Purpose: Omadacycline (PTK-0796) is a first-in-class aminomethylcycline for adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible pathogens. We investigated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of omadacycline, considering the impact of covariates, particularly ethnicity, on PK and determined the PK/PD cutoff values for dosing regimens.
Methods: Utilizing nonlinear mixed-effects modeling, we pooled data from 11 clinical trials for PopPK analysis. The first-order conditional estimation with interaction (FOCEI) method in NONMEM facilitated model parameter estimation. Employing a stepwise model selection strategy, with forward addition (P < 0.01) and backward deletion (P < 0.001), we assessed the potential impacts of covariates on omadacycline PK, including baseline age, body weight, sex, race, body mass index, body surface area, baseline albumin, creatine clearance, and formulation. After validating the model through various methods, the final PopPK model underwent Monte Carlo simulations to generate the PK profile for the Chinese population. This enabled AUC calculation and assessment of the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for various dosing regimens and bacterial strains.
Results: Omadacycline's PK can be adequately characterized by a three-compartment model. Body weight, sex, race, and drug formulation statistically influenced its PK. Asians and non-Asians exhibit similar exposure after intravenous infusion, but oral dosing results in much higher exposures than in non-Asians. Monte Carlo simulation indicates that IV-only or IV/PO sequential therapy regimens provide adequate attainment for all major pathogens causing ABSSSI and CABP. PK/PD cutoffs were generally above the MIC value of recent clinical isolates from China.
Conclusions: In conclusion, the approved regimen for China achieved adequate target attainment for all pathogens typically associated with these infections. The higher oral exposure observed in Asians may enhance efficacy without affecting safety or tolerability.
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http://dx.doi.org/10.1016/j.ejps.2024.106713 | DOI Listing |
Gastroenterol Hepatol
January 2025
Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Background: Mesalamine is the first-line drug for treating mild-to-moderate ulcerative colitis (UC); however, some patients develop symptoms of intolerance. Although several desensitization methods have been reported, these desensitization regimens were rather complicated for physicians to prescribe in daily clinical practice; therefore, it has not yet become a major therapeutic option for intolerance patients. Thus, we developed an alternative desensitization protocol.
View Article and Find Full Text PDFLancet Infect Dis
January 2025
Geneva Centre for Emerging Viral Diseases, Geneva University Hospitals, Geneva, Switzerland; Médecins Sans Frontières, Geneva, Switzerland; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Division of Tropical and Humanitarian Medicine, Geneva University Hospitals, Geneva, Switzerland. Electronic address:
Background: Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis, particularly in Asia and Africa, where HEV genotypes 1 and 2 are prevalent. Although a recombinant vaccine, Hecolin, is available, it has not been used to control outbreaks. The licensed three-dose regimen might pose challenges for it to be an impactful outbreak control tool.
View Article and Find Full Text PDFMil Med
January 2025
Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Introduction: Vaccine mandates have been used to minimize the duty days lost and deaths attributable to infectious disease among active duty Service members (ADSMs). In response to the global COVID-19 pandemic, in August 2021, the U.S.
View Article and Find Full Text PDFImmunol Med
January 2025
Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo Medical University School of Medicine, Hyogo, Japan.
Rituximab (RTX) has been reported to effectively maintain remission in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). In this multicenter study involving 57 patients who achieved remission after 24 weeks, we evaluated the effectiveness of RTX in maintaining remission in patients with AAV. Patients were divided into three groups based on RTX administration: continuous, induction phase-only, and maintenance phase-only groups.
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