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Nafziger A.N.,Bertino Consulting | Nafziger A.N.,State University of New York at Buffalo | Pratt D.S.,Schenectady County Public Health Services
Journal of Clinical Pharmacology | Year: 2014

Seasonal influenza is a serious respiratory illness that causes annual worldwide epidemics resulting in significant morbidity and mortality. Influenza pandemics occur about every 40 yrs, and may carry a greater burden of illness and death than seasonal influenza. Both seasonal influenza and pandemic influenza have profound economic consequences. The combination of current vaccine efficacy and viral antigenic drifts and shifts necessitates annual vaccination. New manufacturing technologies in influenza vaccine development employ cell culture and recombinant techniques. Both allow more rapid vaccine creation and production. In the past 5 years, brisk, highly creative activity in influenza vaccine research and development has begun. New vaccine technologies and vaccination strategies are addressing the need for viable alternatives to egg production methods and improved efficacy. At present, stubborn problems of sub-optimal efficacy and the need for annual immunization persist. There is an obvious need for more efficacious vaccines and improved vaccination strategies to make immunization easier for providers and patients. Mitigating this serious annual health threat remains an important public health priority. © 2014, The American College of Clinical Pharmacology. Source


Pai M.P.,Albany College of Pharmacy and Health Sciences | Nafziger A.N.,Bertino Consulting | Bertino Jr. J.S.,Bertino Consulting
Antimicrobial Agents and Chemotherapy | Year: 2011

Aminoglycosides are an important class of agents that are used in combination antimicrobial regimens to treat bacterial pathogens. Dosing of aminoglycosides is typically based on total body weight. However, the most appropriate alternative body size descriptor for dosing aminoglycosides at the extremes of weight (underweight and obese) is not known. Also, the predictive performance of newer formulas to assess kidney function, such as the modification of diet in renal Disease (MDRD) and chronic kidney disease-epidemiology (CKD-EPI) equations compared to the Cockcroft-Gault equation to predict aminoglycoside clearance, is not known. We sought to examine dosing of aminoglycosides across the extremes of weight using a variety of formulas to assess kidney function. Pharmacokinetic data were obtained from a set of prospectively collected data (1982 to 2003) of 2,073 (53.5% male) adult patients that included 497 tobramycin- and 1,576 gentamicin-treated cases. The median (minimum, maximum) age, weight, and body mass index were 66 (18, 98) years, 70.0 (29.7, 206.7) kg, and 24.4 (11.3, 73.8) kg/m2, respectively. The percentage of underweight, normal-weight, overweight, and obese cases based on the World Health Organization classification were 8.8%, 45.5%, 26.5%, and 19.2%, respectively. The aminoglycoside volume of distribution was normalized to several alternative body size descriptors. Only lean body weight estimated by the method of S. Janmahasatian et al. (Clin. Pharmacokinet. 44:1051-1065, 2005) normalized the volume of distribution for both tobramycin and gentamicin across all weight strata, with the estimate being approximately 0.45 liter/kg. Aminoglycoside dosing can be simplified across all weight strata with the use of lean body weight. The CKD-EPI equation best predicts aminoglycoside clearance. Copyright © 2011, American Society for Microbiology. All Rights Reserved. Source


Bertino J.S.,Bertino Consulting | Nafziger A.N.,Bertino Consulting | Kashuba A.D.M.,University of North Carolina at Chapel Hill | Turpault S.,Sanofi S.A. | Lewis L.D.,Dartmouth Hitchcock Medical Center
Therapeutic Drug Monitoring | Year: 2016

Background: Phenotyping cytochrome P450 (CYP) 2C9 activity using S-warfarin has routinely required extensive blood sampling over at least 96 hours after dose to estimate the area under the concentration time curve from zero to infinity (AUC). Alternatively, S-warfarin limited sampling models (LSMs) using one or 2 concentration timepoints have been proposed to estimate AUC. This study evaluated whether S-warfarin LSMs accurately estimate CYP2C9 baseline and induction conditions in healthy adults and in advanced-stage cancer patients. Methods: Plasma S-warfarin concentrations from healthy adults (n = 92) and in advanced-stage cancer patients (n = 22) were obtained from 6 published studies where a single 10 mg dose of oral warfarin was administered at CYP2C9 baseline and induction conditions. S-warfarin observed AUC was determined by noncompartmental analysis, whereas estimated AUC was calculated from the LSMs. Bias and precision were assessed by percent mean prediction error, percent mean absolute error, and percent root mean square error. Results: Different results were observed for S-warfarin LSMs in estimating CYP2C9 baseline activity, with most studies resulting in unacceptable bias and precision. The percent mean prediction error, percent mean absolute error, and/or percent root mean square error exceeded acceptable limits for LSMs in patients with advanced-stage cancer and during CYP2C9 induction with lopinavir/ritonavir. Conclusions: The differing results during CYP2C9 baseline conditions, as well as unacceptable bias and precision in patients with advanced cancer and during CYP2C9 induction, considerably limit the widespread use of previously published S-warfarin LSMs. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Source


Gaedigk A.,The Childrens Mercy Hospital and Clinics | Jaime L.K.M.,Pharmacology Unit | Bertino Jr. J.S.,Bertino Consulting | Berard A.,University of Montreal | And 3 more authors.
Frontiers in Pharmacology | Year: 2010

Polymorphic expression of CYP2D6 contributes to the wide range of activity observed for this clinically important drug metabolizing enzyme. In this report we describe novel CYP2D7/2D6 hybrid genes encoding non-functional and functional CYP2D6 protein and a CYP2D7 variant that mimics a CYP2D7/2D6 hybrid gene. Five-kilobyte-long PCR products encompassing the novel genes were entirely sequenced. A quantitative assay probing in different gene regions was employed to determine CYP2D6 and 2D7 copy number variations and the relative position of the hybrid genes within the locus was assessed by long-range PCR. In addition to the previously known CYP2D6 *13 and *66 hybrids, we describe three novel non-functional CYP2D7-2D6 hybrids with gene switching in exon 2 (CYP2D6 *79), intron 2 (CYP2D6 *80), and intron 5 (CYP2D6*67). A CYP2D7-specific T-ins in exon 1 causes a detrimental frame shift. One subject revealed a CYP2D7 conversion in the 5′-flanking region of a CYP2D6 *35 allele, was otherwise unaffected (designated CYP2D6*35B). Finally, three DNAs revealed a CYP2D7 gene with a CYP2D6-like region downstream of exon 9 (designated CYP2D7[REP6]). Quantitative copy number determination, sequence analyses, and long-range PCR mapping were in agreement and excluded the presence of additional gene units. Undetected hybrid genes may cause over- estimation of CYP2D6 activity (CYP2D6 *1/ *1 vs *1/hybrid, etc), but may also cause results that may interfere with the genotype determination. Detection of hybrid events, " single" and tandem, will contribute to more accurate phenotype prediction from genotype data. © 2010 Gaedigk, Jaime, Bertino, Jr., Bérard, Pratt, Bradford and Leeder. Source


Nafziger A.N.,Bertino Consulting | Bertino Jr. J.S.,Bertino Consulting
Journal of Clinical Pharmacology | Year: 2010

Desirudin is a renally eliminated direct thrombin inhibitor approved to prevent venous thromboembolism. Empiric dosage adjustment and activated partial thromboplastin time (aPTT) monitoring in patients with moderate renal impairment are recommended, but supportive data are lacking. The objective of this study was to evaluate appropriate desirudin dosing in moderate renal impairment and the effect of desirudin on aPTT in moderate renal impairment. Desirudin plasma concentration and aPTT data were extracted from 6 studies. Participants with normal renal function or moderate renal impairment (creatinine clearance [ClCr] 31-60 mL/min) were included. Pharmacokinetic and Monte Carlo simulations were done. After administration of desirudin 15 mg every 12 hours subcutaneously (SC) to steady state, peak desirudin concentrations were 35 and 47 nmol/L in the normal and moderate renal function groups, respectively. Monte Carlo simulations found median 2-hour Cmax concentrations of 51.7 nmol/L in normal renal function and 52.4 nmol/L in moderate renal impairment. Desirudin exhibits a linear relationship when the square root of desirudin concentration is plotted versus the aPTT ratio (r2 = 0.76). These analyses support the dosing of desirudin at 15 mg every 12 hours SC without aPTT monitoring in patients with moderate renal impairment. © 2010 The Author(s). Source

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