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

Trang, Michael; Seroogy, Julie; Wart, Scott A. Van; Bhavnani, Sujata M.; Kim, Aryun; Gibbons, Jacqueline A.; Ambrose, Paul G.; Rubino, Christopher M.

doi:10.1128/aac.02329-18

Cited by 20 publications

(20 citation statements)

References 43 publications

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“…However, both the maximum increase in absolute bioavailability in the absence of food (F max ) and V p1 had marked increases in IIV. This was not surprising, given the increased PK variability that has been observed for infected patients compared to that of healthy volunteers (18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 92%

Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data

Lakota

Wart

Trang

et al. 2020

Antimicrob Agents Chemother

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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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Section: Discussionmentioning

confidence: 92%

Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data

Lakota

Wart

Trang

et al. 2020

Antimicrob Agents Chemother

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“…By comparison, in a phase 3 clinical study of plazomicin in patients with cUTI, 13 the therapeutic dose was associated with a mean (SD) C max of 46.6 mg/L (43.0%) and AUC 0-24h of 234 mg·h/L (38.5%) (n = 281 patients). 31 As the phase 3 study included dose adjustments for renal impairment similar to those recommended in the drug product label, the exposures achieved with the supratherapeutic dose in this study are expected to be higher than those broadly encountered in the intended-use patient population.…”

Section: Discussionmentioning

confidence: 99%

A Phase 1 Study of Intravenous Plazomicin in Healthy Adults to Assess Potential Effects on the QT/QTc Interval, Safety, and Pharmacokinetics

Gall¹,

Choi²,

Riddle³

et al. 2019

Clinical Pharm in Drug Dev

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Plazomicin is an aminoglycoside with in vitro activity against multidrug‐resistant Enterobacteriaceae. A phase 1, randomized, double‐blind, crossover study assessed the potential effects of plazomicin on cardiac repolarization (NCT01514929). Fifty‐six healthy adults (24 men, 32 women) received a single therapeutic dose of plazomicin (15 mg/kg administered by 30‐minute intravenous infusion), a single supratherapeutic dose of plazomicin (20 mg/kg administered by 30‐minute intravenous infusion), placebo, or oral moxifloxacin (400 mg). The primary end point was the baseline‐adjusted, placebo‐corrected QTc interval using the Fridericia formula (ΔΔQTcF). Assay sensitivity was concluded if the lower limit of a 1‐sided 95%CI (adjusted for multiplicity using the Hochberg procedure) for moxifloxacin ΔΔQTcF was >5 milliseconds at ≥1 prespecified time points. No QT prolongation effect for plazomicin was concluded if the largest mean effect was <5 milliseconds, and the upper limit of a 2‐sided 90%CI for plazomicin ΔΔQTcF was <10 milliseconds at all time points. Assay sensitivity was demonstrated based on moxifloxacin ΔΔQTcF. No QT prolongation effect for plazomicin was concluded because the largest mean ΔΔQTcF for plazomicin was 3.5 milliseconds, and the highest upper limit was 5.6 milliseconds. No clinically relevant changes were observed in electrocardiograms. For the 15‐ and 20‐mg/kg dose levels of plazomicin, mean peak plasma concentration values were 76.0 and 96.6 mg/L, and mean values of the area under the concentration‐time curve over 24 hours were 263 and 327 mg·h/L, respectively. Model‐derived pharmacokinetic parameters and safety findings were generally consistent with previously reported plazomicin studies. In conclusion, therapeutic and supratherapeutic doses of plazomicin had no clinically significant effect on cardiac repolarization and were generally well tolerated.

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“…Plazomicin, administered as a once daily aminoglycoside, takes advantage of this class-wide pharmacodynamic strategy. Of note, the plazomicin AUC/MIC ratio been shown to correlate best with efficacy in animal and in vitro models of infection (9,22).…”

Section: Discussionmentioning

confidence: 99%

Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection

Asempa

Kuti

Seroogy³

et al. 2019

Antimicrob Agents Chemother

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Plazomicin is a new FDA-approved aminoglycoside antibiotic for complicated urinary tract infections (cUTI). In the product labeling, trough-based therapeutic drug management (TDM) is recommended for cUTI patients with renal impairment to prevent elevated trough concentrations associated with serum creatinine increases of ≥0.5 mg/dl above baseline. Herein, the utility of the Hartford nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3 μg/ml and optimize the area under the curve (AUC) was assessed. The AUC reference range was defined as the 5th to 95th percentile AUC observed in the phase 3 cUTI trial (EPIC) (121 to 368 μg · h/ml). Observed 10-h plazomicin concentrations from patients in EPIC (n = 281) were plotted on the nomogram to determine an eligible dosing interval (every 24 h [q24h], q36h, q48h). Based on creatinine clearance (CLcr), a 15- or 10-mg/kg of body weight dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (q36h and q48h) in 31% of patients. Compared with the 15 mg/kg q24h regimen received by patients with CLcr of ≥60 ml/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs of ≥3 μg/ml (q36h, 27% versus 0%, P = 0.021; q48h, 57% versus 0%, P = 0.002) while significantly increasing the number of patients within the AUC range. Compared with the 8 to 12 mg/kg q24h regimen (received by patients with CLcr of >30 to 59 ml/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs of ≥3μg/ml in the q48h cohort (72% versus 0%, P < 0.001) while maintaining a similar proportion of patients in the AUC range. Simulated application of the Hartford nomogram optimized plazomicin exposures in patients with cUTI while reducing troughs to <3 μg/ml.

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

Cited by 20 publications

References 43 publications

Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data

Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data

A Phase 1 Study of Intravenous Plazomicin in Healthy Adults to Assess Potential Effects on the QT/QTc Interval, Safety, and Pharmacokinetics

Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection

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