Development and owns stock and stock options. James B. Kahn is an employee of OrthoMcNeil Pharmaceutical and owns stock and stock options. Nonstandard abbreviations used: minimum inhibitory concentration (MIC); Mueller-Hinton II broth (MHB); minimum bactericidal concentration (MBC); area under the concentration time curve (AUC); nonparametric expectation maximization 2 (NPEM2); maximum a posteriori probability (MAP); quinolone resistance-determining region (QRDR).caused by antibiotic-resistant bacteria are more difficult to treat, resulting in excess morbidity and mortality as well as higher health care costs. Therefore, it is imperative to identify ways of suppressing the emergence of antibiotic-resistant mutants.Current preclinical methods for assessing the efficacy of an antimicrobial agent most often evaluate the effect of selected dosages of the compound on the reduction in the total bacterial population at an infection site. The impact of drug pressure on the amplification of the drug-resistant subpopulation is ignored (1-3).For some antibiotic dosages, the drug-susceptible population may be completely replaced with resistant mutants over time. Clinically, this may manifest as the failure of an infection to respond to therapy or a relapse of infection with drug-resistant mutants shortly after a prescribed course of antibiotic therapy is completed.The probability that a resistant subpopulation exists within a predominantly drug-susceptible wildtype population is dependent on the number of organisms at the infection site (total population burden) and the mutational frequency to resistance to The worldwide increase in the prevalence of multi-antibiotic-resistant bacteria has threatened the physician's ability to provide appropriate therapy for infections. The relationship between antimicrobial drug concentration and infecting pathogen population reduction is of primary interest. Using data derived from mice infected with the bacterium Pseudomonas aeruginosa and treated with a fluoroquinolone antibiotic, a mathematical model was developed that described relationships between antimicrobial drug exposures and changes in drug-susceptible and -resistant bacterial subpopulations at an infection site. Dosing regimens and consequent drug exposures that amplify or suppress the emergence of resistant bacterial subpopulations were identified and prospectively validated. Resistant clones selected in vivo by suboptimal regimens were characterized. No mutations were identified in the quinolone resistance-determining regions of gyrA/B or parC/E. However, all resistant clones demonstrated efflux pump overexpression. At base line, MexAB-OprM, MexCD-OprJ, and MexEF-OprN were represented in the drug-resistant population. After 28 hours of therapy, MexCD-OprJ became the predominant pump expressed in the resistant clones. The likelihood of achieving resistance-suppression exposure in humans with a clinically prescribed antibiotic dose was determined. The methods developed in this study provide insight regarding how mathematical m...

We propose a model that characterizes and links the complexity and diversity of clinically observed hepatitis C viral kinetics to sustained virologic response (SVR)—the primary clinical end point of hepatitis C treatment, defined as an undetectable viral load at 24 weeks after completion of treatment)—in patients with chronic hepatitis C (CHC) who have received treatment with peginterferon α‐2a ± ribavirin. The new attributes of our hepatitis C viral kinetic model are (i) the implementation of a cure/viral eradication boundary, (ii) employment of all hepatitis C virus (HCV) RNA measurements, including those below the lower limit of quantification (LLOQ), and (iii) implementation of a population modeling approach. The model demonstrated excellent positive (99.3%) and negative (97.1%) predictive values for SVR as well as high sensitivity (96.6%) and specificity (99.4%). The proposed viral kinetic model provides a framework for mechanistic exploration of treatment outcome and permits evaluation of alternative CHC treatment options with the ultimate aim of developing and testing hypotheses for personalizing treatments in this disease. Clinical Pharmacology & Therapeutics (2010) 87 6, 706–713. doi:

PURPOSE. To characterize ranibizumab pharmacokinetics in patients with AMD. METHODS.A population approach of nonlinear mixed-effect pharmacokinetic modeling based on concentration-time data from 2993 serum samples from 674 AMD patients enrolled in 5 phase 1 to 3 clinical trials of single or multiple intravitreal (ITV) doses of ranibizumab (0.3-2.0 mg/eye) administered biweekly or monthly for up to 24 months. RESULTS.A total of 696 concentration-time records from 229 subjects with one or more measurable total serum ranibizumab concentrations were analyzed. The systemic concentration-time data for ranibizumab were best described by a one-compartment model with first-order absorption into and first-order elimination from the systemic circulation. Vitreous elimination half-life (t 1/2 ) was calculated to be 9 days and the intrinsic systemic elimination t 1/2 was calculated to be approximately 2 hours. Following ITV administration, ranibizumab egresses slowly into the systemic circulation, resulting in an apparent serum t 1/2 of 9 days. Systemic-to-vitreous exposure ratio was estimated to be 1:90,000. With monthly and quarterly ITV regimens, the serum concentrations of ranibizumab at steadystate for both the 0.3 and 0.5 mg/eye dose levels were estimated to be below the range needed to inhibit VEGF-A-induced endothelial cell proliferation in vitro by 50% at all times.CONCLUSIONS. Systemic exposure to ranibizumab after ITV injection was very low due to elimination on reaching systemic circulation from the vitreous. Population pharmacokinetic analysis of data from a representative sample of AMD patients did not identify clinically significant sources or correlates of variability in ranibizumab exposure. (ClinicalTrials.gov numbers, NCT00056836, NCT00056823.) (Invest Ophthalmol Vis

Infancy and early childhood are periods of rapid brain development, during which brain structure and function mature alongside evolving cognitive ability. An important neurodevelopmental process during this postnatal period is the maturation of the myelinated white matter, which facilitates rapid communication across neural systems and networks. Though prior brain imaging studies in children (4 years of age and above), adolescents, and adults have consistently linked white matter development with cognitive maturation and intelligence, few studies have examined how these processes are related throughout early development (birth to 4 years of age). Here, we show that the profile of white matter myelination across the first 5 years of life is strongly and specifically related to cognitive ability. Using a longitudinal design, coupled with advanced magnetic resonance imaging, we demonstrate that children with above-average ability show differential trajectories of myelin development compared to average and below average ability children, even when controlling for socioeconomic status, gestation, and birth weight. Specifically, higher ability children exhibit slower but more prolonged early development, resulting in overall increased myelin measures by ~3 years of age. These results provide new insight into the early neuroanatomical correlates of cognitive ability, and suggest an early period of prolonged maturation with associated protracted white matter plasticity may result in strengthened neural networks that can better support later development. Further, these results reinforce the necessity of a longitudinal perspective in investigating typical or suspected atypical cognitive maturation.

Daptomycin is a lipopeptide antibiotic with activity against gram-positive bacteria, including Staphylococcus aureus. We defined the pharmacodynamic parameters that determine the activity of daptomycin for S. aureus using in vitro methods and the Craig (W. A. Craig, J. Redington, and S. C. Ebert, J. Antimicrob. Chemother. 27[Suppl. C]:29-40, 1991) neutropenic mouse thigh infection model. In Mueller-Hinton broth, the MICs for three S. aureus isolates were 0.1 to 0.2 g/ml. In mouse serum, the MICs were 1.0 g/ml. The protein binding of daptomycin was 90 to 92.5% in mouse serum. Single-dose intraperitoneal (i.p.) pharmacokinetic studies with infected mice showed a linear relationship between dose versus the maximum concentration of drug in serum and dose versus the area under the concentration-time curve (AUC). The serum half-life of daptomycin in infected mice was approximately 1.8 h. In single-dose, dose-ranging studies using mice, daptomycin showed a dose-response effect described by an inhibitory sigmoid E max (maximum effect) curve (r ‫؍‬ 0.974; P Ͻ Ͻ 0.001). The density of S. aureus in untreated controls was 8.26 log 10 CFU/g, and the E max was 3.97 log 10 CFU/g. The 50% effective dose (ED 50 ) was 3.7 mg/kg of body weight i.p. and the stasis dose was 7.1 mg/kg. Dose fractionation studies at schedules of Q6h, Q12h, and Q24h, for total 24-h ED 30 , ED 60 , and ED 80 doses of 2.5, 5.6, and 15 mg/kg i.p., showed no difference in effect at each total 24-h dose level by schedule, indicating that the AUC/MIC ratio is the dynamically linked variable.The incidence of community-and nosocomially acquired infections due to the bacterium Staphylococcus aureus is rising (24). From 1990 to 1992 this microorganism was the most common cause of nosocomial pneumonias and surgical wound infections (14). Although the antistaphylococcal beta-lactam antibiotics are the most active agents available for the treatment of methicillin-susceptible S. aureus, the National Nosocomial Infections Surveillance System of the Centers for Disease Control and Prevention reports that in 1997, 56.2% of S. aureus isolates were resistant to these agents (24). Vancomycin is considered the drug of choice for the treatment of methicillin-resistant S. aureus infections. However, this drug is slowly bactericidal and is associated with higher failure and relapse rates than beta-lactam therapy for the treatment of S. aureus endocarditis. Also, strains of S. aureus demonstrating decreased susceptibility to vancomycin have been described in Japan (18,19) and the United States (8).Daptomycin is an acidic lipopeptide antibiotic that is active against gram-positive bacteria, including S. aureus and enterococci (13,20,23,31). Importantly, the mechanism of action of daptomycin is distinctly different from that of other antimicrobial agents (2, 3). Thus daptomycin is active against Staphylococcus and Enterococcus species that are resistant to vancomycin (6, 31; N. V. Jacobus, J. R. McDermott, J. M. Lonks, J. M. Boyce, and D. R. Snydman, Abstr. 38th Intersci. Conf....

Trastuzumab-DM1 (T-DM1) is a novel antibody-drug conjugate under investigation for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. One challenge in oncologic drug development is determining the optimal dose and treatment schedule. A novel dose regimen-finding strategy was developed for T-DM1 using experimental data and pharmacokinetic/pharmacodynamic modeling. To characterize the disposition of T-DM1, pharmacokinetic studies were conducted in athymic nude and beige nude mice. The pharmacokinetics of T-DM1 were described well by a two-compartment model. Tumor response data were obtained from single-dose, multiple-dose and time-dose-fractionation studies of T-DM1 in animal models of HER2-positive breast cancer, specifically engineered to be insensitive to trastuzumab. A sequential population-based pharmacokinetic/pharmacodynamic modeling approach was developed to describe the anti-tumor activity of T-DM1. A cell-cycle-phase nonspecific tumor cell kill model incorporating transit compartments captured well the features of tumor growth and the activity of T-DM1. Key findings of the model were that tumor cell growth rate played a significant role in the sensitivity of tumors to T-DM1; anti-tumor activity was schedule independent; and tumor response was linked to the ratio of exposure to a concentration required for tumor stasis.

These data strongly support regulation by progesterone of Dkk-1 mRNA synthesis and protein expression in human endometrial stromal cells and that the response is specific for progesterone and independent of cAMP and estradiol.

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