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ABSTRACT: Oseltamivir is a potent inhibitor of influenza neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on PK variability of oseltamivir and its active metabolite oseltamivir carboxylate (OC). Dosing history, plasma concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1-78 years and given oseltamivir doses of 20-1000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated in NONMEM and subject covariates were assessed using stepwise forward selection (α=0.01) and backward elimination (α=0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC, and a one-compartment model with first-order elimination of OC was utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent clearance OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F while Vcm/F also decreased linearly with age. A visual predictive check indicated the final model described oseltamivir and OC plasma concentrations adequately across dose regimens and subject covariate ranges. Concordance of population mean and individual post-hoc predictions of Cmax and AUC0-24 was high (r(2)=0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.
Antimicrobial Agents and Chemotherapy 05/2013; · 4.84 Impact Factor
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Brian Vanscoy,
Rodrigo E Mendes,
Anthony M Nicasio,
Mariana Castanheira, Catharine C Bulik,
Olanrewaju O Okusanya,
Sujata M Bhavnani,
Alan Forrest,
Ronald N Jones,
Lawrence V Friedrich,
Judith N Steenbergen,
Paul G Ambrose
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ABSTRACT: Despite β-lactamase inhibitors being available for clinical use for nearly 30 years, a paucity of data exists describing the pharmacokinetic-pharmacodynamic (PK-PD) determinants of efficacy for these agents. Herein, we describe dose-fractionation studies designed to determine the exposure measure most predictive of tazobactam efficacy in combination with ceftolozane and the magnitude of this measure necessary for efficacy in a PK-PD in vitro infection model. The challenge organism panel was comprised of an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of blaCTX-M-15. These recombinant strains exhibited ceftolozane MIC values of 4 (low-), 16 (moderate-), and 64 (high-level of CTX-M-15) mcg/mL. Different blaCTX-M-15 transcription levels were confirmed by relative qRT-PCR and β-lactamase hydrolytic assays. The exposure measure associated with efficacy was the percent of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold), regardless of enzyme expression (r(2) = 0.938). The threshold concentrations identified were 0.05 mcg/mL for low- and moderate and 0.25 mcg/mL for the high-β-lactamase expression strain constructs. The magnitude of %Time>threshold for tazobactam associated with net bacterial stasis, and a 1- and 2-log10 CFU reduction in bacteria at 24 hours was approximately 35, 50, and 70%, respectively. These data provide an initial target tazobactam concentration-time profile and a paradigm to optimize tazobactam dosing when combined with ceftolozane.
Antimicrobial Agents and Chemotherapy 04/2013; · 4.84 Impact Factor
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ABSTRACT: The pharmacokinetics-pharmacodynamics (PK-PD) of fusidic acid were investigated against methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pyogenes using in vitro infection models. Front-loaded and non-front-loaded fusidic acid dosing regimens were evaluated over 48 h using a 1-compartment infection model and over 240 h using a hollow fiber infection model (HFIM). All dosing regimens demonstrated initial decreases in bacterial density against both isolates in both in vitro models. A mechanism-based PK-PD model was developed to describe the effect of the concentration-time course of fusidic acid on the time course of MRSA in the in vitro infection model. With the use of this model and Monte Carlo simulation to evaluate the effect of different dosing regimens against MRSA, front-loaded [≥ 1200 mg every 12 h (Q12) × 2 doses followed by ≥ 600 mg Q12 h] compared to non-front-loaded (600 mg Q12 h) dosing regimens demonstrated better activity. HFIM data confirmed the effect of the front-loaded dosing regimens over 48 h and also demonstrated the suppression of growth of the total population and resistant subpopulations for MRSA over 96 and 120 h, respectively, associated with these dosing regimens.
Diagnostic microbiology and infectious disease 05/2011; 70(1):101-11. · 2.45 Impact Factor
