase 1 study in healthy volunteers accurately predicted the actual clinical exposure to ceftobiprole. The difference at 50%fT> MIC at an MIC of 4 mg/liter was 3.5% for PK-sampled patients. For higher values of percentfT> MIC and MICs, the MCS slightly underestimated the target attainment, probably due to extreme values in the PK profile distribution used in the simulations. The probability of target attainment based on MCS in healthy volunteers adequately predicted the actual exposures in a patient population, including severely ill patients.

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Population Pharmacokinetics of Telavancin in Healthy Subjects and Patients with Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05915-11 ◽

2012 ◽

Vol 56 (4) ◽

pp. 2067-2073 ◽

Cited By ~ 20

Author(s):

Emil Samara ◽

Jeng-Pyng Shaw ◽

Steven L. Barriere ◽

Shekman L. Wong ◽

Philip Worboys

Keyword(s):

Renal Function ◽

Healthy Subjects ◽

Phase 1 ◽

Population Pharmacokinetic ◽

Phase 3 ◽

Two Phase ◽

Complicated Skin ◽

Hospital Acquired Pneumonia ◽

Highly Correlated ◽

Hospital Acquired

ABSTRACTA population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP. Telavancin clearance was highly correlated with renal function and, to a lesser extent, with body weight. Other covariates were related to at least one parameter in cSSSI (gender, bacterial eradication, and surgery) or HAP (age of ≥75 years) but did not markedly affect exposure. These analyses support current dosing recommendations for telavancin based on patient weight and renal function.

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Population Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2, and 3 Clinical Studies

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02329-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 6

Author(s):

Michael Trang ◽

Julie D. Seroogy ◽

Scott A. Van Wart ◽

Sujata M. Bhavnani ◽

Aryun Kim ◽

...

Keyword(s):

Body Weight ◽

Intravenous Infusion ◽

Bacterial Pneumonia ◽

Structural Model ◽

Phase 1 ◽

Complicated Urinary Tract Infection ◽

Pharmacokinetic Analysis ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Related Factors

ABSTRACTPlazomicin is an aminoglycoside with activity against multidrug-resistantEnterobacteriaceae. Plazomicin is dosed on a milligram-per-kilogram-of-body-weight basis and administered by a 30-min intravenous infusion every 24 h, with dose adjustments being made for renal impairment and a body weight (BW) of ≥125% of ideal BW. A population pharmacokinetic analysis was performed to identify patient factors that account for variability in pharmacokinetics and to determine if dose adjustments are warranted based on covariates. The analysis included 143 healthy adults and 421 adults with complicated urinary tract infection (cUTI), acute pyelonephritis, bloodstream infection, or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) from seven studies (phases 1 to 3). A three-compartment structural pharmacokinetic model with a zero-order rate constant for the intravenous infusion and linear first-order elimination kinetics best described the plasma concentration-time profiles. The base structural model included creatinine clearance (CLCR) as a time-varying covariate for clearance. The covariates included age, BW, height, body surface area, body mass index, sex, race, and disease-related factors. The ranges of the α-, β-, and γ-phase half-lives for the analysis population were 0.328 to 1.58, 2.77 to 5.38, and 25.8 to 36.5 h, respectively. Total and renal clearances in a typical cUTI or HABP/VABP patient were 4.57 and 4.08 liters/h, respectively. Starting dose adjustments for CLCRare sufficient for minimizing the variation in plasma exposure across patient populations; adjustments based on other covariates are not warranted. The results support initial dosing on a milligram-per-kilogram basis with adjustments for CLCRand BW. Subsequent adjustments based on therapeutic drug management are recommended in certain subsets of patients, including the critically ill and renally impaired.

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