Joel S. Owen

Pharmacokinetic-Pharmacodynamic Relationships Describing the Efficacy of Oritavancin in Patients with Staphylococcus aureus Bacteremia

ABSTRACT Bloodstream infections due to antimicrobial-resistant Staphylococcus aureus occur with increasing frequency and represent an important cause of morbidity and mortality. To date, the evaluation of pharmacokinetic-pharmacodynamic relationships for efficacy among patients with bacteremia has been limited. The objectives of these analyses were to evaluate relationships between microbiological and clinical responses for patients with S. aureus bacteremia and exposures for oritavancin, a novel bactericidal glycopeptide in development. Bayesian oritavancin exposure predictions, following treatment with 5, 6.5, 8, or 10 mg/kg of body weight/day, were derived using a validated population pharmacokinetic model for 55 patients with S. aureus bacteremia. Using classification and regression tree analysis, a breakpoint of the percentage of the dosing interval duration for which free-drug concentrations were above the MIC (free-drug % time > MIC) of 22% was identified for microbiological response; the probabilities of success greater than or equal to and less than this value were 93% and 76%, respectively. Using logistic regression, a relationship was found between microbiological response and free-drug % time > MIC (odds ratio = 4.42, P = 0.09, and odds ratio = 8.84, P = 0.05, when one patient, a medical outlier, was excluded). A similar relationship was found for clinical response. These results will be valuable in supporting dose selection of oritavancin for patients with S. aureus bacteremia.

Population Pharmacokinetics of Tigecycline in Patients with Complicated Intra-Abdominal or Skin and Skin Structure Infections

ABSTRACT Tigecycline, a first-in-class expanded glycylcycline antimicrobial agent, has demonstrated efficacy in the treatment of complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal (cIAI) infections. A population pharmacokinetic (PK) model for tigecycline was developed for patients with cSSSI or cIAI enrolled in two phase 2 clinical trials, and the influence of selected demographic factors and clinical laboratory measures was investigated. Tigecycline was administered as an intravenous loading dose followed by a 0.5- or 1-h infusion every 12 h for up to 14 days. Blood samples were collected the day before or the day of hospital discharge for the determination of serum tigecycline concentrations. Patient covariates were evaluated using stepwise forward (α = 0.05) and backward (α = 0.001) procedures. The predictive performance of the model was assessed separately using pooled data from either two phase 3 studies for patients with cSSSI or two phase 3 studies for patients with cIAI. A two-compartment model with zero-order input and first-order elimination adequately described the steady-state tigecycline concentration-time data. Tigecycline clearance was shown to increase with increasing weight, increasing creatinine clearance, and male gender (P < 0.001). The final model provided a relatively unbiased fit to each data set. Individual predicted values of the area under the concentration-time curve from 0 to 12 h (AUC0-12) were generally unbiased (median prediction error, −1.60% to −3.78%) and were similarly precise (median absolute prediction error, <4%) when compared across data sets. The population PK model provided the basis to obtain individual estimates of steady-state AUC0-12 in later exposure-response analyses of tigecycline safety and efficacy in patients with cSSSI or cIAI.

Pharmacogenetic-Based Efavirenz Dose Modification: Suggestions for an African Population and the Different CYP2B6 Genotypes

Background Pharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans. Methods In total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg. Results EFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients. Conclusion Results of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively.

Use of Pharmacodynamic End Points in the Evaluation of Gatifloxacin for the Treatment of Acute Maxillary Sinusitis

The relationship between drug exposure and the time course of antimicrobial effect at the primary infection site for acute maxillary sinusitis has not previously been explored. This single-center, open-label study quantified the time course of sinus sterilization, described gatifloxacin exposure at the infection site, and posed the hypothesis that the use of continuous and quantitative time-related end points may allow for better characterization of drug effect with fewer patients than traditional clinical trial approaches. Of the 12 enrolled patients, 10 were clinically evaluable, from whom 7 pathogens were isolated: 4 Streptococcus pneumoniae, 2 staphylococci, and 1 Enterobacter aerogenes. The median predicted 24-h area under the curve (AUC) in sinus aspirates and plasma samples was 54.7 mg x h/L and 30.1 mg x h/L, respectively. The median 24-h AUC ratio for sinus aspirates and plasma samples was 1.51 (range, 0.88-2.23). For patients infected with pneumococci, the median time to sinus sterilization was 50 h. The use of quantitative time-related end points may be useful in evaluating the efficacy of antimicrobial agents with fewer patients.

Population Pharmacokinetic Meta-Analysis of Trabectedin (ET-743, Yondelis®) in Cancer Patients

ObjectiveTo characterise the population pharmacokinetics of trabectedin (ET-743, Yondelis®) in cancer patients.MethodsA total of 603 patients (945 cycles) receiving intravenous trabectedin as monotherapy at doses ranging from 0.024 to 1.8 mg/m2 and given as a 1-, 3- or 24-hour infusion every 21 days; a 1- or 3-hour infusion on days 1, 8 and 15 of a 28-day cycle; or a 1-hour infusion daily for 5 consecutive days every 21 days were included in the analysis. An open four-compartment pharmacokinetic model with linear elimination, linear and nonlinear distribution to the deep and shallow peripheral compartments, respectively, and a catenary compartment off the shallow compartment was developed to best describe the index dataset using NONMEM V software. The effect of selected patient covariates on trabectedin pharmacokinetics was investigated. Model evaluation was performed using good-ness-of-fit plots and relative error measurements for the test dataset. Simulations were undertaken to evaluate covariate effects on trabectedin pharmacokinetics.ResultsThe mean (SD) trabectedin elimination half-life was approximately 180 (61.4) hours. Plasma accumulation was limited when trabectedin was given every 3 weeks. Systemic clearance (31.5 L/h, coefficient of variation 51%) was 19.2% higher in patients receiving concomitant dexamethasone. The typical values of the volume of distribution at steady state for male and female patients were 6070L and 5240L, respectively. Within the range studied, age, body size variables, AST, ALT, alkaline Phosphatase, lactate dehydrogenase, total bilirubin, Creatinine clearance, albumin, total protein, Eastern Cooperative Oncology Group performance status and presence of liver metastases were not statistically related to trabectedin pharmacokinetic parameters. The pharmacokinetic parameters of trabectedin were consistent across the infusion durations and dose regimens evaluated.ConclusionsThe integration of trabectedin pharmacokinetic data demonstrated linear elimination, dose-proportionality up to 1.8 mg/m2 and time-independent pharmacokinetics. The pharmacokinetic impact of dexamethasone and sex covariates is probably limited given the moderate to large interindividual pharmacokinetic variability of trabectedin. The antiemetic and hepatoprotective effects are still a valid rationale to recommend dexamethasone as a supportive treatment for trabectedin.

Population pharmacokinetics of tigecycline in healthy volunteers.

Tigecycline, a novel glycylcycline, possesses broad‐spectrum antimicrobial activity. A structural population pharmacokinetic model for tigecycline was developed based on data pooled from 5 phase I studies. Intravenous tigecycline was administered as single (12.5–300 mg) or multiple (25–100 mg) doses every 12 hours for up to 10 days. Three‐compartment models with zero‐order input and first‐order elimination separately described the single‐ or multiple‐dose full‐profile data. Additional models were evaluated using a subset of the phase I data mimicking the phase II/III trial sparse‐sampling scheme and dosage. A 2‐compartment model best described the reduced phase I data following single or multiple doses and provided reliably accurate estimates of tigecycline AUC0–12. This modeling supported phase II/III population pharmacokinetic model development to further determine individual patient tigecycline exposures for safety and efficacy analyses.

Plasma Pharmacokinetics of Two Consecutive Doses of Ferumoxytol in Healthy Subjects

Intravenous (IV) iron is used to treat iron‐deficiency anemia in patients with chronic kidney disease (CKD). Ferumoxytol is a novel iron formulation administered rapidly as two IV boluses of 510 mg each. In this placebo‐controlled, double‐blind, parallel‐group study, 58 healthy volunteers received ferumoxytol in two 510 mg doses administered 24 h apart. Population pharmacokinetics (PK) analysis was conducted, and a two‐compartment open model with zero‐order input and Michaelis–Menten elimination was found to best describe the data. The population mean estimates for volume of distribution of the central compartment (V1), maximal elimination rate (Vmax), and ferumoxytol concentration at which rate of metabolism would be one‐half of Vmax (Km) were 2.71 l, 14.3 mg/h, and 77.5 mg/l, respectively. When the effect of body weight on V1 was added in the analysis, interindividual variability was found to be reduced. A noncompartmental analysis of two simulated 510‐mg ferumoxytol doses was also performed to provide clinically interpretable data on half life and exposure. Ferumoxytol given as two consecutive 510‐mg doses was well tolerated.

Challenges in the Transition to Model-Based Development

Practitioners of the art and science of pharmacometrics are well aware of the considerable effort required to successfully complete modeling and simulation activities for drug development programs. This is particularly true because of the current, ad hoc implementation wherein modeling and simulation activities are piggybacked onto traditional development programs. This effort, coupled with the failure to explicitly design development programs around modeling and simulation, will continue to be an important obstacle, to the successful transition to model-based drug development. Challenges with timely data availability, high data discard rates, delays in completing modeling and simulation activities, and resistance of development teams to the use of modeling and simulation in decision making are all symptoms of an immature process capability for performing modeling and simulation.A process that will fulfill the promise of model-based development will require the development and deployment of three critical elements. The first is the infrastructure—the data definitions and assembly processes that will allow efficient pooling of data across trials and development programs. The second is the process itself—developing guidelines for deciding when and where modeling and simulation should be applied and the criteria for assessing performance and impact. The third element concerns the organization and culture—the establishment of truly integrated, multidisciplinary, and multiorganizational development teams trained in the use of modeling and simulation in decision-making. Creating these capabilities, infrastructure, and incentivizations are critical to realizing the full value of modeling and simulation in drug development.

Introduction to Population Pharmacokinetic / Pharmacodynamic Analysis with Nonlinear Mixed Effects Models: Owen/Introduction to Population Pharmacokinetic / Pharmacodynamic Analysis with Nonlinear Mixed Effects Models

This book provides a user-friendly, hands-on introduction to the Nonlinear Mixed Effects Modeling (NONMEM) system, the most powerful tool for pharmacokinetic / Cwers conditional weighted least in each individual clearances of collinearity. Statistical model describing noise rather than articles and individual. A given by hearing lectures for unexplainable random effects as a requirement relevant. Qq quantilequantile qq plots of quantification lloq pharmacokinetic pharmacodynamic analysis evaluating. Body build basic principles and type are not deviate. Eq jill fiedler kelly is, not physically entering. Population parameters are available at ecog, and individual subjects generally need.

CYP2B6 genotype-based efavirenz dose recommendations during rifampicin-based antituberculosis cotreatment for a sub-Saharan Africa population.

AIM To assess genotype effect on efavirenz (EFV) pharmacokinetics, treatment outcomes and provide genotype-based EFV doses recommendations during for tuberculosis (TB)-HIV-1 cotreatment. MATERIALS & METHODS EFV concentrations from 158 HIV-TB co-infected patients treated with EFV/lamivudine/zidovidine and rifampicin were analyzed. Genotype and CD4 and viral load data were analyzed using a population PK model. RESULTS Simulated AUCs for 600 mg EFV dose were 1.2- and 2.4-times greater than the product label for Ugandans in general and CYP2B6*6/*6 genotypes respectively. EFV daily doses of 450 and 250 mg for Ugandans and CYP2B6*6/*6 genotypes, respectively, yielded simulated exposures comparable to the product label. CONCLUSIONS Around 450 and 250 mg daily doses might meet EFV dosing needs of HIV-TB infected Ugandans in general and CYP2B6*6/*6 genotypes, respectively.