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Supplementary Tables 1-6, Figures 1-4 from Randomized Study of Paclitaxel and Tamoxifen Deposition into Human Brain Tumors: Implications for the Treatment of Metastatic Brain Tumors

Purpose: Drug resistance in brain tumors is partially mediated by the blood-brain barrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition.Experimental Design: Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m2/i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen.Results: Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms.Conclusions: Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumor's histopathology.

S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults. In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient (R2) >0.9, relative percent mean prediction error (%MPE) >−5 to

We have previously described a midazolam limited sampling strategy employing a population pharmacokinetic (PK) approach to estimate constitutive cytochrome P450 (CYP) 3A activity. This study evaluated expansion of this approach to estimate CYP3A constitutive, inhibitory, and induction activities. Midazolam concentrations (n = 4441) from adults (n = 152) were obtained from previous studies after single, oral, or intravenous administration with intensive sample collection. Data were fit to a 2-compartment population PK model that incorporated CYP3A conditions as covariates for clearance (CL), volume of distribution, and bioavailability (F). Limited sampling models using single- or 2-time point concentrations were compared with full PK profiles using the empiric Bayesian post hoc estimations of midazolam area under the plasma concentration-time curve derived from the population PK model. Ketoconazole, rifampin, and pleconaril were significant covariates of CL, while ketoconazole, rifampin, and grapefruit juice were significant covariates for F. Typical midazolam CL and F estimates were 32.9 L/h and 0.31 for the constituent state, while the ratio of inducer/inhibitor for midazolam CL and CL/F for the induced/inhibited (rifampin/ketoconazole) states were 14.2 and 85.3. Upon comparison to the population PK model, the majority of evaluated single- and 2-time point limited sampling models estimated area under the plasma concentration-time curve had unacceptable r2 and/or unacceptable bias and precision. Exclusively during CYP3A inhibitory conditions, the 4- and 6-hour limited sampling model had acceptable limits of r2 , bias, and precision. Consequently, development of a single- or 2-time point midazolam limited sampling model for general, widespread use to simultaneously evaluate various CYP3A conditions remains elusive.

S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults.In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient (RS-warfarin concentrations (n=2540) were well described with a two-compartment model. Mean apparent oral clearance was 0.56 L/hr and volume of distribution was 35.5 L. Clearance decreased 33% with the CYP2C9 *3 allele and increased 42% with lopinavir/ritonavir co-administration. During CYP2C9 constitutive conditions, LSMs at 48 hr and at 72 hr as well as 2-timepoint LSMs were within acceptable limits for RPhenotyping studies with S-warfarin in healthy subjects can utilize a single- and/or a 2-timepoint LSM with a population PK approach to estimate constitutive CYP2C9 activity.

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.

Despite a number of studies reporting that ertapenem pharmacokinetic parameters differ considerably in obese patients from those in healthy volunteers, functions describing the relationships between this agent's pharmacokinetics and indicators of body size have not been developed. The aim of this analysis was to develop an ertapenem population pharmacokinetic model using data from a previously described study in normal-weight, obese, and morbidly obese healthy volunteers. A single ertapenem 1-g dose administered intravenously was evaluated in 30 subjects within different body mass index (BMI) categories. The population pharmacokinetic model was developed using the first-order conditional estimation method with interaction (FOCE-I) algorithm within NONMEM. The ability of age, sex, renal function, and various body size measures (total body weight, height, body mass index, ideal body weight, fat-free mass, and body surface area [BSA]) to explain a portion of the interindividual variability on select pharmacokinetic parameters was explored using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). The data were best described using a linear three-compartment model with total body weight as a covariate on clearance (CL = 1.79 · [weight/95.90](0.278)) and BSA as a covariate on central volume (Vc = 4.76 · [BSA/2.06](1.86)). After accounting for fixed effects, the estimated interindividual variability was very low (

Background Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity. Methods Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile. Results Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r, range: 0.14-0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r (range: 0.02-0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers. Conclusions Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.

Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single-concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed-effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated. A limited sampling model at 1, 2, 4, or 6 hours was selected and fitted with post hoc estimation with the final population PK model. Preset criterion for the limited sampling model selection was a coefficient of determination ≥0.9. Bias and precision were also evaluated. The studies provided 2122 observations from 152 healthy adults. Midazolam concentrations were adequately described by a two-compartment model with first order absorption. Age and sex were significant covariates of central volume (V2 ) and were retained in the final model. An estimate (interindividual variability) of midazolam clearance was 32.5 L/hr (52.9%), covariate of central volume was 67 L (39.1%), and oral bioavailability was 0.33 (45.5%). The final population parameter estimates were within the 95% confidence intervals and were similar to the median bootstrap estimates. Upon comparison to the population PK model, the 4-hour limited sampling model estimated area under the curve had an acceptable coefficient of determination and acceptable bias and precision limits. A 4-hour, but not the 1-, 2-, and 6-hour, single concentration accurately estimated midazolam area under the curve during constitutive CYP3A conditions in healthy adults.

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 (AUC INF ) and truncated AUCs at 48 h (AUC 48 ), at 72 h (AUC72) and at 96 h (AUC 96 ) 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 AUC 48 and AUC 72 compared to AUC INF during baseline conditions in all evaluated studies and during treatment conditions in 5 of 6 studies. Equivalence was observed for AUC 96 compared to AUC INF 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 AUC INF (LS-GMR [90%CI] = 1.25 [1.16-1.34]) and AUC 96 (1.2 [1.13=1.27]). In contrast, equivalence was observed for AUC 48 (1.15 [1.08-1.22]) and AUC 72 (1.18 [1.11-1.24]). Conclusions: S-warfarin truncated AUC 48 and AUCM 72 poorly characterize AUC INF 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.

To determine the most appropriate methods for assessing the potential effectiveness of the newer topical fluoroquinolones gatifloxacin, moxifloxacin, and besifloxacin.This article is based on a literature search for published articles about the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of and measure of bacterial susceptibility to topical ophthalmic fluoroquinolones. Search terms included fluoroquinolones, susceptibility, resistance, minimal/minimum inhibitory concentration (MIC), PDs, PKs, and ocular, ophthalmic, or topical antibiotics.Topical fluoroquinolones, particularly besifloxacin, gatifloxacin, and moxifloxacin, have become important treatment options for common ocular bacterial infections due to their broad-spectrum bactericidal activity and low toxicity. An important challenge in ophthalmology is identifying the most accurate in vivo and in vitro methods for evaluating the efficacy of these topical fluoroquinolones. The MIC is the most commonly used measure of in vitro susceptibility. In systemic therapy, this measure is combined with PK data of antibiotics to generate PD indices PK/PD whose breakpoints differentiate clinically susceptible from nonsusceptible bacterial pathogen populations. PD breakpoints are further tested in prospective studies for their ability to predict clinical efficacy. However, it is not known whether systemically derived breakpoints apply to the assessment of clinical susceptibility to ocular agents. Topical ocular antibiotics likely achieve higher concentrations at the target site than do systemically administered antibiotics, but these higher concentrations can be quickly reduced by reflex tearing and blinking induced by instillation. Hence, studies have been conducted in animals and humans to determine the PK concentrations of topically administered antibiotics in ocular compartments. When combined with MIC values for topical pathogens, the results have the potential to predict clinical efficacy after identification of the appropriate PK/PD target. Ocular studies incorporating PK/PD assessments have recently begun to be reported with newer fluoroquinolones, including besifloxacin, gatifloxacin, and moxifloxacin, whose prolonged contact time and potent bactericidal activity have translated into some of the most favorable PK/PD target values. However, the clinical relevance of these studies has yet to be determined.There is still a clear need for predictive models to extend our understanding of the clinical susceptibility of ocular pathogens.

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/m 2 , 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.

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.

Study Objective. To compare the pharmacodynamics of uniform versus nonuniform warfarin dosages. Design. Prospective, randomized, crossover study. Setting. Anticoagulation clinic. Subjects. Twenty healthy subjects who had the extensive metabolizer cytochrome P450 (CYP) genotype of 2C9*1/*1 or CYP2C9*1/*3. Intervention. Subjects received either warfarin 5.75 mg once/day (two 1-mg tablets plus one and a half 2.5-mg tablets) as part of the uniform dosage group or warfarin 7.5 mg/day on Mondays and Fridays and 5 mg/day on each of the remaining days of the week as part of the nonuniform dosage group. Subjects received the first regimen for 17 days, had a 2-week washout period, and then were switched to the other regimen for another 17 days. Measurements and Main Results. During both treatment periods, international normalized ratios (INRs) were checked daily using a fingerstick method. Any changes in concomitant drug therapy, including over-the-counter and supplement products, as well as health status were recorded. The Scheffe post hoc test revealed no significant differences in mean INR values obtained during receipt of the two dosage regimens. In both dosage groups, variation in the INR became more pronounced as INR values increased. No adverse events (i.e., major or minor bleeding) or changes in drug therapy were reported during the study. Conclusion. Our findings suggest that it is safe to use a nonuniform dosage regimen of warfarin to reach a target INR range. With both uniform and nonuniform regimens, close monitoring remains important to ensure that patients remain within the desired INR range.

Aplaviroc is a novel CCR5 antagonist, a class of compounds under investigation as viral entry inhibitors for the treatment of human immunodeficiency virus infection. A modified Cooperstown 5 +1 cocktail was used to assess the drug interaction potential of aplaviroc. Fifteen healthy subjects were administered single oral doses of caffeine (CYP1A2), warfarin (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A) alone (reference treatment) and during steady-state administration of aplaviroc (400 mg every 12 hours, test treatment). Metabolite-to-parent area under the plasma concentration versus time curve (AUC) ratios (paraxanthine/caffeine and 5-hydroxyomeprazole/omeprazole), oral clearance (S-warfarin), AUC (midazolam), and metabolite-to-parent urinary excretion ratio (dextrorphan/dextromethorphan) were determined. The test-to-reference treatment ratios (geometric mean ratio and 90% confidence interval) were caffeine, 1.06 (0.97–1.17); S-warfarin, 0.93 (0.76–1.15); omeprazole, 1.07 (0.98–1.16); dextromethorphan, 1.17 (0.97–1.42); midazolam, 1.30 (1.04–1.63). No significant inhibition of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 enzyme activity was observed. Mild inhibition of CYP3A isozymes should not preclude the use of concomitant CYP3A substrates in future clinical studies with aplaviroc.

The effect of cigarette smoking on CYP2C9 activity is unknown. We conducted a study to evaluate whether there is a difference in CYP2C9 activity in smokers versus non-smokers by examining S-warfarin AUC after CYP2C9 inhibition with fluvastatin. In addition, the effect of the CYP2C9 inhibitor fluvastatin was evaluated using S-warfarin as a probe.A randomized, single dose, two-treatment crossover study of warfarin with a washout period of 21 days was performed. Eighteen healthy Caucasian smokers and non-smokers, genotyped as CYP2C9*1/*1 or CYP2C9*1/*2, received warfarin 10 mg plus vitamin K 10 mg to measure baseline CYP2C9 activity. Warfarin dosing was repeated after 18 days of fluvastatin 40 mg twice daily to evaluate CYP2C9 activity after inhibition.The S-warfarin AUC(0-infinity) between smokers and non-smokers did not differ by25% after inhibition. There was no difference in S-warfarin AUC(0-infinity) during baseline (p = 0.45) or inhibition (p = 0.19) periods for smokers versus non-smokers. Fluvastatin increased the AUC of S-warfarin by 42+/-29% and 26+/-18% in smokers and nonsmokers, respectively. Linear regression analyses showed significant but weak correlations between peak concentrations (C(at 1 h)) or (-) 3S,5R-fluvastatin AUC(0-12 h) and extent of warfarin inhibition. For (+) 3R,5S-fluvastatin, a weak correlation was found between C(at 1 h) and extent of warfarin inhibition.Cigarette smoking does not affect CYP2C9 activity as evaluated using S-warfarin as a CYP2C9 probe. Fluvastatin is a weak inhibitor of CYP2C9 activity in both smokers and non-smokers.

The objective of the study were to determine if nationally recognized community-acquired pneumonia (CAP) guidelines (specific to antibiotic therapy) were being followed and to identify outcomes of treatment in hospitals that are VHA members. This was a prospective study using a medication use evaluation in an inpatient setting conducted in 46 institutions in the United States during the 1998-1999 CAP season. The subjects were 875 adult patients (or =18 years of age) admitted from the emergency department or ambulatory care setting with a chest X-ray-confirmed diagnosis of CAP. Treatment pathways were in place in 58.7% (27/46) of institutions, with 18.3% of patients treated according to pathways. Twenty-seven percent of patients were PSI class I or II. A pathogen (blood or sputum) was identified in10% of patients. The first dose of antibiotic was administered to patients 65% of the time in the emergency department. Antibiotic therapy in 592 of the 694 admitted to a general medical unit (mortality rate, 3%) complied with 1998 Infectious Diseases Society of America (IDSA) guidelines compared with 26 of the 65 admitted to the intensive care unit (ICU) (mortality rate, 4.6%). In patients admitted to other nongeneral medical, non-ICU areas, IDSA guidelines were followed in 95% of the patients. Mean length of stay and mortality for PSI classes I-V were 4.5, 4.6, 6.9, 6.2, and 7.1 days, respectively, and 0%, 0.7%, 1.1%, 2.5%, and 10.5%, respectively. Antibiotic therapy was modified in 733 of 875 patients. Approximately 90% of patients were eligible for conversion to oral (per os) therapy before discontinuation of parenteral (intravenous) antibiotics (mean time to eligibility, 1.8 days of parenteral antibiotics), with conversion in 65% (mean time to conversion to oral therapy, 4.6 days). Resolution of CAP occurred in 92% of patients; deterioration was more common in PSI class IV and V patients. In conclusion, inhospital mortality rates for all PSI classes were similar to those found in other recently conducted studies despite limited adherence to pathways. Greater use of treatment guidelines for patients admitted to the ICU and awareness of the intravenous to per os antibiotic conversion process are suggested.

Maribavir (1263W94, VP-41263) is an oral anticytomegalovirus agent under clinical development. The pharmacokinetics and safety of maribavir and the effects of maribavir on the activities of cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N -acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) were evaluated in a randomized, double-blind, placebo-controlled study. Twenty healthy subjects received a five-drug phenotyping cocktail of caffeine (CYP 1A2, NAT-2, XO), warfarin plus vitamin K (CYP 2C9), omeprazole (CYP 2C19), dextromethorphan (CYP 2D6), and midazolam (CYP 3A) 4 days before and after 7 days of treatment with maribavir at 400 mg twice daily (16 subjects) or placebo (4 subjects) for 10 days. Maribavir did not affect the CYP 1A2, CYP 2C9, CYP 3A, NAT-2, or XO activities. Bioequivalence was not demonstrated for CYP 2C19 and CYP 2D6, suggesting a decrease or inhibition of CYP 2C19 and CYP 2D6 activities. The pharmacokinetics of maribavir following a single dose and after 10 days of treatment were similar, with minimal accumulation at steady state. Maribavir was safe and well tolerated. Taste disturbance was the most frequently reported adverse event. These results will further guide evaluation of the drug interaction potential and clinical development of maribavir.

Little is known of the effects of obesity on ertapenem drug disposition and pharmacodynamics. Thirty healthy volunteers in three body mass index (BMI) groups (10 per group), normal weight (BMI, 18.5 to 24.9 kg/m 2 ), class I-II obesity (BMI, 30 to 39.9 kg/m 2 ), and class III obesity (BMI, ≥40 kg/m 2 ), were administered a 1-g dose of ertapenem. Serum concentrations were obtained over 24 h. Population pharmacokinetic data were obtained using a nonparametric adaptive grid followed by Monte Carlo simulation to determine the probability of obtaining the free drug exposure targets of the time that the free drug concentration remains above the MIC ( f T >MIC ) of 20% and 40% for bacteriostatic and maximal bactericidal activity, respectively. Compared to the subjects in the obese groups, area under the concentration-time curve from 0 h to infinity was significantly higher in the normal-weight subjects, whereas the total central compartment volume was higher in the class III obese subjects ( P ≤ 0.05). Achieving a bacteriostatic target of f T >MIC of 20% with a 90% probability was attained at MICs of ≤0.5 μg/ml for normal-weight subjects. Class I-II and class III obese subjects were able to achieve this target only at a MIC of ≤0.25 μg/ml. For maximal bactericidal activity ( f T >MIC , 40%), no group attained the target at the 90% probability level at any tested MIC. The results suggest that the standard 1-g ertapenem dose may not provide adequate drug exposure for any body mass index classification for MICs in excess of 0.25 to 0.5 μg/ml.

To determine the effects of sex and menstrual cycle phase on CYP3A activity and to characterize the intraindividual variability of CYP3A, 24 Caucasian adults were given a single dose of omeprazole every 14th day for 3 months (men) or during the mid-follicular and mid-luteal phases over 3 full menstrual cycles (women). The 2-hour plasma metabolic ratio (MR) (omeprazole/omeprazole sulphone) was used as a measure of CYP3A activity. Overall mean MRs for men (2.4 +/- 1.2) and women (2.3 +/- 0.93) were not significantly different. In women, no difference in mean omeprazole MR was observed between the mid-follicular phase (2.2 +/- 0.85) and mid-luteal phase (2.4 +/- 1.0). When all data in the mid-luteal phase were stratified into 3 groups based on the progesterone concentrations (>50 nM [A], 20-50 nM [B], and

Pleconaril is a viral capsid inhibitor under evaluation for treatment of infections caused by rhinoviruses and enteroviruses. This study evaluated the effect of pleconaril on hepatic cytochrome P450 (CYP) 3A activity as assessed by intravenous (IV) midazolam. Healthy adults received oral pleconaril 400 mg 3 times daily for 16 doses. Single-dose, IV midazolam 0.025 mg/kg was administered before and during pleconaril administration. Midazolam and pleconaril plasma concentrations were assayed by LC/MS/MS. Bioequivalence was assessed by least squares geometric mean ratios (LS-GMR) with 90% confidence intervals (90% CIs) for the measured midazolam pharmacokinetic parameters. Sixteen subjects were enrolled, and 14 subjects completed the study. Pleconaril decreased midazolam AUC(0-infinity) 28% and increased systemic clearance 39%. LS-GMR (90% CI) were 0.718 (0.674-0.765) and 1.392 (1.307-1.483), respectively. Plasma pleconaril concentrations steadily increased over time. Observed changes in midazolam AUC(0-infinity) and systemic clearance suggest that oral pleconaril increased hepatic CYP3A activity in healthy adults.

The effects of a common oral contraceptive preparation on the activity of 7 drug-metabolizing enzymes were investigated using the validated Cooperstown 5+1 Cocktail. In a randomized crossover fashion, 10 premenopausal women received caffeine, dextromethorphan, omeprazole, intravenous midazolam, and warfarin + vitamin K with and without a triphasic oral contraceptive (ethinyl estradiol 35 microg) and varying doses of daily norgestimate (0.18, 0.215, and 0.25 mg). Bioequivalence testing showed nonequivalence in drug versus no-drug treatment on the activity of drug-metabolizing enzymes (as reflected by metabolite ratios following probe drug administration); the activity of CYP1A2, CYP2C19, and NAT-2 decreased following the oral contraceptive, whereas the activity of CYP2C9 and CYP2D6 increased. No effects on xanthine oxidase or hepatic CYP3A were seen. Application of a non-parametric statistical testing approach revealed a significant difference only for CYP1A2 and CYP2C19. This triphasic oral contraceptive may have a clinically significant effect on the activity of some drug-metabolizing enzymes.

Progesterone products are available in prescription form as well as over-the-counter (OTC) topical preparations sold for "cosmetic" uses. In a randomized study design, the authors compared the drug exposure from an OTC progesterone cream to a Food and Drug Administration-approved oral preparation at the labeled daily doses recommended for each product. Twelve healthy postmenopausal women received 200-mg oral progesterone capsules once daily for 12 days or progesterone cream 40 mg twice daily for 12 days. At steady state (day 12 of each phase), whole-blood samples were collected over 24 hours (oral progesterone) or 12 hours (topical progesterone) and assayed for total progesterone concentration. No significant differences were found in dose-normalized 24-hour progesterone exposure comparing the cream to oral capsules (median AUC(0-24) 12.5 ng x h/mL vs 10.5 ng x h/mL, respectively; P = .81). In light of the potential risks associated with long-term progesterone use, the authors question whether topical progesterone products should be available OTC.

The objective of this study was to examine the incidence of aminoglycoside-associated nephrotoxicity related to extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing by applying Bayes theorem. An electronic literature search of MEDLINE (1966-2003) and a manual search of references from published meta-analyses and review articles were performed. Studies using extended-interval dosing, individualized pharmacokinetic monitoring, or multiple-daily dosing and reported aminoglycoside-associated nephrotoxicity for patients > or = 16 years of age were included. Quality scores were assigned based on the rigor of definition of aminoglycoside-associated nephrotoxicity, duration of therapy, and length of follow-up of renal function after completion of therapy. Inclusion criteria were then based on these quality scores. Quantitative data on the incidence of aminoglycoside-associated nephrotoxicity were abstracted. Twelve extended-interval dosing studies (n = 916), 10 individualized pharmacokinetic monitoring studies (n = 2066), and 27 multiple-daily dosing studies (n = 4251) met the inclusion criteria. Prior probabilities of aminoglycoside-associated nephrotoxicity were derived from a combination of a review of published studies and expert judgment. The maximum densities for the final posterior probabilities of aminoglycoside-associated nephrotoxicity for extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing were located at 12% to 13%, 10% to 11%, and 13% to 14%, respectively. Application of Bayes theorem demonstrates that aminoglycoside dosing by individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity than extended-interval dosing or multiple-daily dosing.

Genetic polymorphisms of cytochrome P450 (CYP) enzymes are one of the factors that contribute to the pharmacokinetic (PK) variability of drugs. PK variability is observed in the bimodal distribution between extensive metabolizers (EMs) and poor metabolizers (PMs). PK variability may also exist between individuals genotyped as homozygous EMs and heterozygous EMs. This may carry implications for drug dosing and drug response (e.g., risk of therapeutic failure or drug toxicity). Studies have reported significant PK differences between homozygous and heterozygous EMs. Some literature suggests that this distinction may be of clinical relevance. Due to study design limitations and data that are either sparse or conflicting, generalizations regarding the potential impact of the CYP genotype, within EMs, are difficult. Optimally designed clinical trials are needed. This review evaluates the potential impact of CYP genetic polymorphisms on interindividual PK variability of drugs within an EM population.

Previously, we have validated a 4-drug phenotyping cocktail, the "Cooperstown cocktail," using caffeine (cytochrome p450 [CYP] 1A2, N-acetyltransferase-2 [NAT2], and xanthine oxidase [XO]), dextromethorphan (CYP2D6), omeprazole (CYP2C19), and intravenous midazolam (hepatic CYP3A). Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated. Twelve subjects received the Cooperstown cocktail, warfarin plus vitamin K, and both sets of biomarkers (Cooperstown 5+1 cocktail) in a randomized crossover fashion. On the basis of log-transformed data and a paired t test, no significant difference was seen for S-warfarin area under the serum concentration-time curve from time 0 to infinity (P =.09), omeprazole metabolic ratio (P =.374), caffeine metabolic ratio (P =.169 for CYP1A2 activity), midazolam plasma clearance (P =.573), or dextromethorphan metabolic ratio (P =.747) with the Cooperstown cocktail, warfarin plus vitamin K alone, or the Cooperstown 5+1 cocktail. During drug administration, the only side effect was mild and short-lived sedation after intravenous midazolam administration. Phenotypic measurements were in concordance with the subject's CYP2C9, CYP2C19, and CYP2D6 genotypes. The Cooperstown 5+1 cocktail may be used to simultaneously assess the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT2, and XO.

Drug-metabolizing enzyme activity is one of many factors affecting patient response to medications. The objective of this review is to highlight the potential for genetic variability in cytochrome P450 enzyme activity that can lead to interperson differences in response to drugs. Awareness and application of this knowledge will improve drug use in clinical practice and provide the physician with further appreciation that standard drug dosing may not be appropriate in all patients.

The 30-minute ratio of 1'-hydroxymidazolam:midazolam plasma concentrations has been used as a measure of midazolam clearance in liver transplant patients. This study determined if a single concentration of 1'-hydroxymidazolam or the ratio of 1'-hydroxymidazolam:midazolam could be used to predict midazolam clearance in healthy subjects. Plasma midazolam and 1'-hydroxymidazolam concentrations from three previous studies were used for analyses. Data obtained predose and at 5, 30, 60, 120, 240, 300, and 360 minutes following intravenous doses of midazolam in 61 adults were divided and used to derive and validate equations to predict midazolam clearance. Equations were derived using linear regression and then validated by comparing predicted to observed clearance. Only one equation was related to midazolam clearance as afunction of 1'-hydroxymidazolam, but it did not predict midazolam clearance (r = 0.29, p = 0.31). Single sampling of 1'-hydroxymidazolam or 1'-hydroxymidazolam:midazolam plasma concentrations cannot be used to predict midazolam clearance in healthy adults.

Viral respiratory infections (VRIs) are a common malady associated with considerable costs in terms of decreased productivity and time lost from work or school, visits to health-care providers, and the amount of drugs prescribed. Both total respiratory illness and rhinovirus infection peak during the fall and spring seasons, although the average percentage of office visits by patients with a rhinovirus infection is moderately high throughout the year. Most common cold remedies are relatively ineffective and may produce side effects that contribute to increased health-care costs. Antibiotic therapy is widely overused and misused despite evidence that antibiotics fail to treat the cause of VRI or prevent secondary bacterial infections. Increasing use of antibiotics has a significant impact on health-care costs and the emergence of antimicrobial resistance. Reasons for overprescribing antibiotics are varied, but they often involve physician and patient attitudes and expectations. Although treatment of VRIs poses challenges for effective formulary management, several steps can be taken to facilitate the introduction of antiviral agents, including patient and provider education, the development of rapid diagnostic tests, and medical-economics studies to determine the true cost of antiviral therapy.

Midazolam clearance is used to phenotype hepatic CYP3A activity but requires multiple plasma samples following a single intravenous dose. The authors evaluated the use of a limited sampling scheme, using different assay techniques to determine the reproducibility of such a strategy in estimating midazolam AUC. Seventy-three healthy adults received midazolam as a single intravenous bolus dose. At least eight plasma samples were collected from each subject and were assayed using either LC/MS/MS or electron capture gas chromatography. Eleven subjects were randomly selected for the training set using stepwise linear regression to determine relationships between midazolam plasma concentrations and AUC. Validation of the predictive equations was done using the remaining 62 subjects. Mean percent error (MPE), mean absolute error (MAE), and root mean square error (RMSE) were calculated to determine bias and precision. Based on the training set, five models were generated with coefficients of determination ranging from 0.87 to 0.95. Validation showed that MPE, MAE, and RMSE values were acceptable for three of the models. Intrasubject reproducibility was good. In addition, training set datafrom one institution were able to predict data from the other two institutions using other assay techniques. Minimized plasma sampling mayprovide a simpler method for estimating midazolam AUC for CYP3A phenotyping. A limited sampling strategy is more convenient and cost-effective than standard sampling strategies and is applicable to more than one assay technique.

Background Premarketing trials showed the fluoroquinolone agents to have a favorable side-effect profile, with treatment-related adverse events comprising gastrointestinal, central nervous system, and dermatologic effects that were generally mild and reversible on cessation of treatment. However, postmarketing surveillance studies have identified severe adverse events, including severe anaphylaxis, QTc-interval prolongation, and potential cardiotoxicity, associated with 3 quinolone agents that either resulted in the removal of the agent from the market (temafloxacin and grepafloxacin) or significantly restricted its use due to substantial mortality and morbidity associated with liver toxicity (trovafloxacin). To date, there have been no such significant adverse events associated with the older fluoroquinolone agents, including ciprofloxacin, ofloxacin, norfloxacin, and levofloxacin. However, there are fewer data from postmarketing surveillance studies on the most recently approved agents, such as moxifloxacin and gatifloxacin, or agents awaiting approval, such as gemifloxacin. Objective This paper examines safety data from the premarketing trials and postmarketing surveillance studies of fluoroquinolones available in the United States. Methods A MEDLINE ® search was performed to identify all English-language studies published since 1980 concerning the safety profiles of the fluoroquinolones. Conclusions The fluoroquinolone antibacterial agents offer broad-spectrum therapy in patients with a variety of infections. Given similar spectra of activity, the choice between quinolones may be based on differences in efficacy and safety or tolerability profiles. Most drug reactions involving these agents are minor and reversible on discontinuing treatment, but adverse effects can be associated with significant mortality and morbidity, as was seen in the case of trovafloxacin and temafloxacin.

Cytochrome P450 phenotyping provides valuable information about real-time activity of these important drug-metabolizing enzymes through the use of specific probe drugs. Despite more than 20 years of research, few conclusions regarding optimal phenotyping methods have been reached. Caffeine offers many advantages for CYP1A2 phenotyping, but the widely used caffeine urinary metabolic ratios may not be the optimal method of measuring CYP1A2 activity. Several probes of CYP2C9 activity have been suggested, but little information exists regarding their use, largely due to the narrow therapeutic index of most CYP2C9 probes. Mephenytoin has long been considered the standard CYP2C19 phenotyping probe, but problems such as sample stability and adverse effects have prompted the investigation of potential alternatives, such as omeprazole. Several well-validated CYP2D6 probes are available, including dextromethorphan, debrisoquin and sparteine, but, in most cases, dextromethorphan may be preferred due to its wide safety margin and availability. Chlorzoxazone remains the only CYP2E1 probe that has received much study. However, questions concerning phenotyping method and involvement of other enzymes have impaired its acceptance as a suitable CYP2E1 phenotyping probe. CYP3A phenotyping has been the subject of numerous investigations, reviews and commentaries. Nevertheless, much controversy regarding the selection of an ideal CYP3A probe remains. Of all the proposed methods, midazolam plasma clearance and the erythromycin breath test have been the most rigorously studied and appear to be the most reliable of the available methods. Despite the limitations of many currently available probes, with continued research, phenotyping will become an even more valuable research and clinical resource.

Nosocomial pneumonia is a notable cause of morbidity and mortality and leads to increases in lengths of hospital stays and institutional expenditures. Aminoglycosides are used to treat patients with these infections, but few data on the doses and schedules required to achieve optimal therapeutic outcomes exist. We analyzed aminoglycoside treatment data for 78 patients with nosocomial pneumonia to determine if optimization of aminoglycoside pharmacodynamic parameters results in a more rapid therapeutic response (defined by outcome and days to leukocyte count resolution and temperature resolution). Cox proportional hazards, Classification and Regression Tree (CART), and logistic regression analyses were applied to the data. By all analyses, the first measured maximum concentration of drug in serum ( C max )/MIC predicted days to temperature resolution and the second measured C max /MIC predicted days to leukocyte count resolution. For days to temperature resolution and leukocyte count resolution, CART analyses produced breakpoints, with an 89% success rate at 7 days of therapy for a C max /MIC of >4.7 and an 86% success rate at 7 days of therapy for a C max /MIC of >4.5, respectively. Logistic regression analyses predicted a 90% probability of temperature resolution and leukocyte count resolution by day 7 if a C max /MIC of ≥10 is achieved within the first 48 h of aminoglycoside therapy. Aggressive aminoglycoside dosing immediately followed by individualized pharmacokinetic monitoring would ensure that C max /MIC targets are achieved early in therapy. This would increase the probability of a rapid therapeutic response for pneumonia caused by gram-negative bacteria and potentially decreasing durations of parenteral antibiotic therapy, lengths of hospitalization, and institutional expenditures, a situation in which both the patient and the institution benefit.

Intraindividual variability and the effects of menstrual cycle phase on CYP2D6 activity were evaluated by dextromethorphan phenotyping in 20 Caucasian normal volunteers. Dextromethorphan 30 mg was administered to 10 men every 14 days for 3 months, and to 10 premenopausal women during the mid-follicular and mid-luteal phases of each menstrual cycle for three complete cycles. Urinary dextromethorphan/dextrorphan molar ratios were obtained after an overnight urine collection. Ten women and nine men were extensive metabolizer phenotypes, and one man was a poor metabolizer phenotype (confirmed by genotyping). There was no difference in dextromethorphan metabolic ratios between the mid-follicular (mean +/- SD: 0.00728+/-0.00717) and mid-luteal (0.00745+/-0.00815) phases of the menstrual cycle (P = 0.88). Also, no significant difference was found in the intraindividual variability of the metabolic ratios between the two phases (P = 0.80). No statistically significant sex difference in CYP2D6 activity was found between men (0.00537+/-0.00431) and women (0.00737+/-0.00983) extensive metabolizers (P = 0.84). For all individuals, intraindividual variability in dextromethorphan ratios ranged from 12.1-136.6% with a median of 36.7%. Because hormonal fluctuations within the mid-follicular and mid-luteal phases of the menstrual cycle do not appear to affect CYP2D6 activity, pharmacokinetic or clinical investigations of CYP2D6 substrate activity may not require menstrual cycle phase stratification. Because baseline metabolic ratios may fluctuate an average of 37%, repeat baseline and treatment phenotyping assessments should be obtained for accurate determination of a given drug's effect on CYP2D6 activity when measured by dextromethorphan.