Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate.

OBJECTIVES: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) for focal-onset seizures (FOS). Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to assess dose selection, identify significant AED drug interactions, and quantitate relationships between exposure and safety and efficacy outcomes from Phase 3 trials of adjunctive ESL. METHODS: Eslicarbazepine (the primary active metabolite of ESL) population PK was evaluated using data from 1351 subjects enrolled in 14 studies (11 Phase 1 and three Phase 3 studies) after multiple oral doses ranging from 400 to 1200 mg. Population PK and PD models related individual eslicarbazepine exposures to safety outcomes and efficacy responses. RESULTS: Eslicarbazepine PK was described by a one-compartment model with linear absorption and elimination. The probability of a treatment-emergent adverse event (TEAE; dizziness, headache, or somnolence) was higher with an initial dose of ESL 800 mg than with an initial dose of ESL 400 mg QD. Body weight, sex, region, and baseline use of carbamazepine (CBZ) or lamotrigine were also found to influence the probability of TEAEs. Eslicarbazepine exposure influenced serum sodium concentration, standardized seizure frequency, and probability of response; better efficacy outcomes were predicted in patients not from Western Europe (WE; vs WE patients) and those not taking CBZ (vs taking CBZ) at baseline. CONCLUSIONS: Pharmacokinetic and PK/PD modeling were implemented during the development of ESL for adjunctive treatment of FOS in adults. This quantitative approach supported decision-making during the development of ESL, and contributed to dosing recommendations and labeling information related to drug interactions.

Population Pharmacokinetic and Pharmacodynamic Modeling of LY2510924 in Patients With Advanced Cancer.

The objectives of this study were to characterize the pharmacokinetics (PK) of LY2510924, a potent peptide antagonist of the CXCR4 receptor, after subcutaneous administration in patients with advanced cancer forms and quantify LY2510924 stimulatory effects on the mobilization of cells bearing the cluster of differentiation 34 (CD34) as an indirect reflection of the chemokine C-X-C motif ligand 12/CXCR4 axis inhibition. LY2510924 PK were best characterized by a two-compartment model with first-order absorption and dose-dependent clearance predicting steady state after three daily doses and little accumulation (accumulation ratio <1.17). The dynamics of CD34+ cell counts were best characterized with a precursor model with reversible transfer from the precursor to the central compartment and LY2510924-driven stimulation of cell mobilization. Model-based simulations show that once-daily doses of 20 mg LY2510924 produce maximum CD34+ cell response and that peak effect typically occurs after three daily doses and slowly wanes over time.

Tedizolid population pharmacokinetics, exposure response, and target attainment.

Tedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid. Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, and linear elimination described the PK data well. Variability was small (clearance, 31% coefficient of variation; volume, 13.4% coefficient of variation), and absolute bioavailability was high (86%). No clinically significant covariate effects on tedizolid PK were found. Based on phase 3 data evaluating 200-mg once-daily tedizolid for acute bacterial skin and skin structure infections (ABSSSI), no relationships were seen between various efficacy outcomes and estimated tedizolid exposure; the estimated exposure range (free-drug area under the concentration-time curve over 24 h at steady state [AUCss(0-24)], 7 to 50 µg · h/ml) in these patients was modest. Safety data modeling, using once-daily doses of up to 400 mg, showed a small increase in the probability of an adverse event with increasing model-estimated tedizolid exposure; no such relationship was observed when specifically evaluating the 200-mg dose. There were no trends in neutrophil or platelet counts with increasing tedizolid exposure. Target attainment simulations for 200-mg tedizolid indicated a 98.31% probability of attaining the target measure (AUC for the free, unbound fraction of a drug [fAUC]/MIC = 3) against a Staphylococcus aureus strain for which the MIC was ≤0.5 µg/ml. These findings support 200-mg tedizolid once daily as the optimum dose for treatment of ABSSSI.

Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation.

A population pharmacokinetic and pharmacodynamic analysis evaluated the relationships of dose, plasma concentrations of bupropion and metabolites, and patient covariates with the safety and efficacy of bupropion sustained release (SR) for smoking cessation. A total of 519 outpatient chronic cigarette smokers were randomized to one of three bupropion SR doses: 100, 150, or 300 mg/day or placebo. The bupropion plasma concentration time data were fit and subject-specific bayesian estimates of clearance were obtained. Logistic regression analyses evaluated the role of dose, concentrations, and covariates in predicting efficacy and safety endpoints. For the evaluation of efficacy, patients were classified as quitters or non-quitters on the basis of a 4-week quit variable (defined as complete abstinence for weeks 4-7 of the study). For the evaluation of safety, patients were classified into two categories for each adverse event evaluated, corresponding to whether the patient ever experienced the adverse event during the course of the study or never experienced the event, regardless of whether the event was treatment-emergent. The efficacy of bupropion SR in facilitating smoking cessation was found to be related to dose and a mean metabolite concentration, and quitting in general was found to be related to the number of cigarettes smoked per day at baseline. Smoking cessation was 1.42, 1.69, and 2.84 times more likely in patients receiving 100, 150, and 300 mg/day of bupropion SR, respectively, as compared to placebo (p = 0.0001). As the baseline number of cigarettes smoked per day increased, the likelihood of quitting decreased regardless of the treatment condition. Insomnia and dry mouth were positively associated with mean metabolite concentrations, and dry mouth was inversely related to patient weight. Anxiety was inversely related to predicted steady-state concentration (Cpss), suggesting a positive effect on this withdrawal symptom. Bupropion SR exhibits a statistically significant dose/plasma level-response relationship for smoking cessation. Dry mouth and insomnia, related to concentrations, may be managed with dose reduction, with the realization that smoking cessation may be impaired.

Population pharmacokinetics of tirilazad: effects of weight, gender, concomitant phenytoin, and subarachnoid hemorrhage.

PURPOSE: Data collected during Phase I and II in the development of tirilazad were pooled and analyzed using nonlinear mixed effects models to assess covariates which might affect tirilazad pharmacokinetics. METHODS: Four single dose and five multiple dose studies in normal volunteers were combined with two multiple dose studies performed in patients with subarachnoid hemorrhage (SAH) to identify factors related to intersubject variability in clearance (CL) and central compartment volume (Vc). Data from 253 subjects, which consisted of 7,219 tirilazad concentrations, were analyzed. The effects of weight, gender, patient versus volunteer status, and phenytoin use were evaluated. RESULTS: Relative to male volunteers not receiving concomitant phenytoin, significant effects on clearance included: a 46% increase in volunteers receiving phenytoin, and an 82% increase in clearance associated with SAH patients (all of whom received phenytoin). Significant effects on Vc were: a 26% increase for female volunteers not receiving phenytoin, a 12% decrease for volunteers receiving concomitant phenytoin, a 152% increase for male SAH patients, and a 270% increase for female SAH patients. Incorporating patient covariate effects substantially reduced the interindividual variability (from 27.9% to 24.7% for clearance and from 48.2% to 37.5% for Vc). Residual variability was estimated at 66% coefficient of variation (CV) in SAH patients and at 22-48% CV over the range of predicted concentrations in normal volunteers. CONCLUSIONS: The most important factors affecting tirilazad pharmacokinetics are the administration of phenytoin (increased CL) and SAH (increased Vc and residual variability). The effect of gender on tirilazad pharmacokinetics was modest.

Population pharmacokinetics of lamotrigine adjunctive therapy in adults with epilepsy.

Plasma concentrations of lamotrigine, an antiepileptic drug obtained in three adult controlled clinical trials conducted in the United States were pooled and analyzed using NONMEM, a population pharmacokinetic computer program, to facilitate development of dosing guidelines. A total of 2,407 lamotrigine plasma concentrations from 527 patients with epilepsy were analyzed. Regression equations for oral clearance were developed as a function of body size, age (18-64 years), gender, race, and use of concomitant antiepileptic drugs. The population mean apparent oral clearance of lamotrigine in adult patients receiving one concomitant enzyme-inducing antiepileptic drug and not valproic acid was estimated to be 1 mL/min/kg. Gender and age did not affect clearance significantly. On average, clearance was reduced by 25% in non-whites and increased by 13% in patients receiving more than one concomitant enzyme-inducing antiepileptic agent. Lamotrigine did not influence the disposition of phenytoin or carbamazepine. Dosing adjustments for lamotrigine in patients receiving concomitant enzyme-inducing antiepileptic drugs and not valproic acid should not be necessary for age, gender, or the number of concomitant enzyme-inducing antiepileptic drugs. Lamotrigine does not influence the dosing requirements for phenytoin or carbamazepine.

Dose proportionality of cisatracurium.

The dose proportionality of cisatracurium pharmacokinetics was assessed using a population approach by incorporating the collection of sparse blood samples from patients in clinical trials. Plasma concentration-time data from 131 patients with limited concentration-time data and 38 patients with full sampling were pooled and analyzed using nonlinear mixed-effects modeling (NONMEM). Dose proportionality was assessed using dichotomous parameterization and a linear model. The population pharmacokinetic approach revealed that the pharmacokinetics of cisatracurium are independent of dose between 0.1 mg/kg and 0.4 mg/kg, as was expected based on the importance of Hofmann elimination, a chemical process dependent on pH and temperature.

Prospective use of population pharmacokinetics/pharmacodynamics in the development of cisatracurium.

PURPOSE: The population PK/PD approach was prospectively used to determine the PK/PD of cisatracurium in various subgroups of healthy surgical patients. METHODS: Plasma concentration (Cp) and neuromuscular block data from 241 patients in 8 prospectively-designed Phase I-III trials were pooled and analyzed using NONMEM. The analyses included limited Cp-time data randomly collected from 186 patients in efficacy/safety studies and full Cp-time data from 55 patients in pharmacokinetic studies. The effects of covariates on the PK/PD parameters of cisatracurium were evaluated. The time course of neuromuscular block was predicted for various patient subgroups. RESULTS: The population PK/PD model for cisatracurium revealed that anesthesia type, gender, age, creatinine clearance, and presence of obesity were associated with statistically significant (p < 0.01) effects on the PK/PD parameters of cisatracurium. These covariates were not associated with any clinically significant changes in the predicted recovery profile of cisatracurium. Slight differences in onset were predicted in patients with renal impairment and patients receiving inhalation anesthesia. Based on the validation procedure, the model appears to be accurate and precise. CONCLUSIONS: The prospective incorporation of a population PK/PD strategy into the clinical development of cisatracurium generated information which influenced product labeling and reduced the number of studies needed during development.

Changes in prescribing patterns in long-term care facilities and impact on incidence of adverse events.

The addition of benzodiazepines to the triplicate prescription program in New York State was successful in reducing the use of benzodiazepines in a nursing home population, but the use of alternative agents was substantially increased. The reduction in benzodiazepine use could not be shown to be associated with any reduction in risk of adverse events during a retrospective review. In order to evaluate the impact of a triplicate prescription program on patient care, endpoints of efficacy as well as toxicity must be identified prior to the implementation of new legislation. It should be incumbent upon those States considering implementation of triplicate legislation to realize that the imposition of these regulations is tantamount to forced enrollment in a clinical trial for the patients affected by the legislation. A mechanism must be available to prospectively assess changes in prescribing patterns and their clinical consequences in order to determine objectively whether the legislative intervention was a success.

Predictive performance of population pharmacokinetic parameters of tianeptine as applied to plasma concentrations from a post-marketing study.

The predictive ability of population pharmacokinetic parameters of tianeptine, obtained from a mixed effect analysis of pre-marketing pharmacokinetic studies, was evaluated using tianeptine plasma concentrations obtained during a large multi-center post-marketing surveillance study. The mean prediction error was 7.8 ng.ml-1 and the root mean square prediction error was 52.1 ng/ml when initial estimates of population pharmacokinetic parameters were used to predict drug concentrations in one half of the post-marketing data. When the population parameters were revised to reflect the data collected in the first half of the post-marketing study, the mean prediction error was reduced to -3.2 ng.ml-1 and the root mean square prediction error was reduced to 29.5 ng.ml-1. These results suggest that population pharmacokinetic parameters obtained from pre-marketing data may not accurately predict drug concentrations in patients receiving the drug in the post-marketing setting. Once the population parameters are updated to reflect data from the post-marketing period, the predictive ability of the data-base increases, but substantial variability in the prediction error remains.

Development of a population pharmacokinetic database for tianeptine.

Two thousand three hundred and thirty five plasma concentrations of tianeptine from 112 patients enrolled in nine studies of tianeptine pharmacokinetics performed prior to the marketing of the drug were pooled for analysis using mixed-effect modeling. Studies represented a combination of single dose and multiple dosing at steady-state. Tianeptine plasma concentration time data were fit to a two compartment model with first order absorption using the NONMEM computer program. The results of this analysis suggested that alcoholism is associated with significant increase in clearance (124% increase) and volume of the central compartment (161% increase). The volume of the peripheral compartment is significantly lower in women (31% decrease) and in depressed patients (59% decrease). The population mean (interindividual variability) clearance was equal to 0.17 l.h-1 x kg-1 (28.6%), the volume of central compartment was 0.13 l.kg-1 (60.4%), intercompartmental clearance was 0.07 l.h-1 x kg-1 (30.1%), volume of the tissue compartment was 1.17 l.kg-1 (28.3%), and the absorption rate constant was 0.63 h-1 (21.8%). The residual variability was approximately 30% at concentrations expected during clinical use of the drug. Because of the increased clearance, alcoholic patients would be expected to have significantly reduced concentrations during steady-state dosing. These population parameters provide a basis for developing initial dosing recommendations and for performing bayesian evaluations of drug concentrations obtained in post-marketing studies.

Population pharmacodynamics of doxacurium.

The nonlinear mixed-effects modeling (NONMEM) computer program was used to investigate the variability in the duration of doxacurium-induced neuromuscular block in 408 patients enrolled in phase II and phase III clinical trials of doxacurium. Spontaneous recovery data in the 10% to 90% block range from all patients were pooled and fitted to a linear model. Two parameters were estimated: (1) the slope, which is related to the pharmacokinetics and to the steepness of the dose-response curve, and (2) the intercept, which is linearly related to dose but has no physiologic meaning. The primary goal was to determine the factors affecting the slope by use of univariate and multivariate analyses techniques. Estimates of the slope ranged from 0.67% to 1.1% block/min (interindividual variability, 39%). Factors with clinically significant effects on the slope included the following: age, obesity, and anesthesia type. Thus these factors influence the time course of doxacurium-induced block and may require individualization of dose.

Impact of triplicate prescription program on psychotropic prescribing patterns in long-term care facilities.

OBJECTIVE: To assess the impact of the effect of the New York state triplicate prescription program on psychotropic prescribing patterns in selected long-term care facilities over a one-year period. DESIGN: Retrospective study for changes in psychotropic drug use patterns before and after implementation of the triplicate prescription program. SETTING: Eight private and two public long-term care facilities in the western New York area. PATIENTS: All residents in the long-term care facilities with complete medical records for a one-year period were reviewed. OUTCOME MEASUREMENTS: Charts were reviewed for changes in psychotropic drug patterns and incidence in adverse events such as falls, hip fractures, hospital admission, signs or symptoms of benzodiazepine (BZD) withdrawal syndrome, or behavioral outburst. MAIN RESULTS: BZD use declined precipitously from 25 percent of psychotropic drug orders to 10 percent six months after implementation of the program. The decline in BZD use was accompanied by an increase in the number of orders for alternative psychotropic agents. Although 22 percent of the patients previously receiving BZDs were discontinued from these drugs, more than half of these patients were switched to alternative therapy, including tricyclic antidepressants and antipsychotic drugs. The majority of patients who discontinued BZDs did so without tapering of the dosage; however, few experienced minor withdrawal symptoms and no patient experienced seizures or required hospitalization following discontinuation. The risk of falls, hospital admission for any reason, or combined events was not significantly altered despite a reduction in BZD use. There was a trend, however, for a reduction in falls after implementation of the program. CONCLUSIONS: This study documents that psychotropic drug prescribing patterns were significantly affected by the triplicate prescription program. BZD use declined; however, use of alternative psychotropic drugs increased. Despite changes in psychotropic prescribing patterns, we found no significant risk of adverse events. Further study to evaluate the long-term effect of alternative psychotropic drugs is necessary.

A nationwide survey of clinical laboratory methodologies for fungal infections.

Many hospitalized patients are at risk for fungal infections. In order to characterize present clinical laboratory experience and facilities for diagnosis and management of fungal infections, a nationwide survey of laboratory diagnostic methodologies was conducted. Data from calendar year 1988 were collected from 71 institutions (52 university teaching hospitals and 19 community hospitals) enrolled in the Drug Surveillance Network. Surveyed hospitals received 75,828 specimens for fungal culture in 1988, representing 18,705 positive cultures from 7373 patients. About 1.3% of patients admitted to teaching or community hospitals had positive fungal cultures, the most common isolates being Candida species. Yeast identification was most commonly performed by the germ tube test and carbohydrate assimilation testing. Dimorphic fungi were identified to the species level at 67% of hospitals. Cryptococcal antigen testing was available at all hospitals, and Candida serology testing was done at 55 institutions. A small number of hospitals performed antifungal drug concentration determinations for amphotericin B (n = 9), ketoconazole (n = 7) and flucytosine (n = 12). Fungal susceptibility testing was available at 77% of hospitals, either within the institution or at an external laboratory. Laboratory testing for diagnosis and management of fungal infections represents a major laboratory investment. Proficiency in this area, along with expert clinical advice, will be needed to advance therapy of patients complicated with fungal infections during the next decade.