Bertino Consulting

Schenectady, NY, United States

Bertino Consulting

Schenectady, NY, United States
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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.


Lee L.S.,Bassett Healthcare | Kinzig-Schippers M.,Institute for Biomedical and Pharmaceutical Research IBMP | Nafziger A.N.,Bertino Consulting | Ma L.,Ordway Research Institute | And 5 more authors.
Diagnostic Microbiology and Infectious Disease | Year: 2010

Imipenem/cilastatin and meropenem are carbapenem antibiotics that are infused intravenously (IV) over 30 to 45 min. We evaluated probability of target attainment and cumulative probability of target attainment of 30-min and 3-h infusions for imipenem/cilastatin and meropenem. Eighteen healthy adults in a randomized, 4-phase, crossover study received 1000 mg of imipenem/cilastatin or meropenem as a single-dose IV over 30 min or 3 h. A population pharmacokinetics analysis using a 2-compartment IV infusion model was performed. Monte Carlo simulations using various dosage regimens at steady-state and 30-min and 3-h infusion rates were performed to evaluate the probabilities of attaining 20% (bacteriostatic), 30%, and 40% (maximum kill) time above the MIC. Three-hour infusions of imipenem/cilastatin and meropenem improved the cumulative probability of target attainment for a variety of populations of microorganisms compared to 30-min infusions. Prolonged infusions have the potential to optimize efficacy of imipenem/cilastatin and meropenem. © 2010 Elsevier Inc.


Gaedigk A.,The Childrens Mercy Hospital and Clinics | Jaime L.K.M.,Pharmacology Unit | Bertino Jr. J.S.,Bertino Consulting | Berard A.,University of Montréal | 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.


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.


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.


Ma J.D.,University of California at San Diego | Tsunoda S.M.,University of California at San Diego | Bertino J.S.,Bertino Consulting | Trivedi M.,University of California at San Diego | And 2 more authors.
Clinical Pharmacokinetics | Year: 2010

Drug transporters are involved in clinically relevant drug-drug interactions. P-glycoprotein (P-gp) is an efflux transporter that displays genetic polymorphism. Phenotyping permits evaluation of real-time, in vivo P-gp activity and P-gp-mediated drug-drug interactions. Digoxin, fexofenadine, talinolol and quinidine are commonly used probe drugs for P-gp phenotyping. Although current regulatory guidance documents highlight methodologies for evaluating transporter-based drug-drug interactions, whether current probe drugs are suitable for phenotyping has not been established, and validation criteria are lacking. This review proposes validation criteria and evaluates P-gp probes to determine probe suitability. Based on these criteria, digoxin, fexofenadine, talinolol and quinidine have limitations to their use and are not recommended for P-gp phenotyping. © 2010 Adis Data Information BV. All rights reserved.


Wu J.C.,University of California at San Diego | Nafziger A.N.,Bertino Consulting | Bertino Jr. J.S.,Bertino Consulting | Ma J.D.,University of California at San Diego
Drug Metabolism Letters | Year: 2012

Objective: Phenotyping cytochrome P450 (CYP) 2C9 activity with S-warfarin requires extensive blood sampling to characterize area under the concentration-time curve (AUC). This retrospective data analysis was conducted to determine if truncated S-warfarin AUCs can be used to measure CYP2C9 activity. Methods: S-warfarin plasma concentrations were obtained from healthy adults (n = 84) genotyped as CYP2C9 extensive metabolizers (EMs) from 6 published studies. Subjects received a single 10 mg oral warfarin dose during baseline and treatment conditions. AUC zero to infinity (AUCINF) and truncated AUCs at 48 h (AUC48), at 72 h (AUC72) and at 96 h (AUC96) were determined by noncompartmental analysis. Equivalence was determined via least squares geometric mean ratios (LS-GMRs) with 90% confidence intervals (CI) within 0.8-1.25. Results: A lack of equivalence was observed for AUC48 and AUC72 compared to AUCINF during baseline conditions in all evaluated studies and during treatment conditions in 5 of 6 studies. Equivalence was observed for AUC96 compared to AUCINF during all baseline and treatment conditions. Results were consistent across all evaluated AUCs between baseline and treatment without a CYP2C9-mediated drug-drug interaction and during induction with an oral contraceptive. During inhibition with fluvastatin, a lack of equivalence was observed with AUCINF (LS-GMR [90%CI] = 1.25 [1.16-1.34]) and AUC96 (1.2 [1.13=1.27]). In contrast, equivalence was observed for AUC48 (1.15 [1.08-1.22]) and AUC72 (1.18 [1.11-1.24]). Conclusions: S-warfarin truncated AUC48 and AUC72 poorly characterize AUCINF and are unable to detect weak CYP2C9 inhibition with fluvastatin. S-warfarin phenotyping parameters need to ensure blood sampling of at least 96 h to characterize AUC and thus CYP2C9 activity. © 2012 Bentham Science Publishers.


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).


PubMed | Bertino Consulting
Type: Journal Article | Journal: 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 C(max) 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 (r(2) = 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.

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