Pharmacodynamics of an 800-mg dose of telithromycin in patients with community-acquired pneumonia caused by extracellular pathogens.

The pharmacodynamics of telithromycin, a new ketolide antibacterial, was examined in 115 patients with community-acquired pneumonia (CAP). Patients received telithromycin 800 mg qd for 7-10 days. Pharmacokinetic parameters were determined, and exposure was linked to microbiological outcome using logistic regression analysis. A breakpoint for increased probability of microbiological eradication was developed and was found to be the ratio of area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) of 3.375. The final logistic regression model of microbiological outcome included body weight and AUC/MIC ratio breakpoint. This model was found in analyses of the entire population and when Streptococcus pneumoniae and Haemophilus influenzae were examined separately. The AUC/MIC ratio target attainment rate is expected to be >99.9% for S. pneumoniae and Moraxella catarrhalis and 93.1% for H. influenzae. This study demonstrated a relationship between telithromycin drug exposure and microbiological outcome. Telithromycin is expected to achieve the drug exposure breakpoint for the majority of isolates causing CAP.

The importance of appropriate antimicrobial dosing: pharmacokinetic and pharmacodynamic considerations.

The increasing antimicrobial resistance of common respiratory pathogens has led to a reevaluation of the selection of antimicrobial dosing regimens in terms of their pharmacokinetic (PK) and pharmacodynamic (PD) properties. Pharmacokinetics, when considered as part of a specific dosing regimen, can help determine the time course of drug concentrations in the serum, tissues, body fluids, and at the site of infection. Pharmacodynamics provides surrogate markers for clinical and bacteriologic efficacy based on the relationships between the serum and tissue concentrations of selected antimicrobial agents relative to the mean inhibitory concentrations of causative bacteria over time. Ultimately, the interrelationships between PK and PD parameters measured for standard dosing regimens determine the time course of the drug's concentration at the site of infection and the impact of the agent's bacteriologic and clinical efficacy. In this review, the distinctive patterns of antimicrobial activity based on PK/PD parameters are discussed. Various antibiotics and bacterial pathogens are used as models to demonstrate the utility of PK/PD parameters in predicting the in vivo efficacy of antimicrobial therapy. The use of computer modeling with Monte Carlo population simulations can further enhance the predictability of antimicrobial efficacy when using PK/PD parameters. This article also provides a reevaluation of bacterial susceptibility breakpoints defined by the National Committee for Clinical Laboratory Standards contrasted with the use of PK/PD parameters.

Relationship between fluoroquinolone area under the curve: minimum inhibitory concentration ratio and the probability of eradication of the infecting pathogen, in patients with nosocomial pneumonia.

Our objective was to prospectively determine the factors influencing the probability of a good microbiological or clinical outcome in patients with nosocomial pneumonia treated with a fluoroquinolone. Levofloxacin was administered as an infusion of 500 mg/h for 1.5 h (total dose, 750 mg). For patients with Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus, a second drug was added (ceftazidime or piperacillin/tazobactam for P. aeruginosa and vancomycin for methicillin-resistant S. aureus). Population pharmacokinetic studies of 58 patients demonstrated that this population handled the drug differently from populations of volunteers. Multivariate logistic regression analysis (n=47 patients) demonstrated that only the age of the patient and the achievement of an area under the curve: minimum inhibitory concentration ratio of > or =87 had a significant effect on eradication of the pathogen (P<.001). Achieving the breakpoint made the patient 4 times more likely to achieve eradication. The effect was greatest in patients > or =67 years old.

Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers.

OBJECTIVE: To evaluate the safety and pharmacokinetic interaction between GW433908, ritonavir (RTV), and efavirenz (EFV). METHODS: In period 1, subjects received either a once daily (QD) regimen of GW433908 1395 mg + RTV 200 mg (Study 1) or a twice daily (bid) regimen of GW433908 700 mg + RTV 100 mg (Study 2) for 14 days. In period 2, subjects received EFV 600 mg QD with either the same GW433908 + RTV regimen as in period 1 (arm 1) or with a GW433908 + RTV regimen that included an additional 100 mg of RTV (arm 2) for 14 days. Amprenavir (APV) pharmacokinetic sampling and safety assessments were performed on the last day of each period. RESULTS: Plasma APV exposure was not significantly altered when EFV was coadministered with GW433908 700 mg twice daily (BID) + RTV 100 mg BID. Plasma APV exposure was decreased when EFV was coadministered with GW433908 1395 mg QD + RTV 200 mg QD. However, administration of EFV with GW433908 1395 mg QD + RTV 300 mg QD (i.e., adding an extra 100 mg of RTV) was able to negate this interaction. Adverse events were consistent with prior data for each of the separate agents. CONCLUSION: When EFV is coadministered with the GW433908 700 mg + RTV 100 mg BID regimen, no dosage adjustment is recommended. However, when EFV is coadministered with the GW433908 1400 mg + RTV 200 mg QD regimen, an increase to RTV 300 mg QD is needed to maintain plasma APV exposure.

Comparative pharmacokinetic analysis by standard two-stage method versus nonparametric population modeling.

STUDY OBJECTIVE: To compare the two-stage method, a widely used analytical method in pharmacokinetic studies, with nonparametric population modeling by using the same data set for determining the oral bioavailability of ribavirin. DESIGN: Pharmacokinetic analysis. Clinical research center. MATERIAL: Oral bioavailability data of ribavirin determined previously in six healthy adults. INTERVENTION: After 13C3-ribavirin 150 mg intravenously and unlabeled ribavirin 400 mg orally had been given 1 hour apart, serial serum and urine samples were obtained for up to 169 hours. Concentrations of 13C3-ribavirin and unlabeled ribavirin in serum and urine were determined by a high-performance liquid chromatography tandem mass spectrometric method. MEASUREMENTS AND MAIN RESULTS: Serum and urine concentration-time profiles were comodeled with a three-compartment model. The analysis was performed again by using the nonparametric population analysis technique. Serum ribavirin concentrations underwent Monte Carlo simulation for 1000 subjects receiving a single 600-mg oral dose. Both methods were similar in determining the mean +/- SD bioavailability (51.8 +/- 21.8% by the two-stage method vs 54.8 +/- 16.4% by nonparametric modeling, p=0.79). However, the estimates of dispersion of model parameters and simulated drug exposures were substantially reduced by the population-modeling technique, as it takes into account covariance among model parameters and intersubject variability. CONCLUSION: Although the study sample was small, our parallel analyses of the same data set clearly demonstrated that more precise parameter estimates are likely to result with the population-modeling technique. Having accurate and precise estimation of population pharmacokinetic parameters and their true variances is crucial, as, at any dose, there'will be a lower probability of encountering a concentration-driven toxicity because of fewer outliers as the variance associated with the parameters decreases.

In vitro-in vivo model for evaluating the antiviral activity of amprenavir in combination with ritonavir administered at 600 and 100 milligrams, respectively, every 12 hours.

The study objective was to evaluate the pharmacodynamics of amprenavir in an in vitro system, develop an exposure target for maximal viral suppression, and determine the likelihood of target attainment based on the pharmacokinetics of amprenavir and ritonavir in human immunodeficiency virus (HIV)-infected patients. Population pharmacokinetic data were obtained from 13 HIV-infected patients receiving amprenavir and ritonavir in doses of 600 and 100 mg, respectively, every 12 h. A 2,500-subject Monte Carlo simulation was performed. Target attainment was also estimated for a target derived from clinical data. Maximal viral suppression (in vitro) was achieved when amprenavir free-drug concentrations remained greater than four times the 50% effective concentration (EC(50)) for 80% of the dosing interval. At an amprenavir EC(50) of 0.03 microM, the likelihood of target attainment is 97.4%. For reduced-susceptibility isolates for which the EC(50)s are 0.05 and 0.08 microM, target attainment is 91.0 and 75.8%, respectively. For the clinical target of a trough concentration/EC(50) ratio of 5, the target attainment rates were similar. Treatment with amprenavir and ritonavir at doses of 600 and 100 mg, respectively, twice a day provides excellent suppression of wild-type isolates and reduced-susceptibility isolates up to an EC(50) of 0.05 micro M. Even at 0.12 microM, target attainment likelihood exceeds 50%, making this an option for patients with extensive exposure to protease inhibitors when this treatment is used with additional active antiretroviral agents.

Optimal sampling schedule design for populations of patients.

Generation of pharmacodynamic relationships in the clinical arena requires estimation of pharmacokinetic parameter values for individual patients. When the target population is severely ill, the ability to obtain traditional intensive blood sampling schedules is curtailed. Population modeling guided by optimal sampling theory has provided robust estimates of individual patient pharmacokinetic parameter values. Because of the wide range of parameter values seen in this circumstance, it is important to know how the range of parameter values in the population affects the timing of the optimal samples. We describe a new, simple technique to obtain optimal samples for a population of patients. This technique uses the nonparametric distribution associated with a nonparametric adaptive grid population pharmacokinetic analysis. We used the distribution from an analysis of 58 patients receiving levofloxacin for nosocomial pneumonia at a dose of 750 mg. The collection of parameter vectors and their associated probabilities were entered into a D-optimal design evaluation by using ADAPT II. The sampling times, weighted for their probabilities, were displayed in a frequency histogram (an expression of how system information varies with time for the population). Such an explicit expression of the time distribution of information allows rational sampling design that is robust not only for the population mean vector, as in traditional D-optimal design theory, but also for large portions of the total population. For levofloxacin, one reasonable six-sample design would be 1.5, 2, 2.25, 4, 4.75, and 24 h after starting a 90-min infusion. Such sampling designs allow informative population pharmacokinetic analysis with precise and unbiased estimates after the maximal a posteriori probability Bayesian step. This allows the highest probability of delineating a pharmacodynamic relationship.

Guillain-Barré syndrome associated with immune reconstitution.

We report a case of acute Guillain-Barré syndrome (GBS) associated with a prompt and vigorous immune reconstitution and decrease in the virus load noted during treatment with a potent regimen of highly active antiretroviral therapy. We hypothesize that GBS may have been due to an aberrant immune response or an adverse drug reaction in association with preexisting peripheral neurologic disease.

Pharmacodynamics and clinical use of anti-HIV drugs.

Antiretroviral drug exposure has been linked to both antiviral efficacy and the development of toxicity and further research in this area is ongoing and necessary. Use of these data may have important implications for TDM of HAART regimens in clinical practice. TDM, in conjunction with an assessment of the patient's viral resistance in the form of an IQ, needs to be examined and validated in large clinical trials.

Claiming our place: women with serious mental health issues and support groups for abused women.

Many women with serious mental health issues also deal with abuse and have difficulty accessing services. Despite the fact that groups have been found to be one of the most useful tools in healing from the effects of abuse, many professionals see women with serious mental health issues as unable to benefit from counselling and, in particular, from groups for abused women. This study indicates that, when mental health issues are addressed and the group structures and expectations are modified to allow women control over their participation, serious mental health issues are not a barrier to participation in groups.