Dose-exposure Relationship Research Articles

A first-in-man study to evaluate the safety, tolerability, and pharmacokinetics of pasireotide (SOM230), a multireceptor-targeted somatostatin analog, in healthy volunteers

Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for four of the five somatostatin receptor subtypes (sst1,2,3 and sst5), and potential clinical activity in several neuroendocrine and oncologic conditions, including acromegaly, Cushing’s disease, and neuroendocrine tumors (NET). This manuscript reports the first-in-man dose-escalation study of pasireotide, evaluating its safety, tolerability, and pharmacokinetics (PK) in healthy male volunteers. A single dose of pasireotide 1–1200 μg was administered subcutaneously in four to eight subjects per dose level, with two additional subjects per cohort administered placebo. PK and safety evaluations were carried out over 7 days post-dose. Growth hormone (GH) suppression was evaluated using a GH-releasing hormone stimulation test on Day –1 and Day 1 at 3–5 hours post-injection. Seventy-two subjects completed the study. Pasireotide was well tolerated with no serious adverse events observed at any dose. Transient elevations in blood glucose levels were observed 2–6 hours after administration of pasireotide at doses between 200 μg and 1200 μg, but this resolved without intervention by 23 hours post-dosing. The maximum tolerable dose was not established within the tested range. Pasireotide demonstrated a favorable PK profile with fast absorption (tmax: 0.25–0.5 hours), low clearance (CL/F: 8–13 L/hour), long effective elimination half-life (mean t½,β: 7–11 hours), and a proportional dose-exposure relationship. GH suppression of 79%–96% was observed at single pasireotide doses between 200 μg and 1200 μg. In conclusion, pasireotide demonstrated favorable safety, tolerability, and PK profiles, as well as promising activity in suppressing the release of GH. The efficacy and safety of pasireotide is currently being evaluated in patients with acromegaly, Cushing’s disease, NET, and various non-neuroendocrine disorders.

A Semiphysiologically Based Pharmacokinetic Modeling Approach to Predict the Dose-Exposure Relationship of an Antiparasitic Prodrug/Active Metabolite Pair

A Semiphysiologically Based Pharmacokinetic Modeling Approach to Predict the Dose-Exposure Relationship of an Antiparasitic Prodrug/Active Metabolite Pair

Population pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase

We investigated the population pharmacokinetics and exposure-response relationship of nilotinib in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase. Nilotinib was given at 300 mg or 400 mg twice daily. Serum concentration data (sparse and full pharmacokinetic profiles) were obtained from 542 patients over 12 months. A population pharmacokinetic analysis was performed using nonlinear mixed-effect modeling. Exposure-response relationships were explored graphically or using logistic regression models. Nilotinib concentrations were stable over 12 months. Patients in the 400 mg twice-daily arm had an 11.5% higher exposure than did those in the 300 mg twice-daily arm, and the relative bioavailability of nilotinib 400 mg twice daily was 0.84 times that of 300 mg twice daily. Patient demographics did not significantly affect nilotinib pharmacokinetics. The occurrence of all-grade total bilirubin elevation was significantly higher in patients with higher nilotinib exposure, and a positive correlation was also observed between nilotinib exposure and QTcF change on electrocardiograms from baseline. There was no significant relationship between nilotinib exposure and major molecular response at 12 months. There is a less than proportional dose-exposure relationship between nilotinib 300 mg and 400 mg twice-daily doses. Blood level testing is unlikely to play an important role in the general management of patients with newly diagnosed CML treated with nilotinib.

A Semiphysiologically Based Pharmacokinetic Modeling Approach to Predict the Dose-Exposure Relationship of an Antiparasitic Prodrug/Active Metabolite Pair

Dose selection during antiparasitic drug development in animal models and humans traditionally has relied on correlations between plasma concentrations obtained at or below maximally tolerated doses that are efficacious. The objective of this study was to improve the understanding of the relationship between dose and plasma/tissue exposure of the model antiparasitic agent, pafuramidine, using a semiphysiologically based pharmacokinetic (semi-PBPK) modeling approach. Preclinical and clinical data generated during the development of pafuramidine, a prodrug of the active metabolite, furamidine, were used. A whole-body semi-PBPK model for rats was developed based on a whole-liver PBPK model using rat isolated perfused liver data. A whole-body semi-PBPK model for humans was developed on the basis of the whole-body rat model. Scaling factors were calculated using metabolic and transport clearance data generated from rat and human sandwich-cultured hepatocytes. Both whole-body models described pafuramidine and furamidine disposition in plasma and predicted furamidine tissue (liver and kidney) exposure and excretion profiles (biliary and renal). The whole-body models predicted that the intestine contributes significantly (30-40%) to presystemic furamidine formation in both rats and humans. The predicted terminal elimination half-life of furamidine in plasma was 3- to 4-fold longer than that of pafuramidine in rats (170 versus 47 h) and humans (64 versus 19 h). The dose-plasma/tissue exposure relationship for the prodrug/active metabolite pair was determined using the whole-body models. The human model proposed a dose regimen of pafuramidine (40 mg once daily) based on a predefined efficacy-safety index. A similar approach could be used to guide dose-ranging studies in humans for next-in-class compounds.

Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose

In this study, we evaluated (a) the contribution of SLCO1B3 and UGT1A polymorphisms to the pharmacokinetics of telmisartan in two forms, a microdose (MD) and a therapeutic dose (TD); (b) linkage disequilibrium (LD) between UGT1A1 and UGT1A3; and (c) linearity in the pharmacokinetics of telmisartan between the two forms. Telmisartan was orally administered at MD condition (100 μg), and then at TD condition (80 mg) to 33 healthy volunteers whose genotypes were prescreened by DMET Plus. Plasma concentrations of telmisartan and its glucuronide were measured by LC-MS/MS, and population pharmacokinetic analysis was performed. No obvious effect of SLCO1B3 polymorphisms (334T>G, 699G>A, and rs11045585) on the pharmacokinetics of telmisartan was observed. The strong LD between UGT1A1*6 and UGT1A3*4a, and between UGT1A1*28 and UGT1A3*2a were observed. After both MD and TD administration, the mean area under the curve0-24 (±standard deviation) of telmisartan was significantly lower and higher in individuals with the UGT1A3*2a (TD, 1701±970 ng hr/ml; MD, 978±537 pg hr/ml) and *4a variants (TD, 5340±1168; MD, 3145±1093), respectively, compared with those in individuals with UGT1A3*1/*1 (TD, 2969±1456; MD, 1669±726). These results were quantitatively confirmed by population pharmacokinetic analysis. Nonlinearity of the dose-exposure relationship was observed between the MD and TD. The haplotypes of UGT1A3 significantly influenced pharmacokinetics of telmisartan and a strong LD between UGT1A1 genotype and UGT1A3 haplotype was observed. These findings are potentially of pharmacological and toxicological importance to the development and clinical use of drugs.

Automated blood sampling to identify pharmacodynamics biomarkers of corticotrophin releasing factor receptor 1 antagonism

Introduction The aim of this study was to use an automated blood sampling technique to measure soluble hormones following an ovine corticotrophin releasing factor (oCRF) challenge using pharmacological doses that significantly inhibit brain CRF 1 receptors. Methods A high throughput crude homogenate CRF 1 receptor binding assay was used to measure binding affinity, dose and time occupancy and exposure relationships in rat brain. From these studies a 30 mg/kg dose of DMP904 was selected to test in an oCRF challenged hormone release assay using an automated blood sampler. Results DMP904 dose-dependently displaced [ 125I]oCRF ex vivo binding in crude rat cortex homogenates with a mean ID 50 of 0.4 ± 0.08 mg/kg (n = 4). DMP904 receptor occupancy remained greater than 90% over a 24 h time period, despite a decrease in free plasma concentration. A dose of 30 mg/kg completely abolished an oCRF stimulated increase in plasma corticosterone and adrenocorticotropic hormone (ACTH), as measured by an automated blood sampler. There were no significant alterations to either basal or stimulated pituitary derived hormones measured. Discussion In conclusion, we have shown for the first time, an automated blood sampling technique that can be incorporated to identify pharmacodynamic biomarkers in-vivo. This technology can be used successfully to reduce the number of animals and improve the quality of biomarker measures. Furthermore, at least for DMP904, to elicit a marked inhibition on plasma corticosterone levels, doses that produce greater than 95% brain occupancy are required.

Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients

This study was designed to characterize the population pharmacokinetics of isoniazid in South African pulmonary tuberculosis patients. Concentration-time measurements obtained from 235 patients receiving oral doses of isoniazid as part of routine tuberculosis chemotherapy in two clinical studies were pooled and subjected to nonlinear mixed-effects analysis. A two-compartmental model, including first-order absorption and elimination with allometric scaling, was found to describe the observed dose-exposure relationship for oral isoniazid adequately. A mixture model was used to characterize dual rates of isoniazid elimination. Estimates of apparent clearance in slow and fast eliminators were 9.70 and 21.6 l h(-1) , respectively. The proportion of fast eliminators in the population was estimated to be 13.2%. Central volume of distribution was estimated to be 10% smaller in female patients and clearance was found to be 17% lower in patients with HIV. Variability in absorption rate (90%) was completely interoccasional in nature, whereas in relative bioavailability, interoccasional variability (8.4%) was lower than interindividual variability (26%). Oral doses, given once daily according to dosing policies at the time, were sufficient to reach therapeutic concentrations in the majority of the studied population, regardless of eliminator phenotype. Simulations suggested that current treatment guidelines (5 mg kg(-1) ) may be suboptimal in fast eliminators with low body weight. A population pharmacokinetic model was developed to characterize the highly variable pharmacokinetics of isoniazid in a South African pulmonary tuberculosis patient population. Current treatment guidelines may lead to underexposure in rapid isoniazid eliminators.

Pharmacologic Considerations for Oseltamivir Disposition

Across much of the world, pandemic H1N1 infection has produced a significant healthcare crisis, reflected in significant morbidity and mortality. Statistics reveal that infection-associated deaths among individuals without pre-existing conditions (e.g. immunosuppression) are clustered in pregnant women and young infants. In developing countries where the availability of influenzae vaccine is limited, the only currently available pharmacologic counter-measure for H1N1 disease is oseltamivir, a neuraminidase inhibitor with excellent in vitro activity against the virus. This drug is available in oral solid and liquid formulations, has excellent peroral bioavailability in adults, and generally has a very favorable safety profile. Many observational studies indicate that oseltamivir treatment is associated with symptomatic improvement in pediatric patients with H1N1 infection and, therefore, is considered to represent a viable therapeutic option for use in children. However, the disposition of the ethyl ester prodrug and its active metabolite has not been well characterized in infants and children. Presently, data are available from only two published investigations and preliminary summary information from a recent presentation of an ongoing study. Given that recent in vitro data support the importance of a target exposure-response profile for the active metabolite of oseltamivir and that many processes known to modulate drug disposition have a developmental basis, understanding the potential impact of age on oseltamivir disposition becomes crucial in the development of age-appropriate dosing regimens for the drug. In this review, the impact of ontogeny on processes that are important in regulating the absorption, distribution, metabolism, and excretion of oseltamivir and its active metabolite are considered. Data from both animal and human investigations are presented in the context of defining how development might influence the dose-exposure relationship and, most importantly, the significant variability associated with it. In addition, the available pediatric pharmacokinetic data for oseltamivir and its active metabolite are summarized and current 'information gaps' deserving of future study are presented.

The Need for Modeling and Simulation to Design Clinical Investigations in Children

Recent legislation in the United States and Europe has resulted in an increased number of clinical trials of pharmaceutical agents in children. Creating a well-designed clinical trial that can be successfully completed is a challenging task, particularly as the study population includes younger and smaller children. Although there are some established principles for initially estimating appropriate doses of pharmaceutical agents in children based on known effective doses in adults, these rules are inadequate as the sole basis for designing a clinical trial in children. Factors such as maturation of metabolizing enzymes, relative physical maturation of the child, and altered absorption because of physiological differences in adults and children may contribute to alterations in the dose-exposure relationship. To account for the impact of these potential factors on a clinical trial, the use of modeling and simulation is necessary to anticipate the influence these variables can have on the desired clinical question to be addressed. The examples presented in this article highlight the principle that modeling and simulation is critical for adequately designing pediatrics trials.

Population pharmacokinetic (PK) and exposure-response analysis of nilotinib in newly diagnosed Ph+ chronic myeloid leukemia in chronic phase: Results from ENESTnd.

6556 Background: Results from ENESTnd at 12 months (mo) demonstrated superior efficacy of nilotinib at both 300 mg BID and 400 mg BID doses over imatinib 400 mg QD. Methods: Full PK profiles of nilotinib were obtained at steady state from a subgroup of 34 pts, and sparse (pre-dose/Cmin and 3 hr post-dose/Cmax) concentration data were obtained over 12 mo from 542/563 treated pts. Results: Nilotinib concentrations were stable over 12 mo in both arms (Cmin: 1,158 ± 568 ng/mL [median 1,097 ng/mL] for 300 mg BID; 1,340 ± 621 ng/mL [median 1,217 ng/mL] for 400 mg BID). The average nilotinib Cmin and Cmax were 15.7% and 14.8% higher in the 400 mg BID arm than the 300 mg BID arm. Estimated relative bioavailability ratio was 0.84 for nilotinib 400 mg BID to 300 mg BID. Gender was a statistically significant covariate for nilotinib bioavailability: male pts had 10% lower bioavailability and systemic exposure than females, although this difference is not clinically meaningful. Age, body weight, ethnicity, and racial group did not significantly affect nilotinib PK. Total bilirubin elevation was higher in pts with higher nilotinib concentrations. For example, pts with nilotinib Cmin in quartiles Q1 (< 829 ng/mL, n = 113), Q2/3 (≥ 829 and ≤ 1,569 ng/mL, n = 229) and Q4 (> 1,569 ng/mL, n = 113), 0.9%, 4.8% and 7.1%, respectively, had grade 3/4 bilirubin elevation. Logistic regression confirmed a significant correlation between nilotinib daily AUC and total bilirubin. There was little evidence for a correlation between nilotinib exposure and elevation in AST or lipase. On average, an increase of 1000 ng/mL in nilotinib serum concentrations was associated with minimal increase in QTcF (4.2 to 6.9 msec). Although no relationship was observed for MMR at 12 mo with average nilotinib Cmin, there was a positive correlation with BCR-ABL transcript level reductions at 12 mo with nilotinib Cmin. Conclusions: There is a less than proportional dose-exposure relationship between nilotinib 300 mg BID and 400 mg BID. Exposure was stable over the 12 mo treatment course at both doses. Demographics were not a clinically important factor affecting nilotinib PK. The study is ongoing and additional PK data will be available. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Merck, Novartis Novartis Bristol-Myers Squibb, Merck, Novartis Bristol-Myers Squibb, Genzyme, Novartis The Royal Collage of Pathologists

Understanding the clinical pharmacokinetics of a GABAA partial agonist by application of in vitro tools

4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide (1), developed for general anxiety disorder, was discontinued from clinical development due to unsuitable oral pharmacokinetics.In humans, (1) demonstrated an unacceptable high apparent oral clearance (Clp/F) that also demonstrated a supraproportional dose-exposure relationship. Secondary peaks in the plasma concentration-time profile suggested possible enterohepatic recirculation of (1). A combination of in vitro mechanistic tools was applied to better understand the processes underlying these complex clinical pharmacokinetic profiles of (1).In metabolism experiments, (1) was shown to be a substrate of monoamine oxidase A (MAO-A) as well as being metabolized by cytochrome P450. The former appeared to be a high KM process with a high capacity, while the latter showed saturation between 1 and 10 μM, consistent with the supraproportional dose-exposure relationship.In a sandwich-cultured hepatocyte model, (1) was shown to be a substrate for both uptake and efflux into the canicular space, which is consistent with the observation of pharmacokinetics suggestive of enterohepatic recirculation. Finally, in human epithelial colon adenocarcinoma cell line (Caco-2) and Madin-Darby canine kidney cells transwell flux experiments, (1) was shown to have relatively low permeability and a basolateral-to-apical flux ratio consistent with the activity of P-glycoprotein.In combination, a compounding of the contributions of MAO-A, hepatic uptake and efflux transporters, and P-glycoprotein to the disposition of (1) may underlie the low oral exposure, saturable clearance, and aberrant concentration versus time profiles observed for this compound in humans.

Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.

The role of population PK-PD modelling in paediatric clinical research.

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK–PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK–PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK–PD parameters with the highest precision. Once a population PK–PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child.

Patient variation in veterinary medicine: part I. Influence of altered physiological states

In veterinary medicine, the characterization of a drug's pharmacokinetic (PK) properties is generally based upon data that are derived from studies that employ small groups of young healthy animals, often of a single breed. These are also the data from which population predictions are often generated to forecast drug exposure characteristics in the target population under clinical conditions of use. In veterinary medicine, it is rare to find information on the covariates that can influence drug exposure characteristics. Therefore, it is important to recognize some of the factors that can alter the outcome of PK studies and therefore potentially alter the pharmacological response. Some of these factors are easily identified, such as breed, gender, age, and body weight. Others are less obvious, such as disease, heritable traits, and environmental factors. This manuscript provides an overview of the various stressors (such as disease, inflammation, pregnancy, and lactation) that can substantially alter drug PK. Part II of this series provides an overview of the potential impact of physiological variables such as age, weight, and heritable traits, on drug PK. Ultimately, failure to identify appropriate covariates can lead to substantial error when predicting the dose-exposure relationship within a population.

Species differences in the multiple-dose pharmacokinetics of the non-nucleoside reverse transcriptase inhibitor (NNRTI) UK-453,061 in animals and man: implications for safety considerations

The requirements for safe testing of pharmaceuticals in humans places substantial emphasis on the translation of safety testing performed in animals to man.The comparison of systemic exposure in animals and man has taken on increasing importance in this assessment, with the underlying assumption that plasma concentrations will elicit the same response in different species. This assumption may be flawed for a number of different reasons, one of which is differences in drug disposition between species leading to high doses required in animal species to yield equivalent systemic exposure to humans and consequent higher exposure to organs such as the intestine and liver.Hepatic clearance can vary substantially, particularly between rodents and man, resulting in vast differences in the dose–exposure relationship. A specific example of a non-nucleoside reverse transcriptase inhibitor, which causes substantial auto-induction in rodents, is used to illustrate this situation and the impact this has on the interpretation of safety extrapolation from animals to man.In such circumstances, it is important to recognize the impact of species differences in drug clearance and disposition and consider broader input in the assessment of clinical safety.

Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications

The successful management of invasive fungal infections continues to pose a difficult challenge to clinicians. As the population of at-risk immunocompromised patients increases, the incidence of invasive mycosis has risen in parallel (57). Despite recent advances in antifungal pharmacology, the morbidity and mortality due to invasive fungal infections remain unacceptably high. Numerous factors determine the outcome of these infections, including the host immune state, pathogen variables including drug susceptibility, location of the infection, timing of diagnosis relative to initiation of antifungal therapy, management of the infection source (e.g., surgery or vascular catheter removal), and effective administration of the appropriate dose of the most potent and safe antifungal drug (Fig. ​(Fig.1).1). Few of these variables are under the control of the clinician. The choices of antifungal drug and dosing regimen are among the factors which the clinician can dictate. However, even if the appropriate drug and regimen are initiated, drug exposure at the site of infection may be inadequate due to pharmacokinetic variability and may contribute to treatment failure. Conversely, antifungal exposures may exceed those anticipated and may result in toxicity. Many antifungal drugs exhibit marked variability in drug blood concentrations due to inconsistent absorption, metabolism, elimination, or interaction with concomitant medications. An understanding of the pharmacokinetics and pharmacodynamics of these drugs has been demonstrated to be important to optimize drug choice and dosing regimen design. One tool to detect drug exposures outside of the therapeutic window is monitoring of drug concentration in blood. The utility of this tool to inform drug choice and dosing decisions is being increasingly explored. FIG. 1. Determinants for outcome of invasive mycoses. Several factors must be considered in determining the role of therapeutic drug monitoring in patient management (32, 86, 88). An accurate, rapid, and cost-effective drug assay must be readily available to the clinician. Two pharmacological features then determine the relevance of monitoring of concentrations of drug in blood. The foremost variable is an unpredictable drug dose-exposure relationship. Next, there must be a clear relationship between concentrations of drug in blood and either toxicity or treatment efficacy. Consideration of these pharmacological variables for available antifungal compounds is the focus of this review.

Relationships of neuroticism and extraversion with axis I and II comorbidity among patients with DSM-IV major depressive disorder

Background High comorbidity with axis I and II disorders among major depressive disorder (MDD) patients may in part be due to the predisposing personality dimensions of neuroticism and extraversion. However, a comprehensive view of this relationship is lacking. Methods MDD patients ( n = 193) in the Vantaa Depression Study were interviewed at baseline and at 6 and 18 months with the SCAN and SCID-II, and a general population comparison group ( n = 388) surveyed by mail. Neuroticism and extraversion were measured with the Eysenck Personality Inventory. A dose–exposure relationship between standardized levels of neuroticism and extraversion and type and number of comorbid axis I and II disorders among patients with MDD was hypothesized. Results Prevalence and number of comorbid axis I and II disorders increased significantly with increasing level of neuroticism. In contrast, as the level of extraversion increased, the prevalences of social phobia and cluster C personality disorders decreased. Patients with pure MDD or with any comorbid axis I or II disorder had z-scores of neuroticism of + 0.46, + 0.90 and + 1.30 and of extraversion of − 0.34, − 0.47 and − 0.84, respectively. Limitations Patients' personality scores were not pre-morbid. Conclusion Among MDD patients, a positive dose–exposure relationship appears to exist between neuroticism and prevalence and number of comorbid axis I and II disorders. A negative relationship exists between level of extraversion and prevalence of social phobia and cluster C personality disorders. These findings are consistent with the hypothesis that high neuroticism and low extraversion predispose to comorbid axis I and II disorders among patients with MDD.

Pharmacokinetics and immunomodulatory effects of phytotherapeutic lozenges (bonbons) with Echinacea purpurea extract

The relative bioavailability of the major alkamides, dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides, from Echinacea purpurea phytotherapeutic lozenges at three different dose levels (0.07, 0.21 and 0.9 mg) was evaluated in a pharmacokinetic study in humans and the possible effects on the immunological system were measured. Alkamides were found to be rapidly absorbed and measurable in plasma 10 min after administration of 0.21 and 0.9 mg lozenges and remained detectable for 3h for the 0.21 mg lozenges and for more then 3h for the 0.9 mg lozenges; 0.07 mg lozenges were measurable 20 min after administration and remained detectable for only 2h after the administration. A significant dose-independent down-regulation of the pro-inflammatory cytokines IL-12p70, IL-8, IL-6, IL-10 and TNF was observed 24h after oral administration. The results of non-compartmental pharmacokinetic analysis revealed that a C(max) of (0.65+/-0.41 ng/ml) was reached at 32 min with the 0.07 mg lozenges, (1.00+/-0.21ng/ml) at 25 min with the 0.21 mg lozenges and (8.88+/-5.89 ng/ml) at 19 with the 0.9mg lozenges. As evidenced by the dose-exposure relationship, no significant departure from dose proportionality was observed, indicating linearity in pharmacokinetics. To get a further insight in pharmacokinetics of dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamides a compartmental population pharmacokinetic model was developed applying mixed effect modelling procedure. The results demonstrate that within the dose range studied pharmacokinetics of dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamides are linear and that absorption is very rapid (t(1/2)=6 min) with apparently no lag time, thus indicating the possibility that a fraction of the drug is absorbed through the oral mucosa.

Pharmacokinetics of Aztreonam in Healthy Subjects and Patients with Cystic Fibrosis and Evaluation of Dose-Exposure Relationships Using Monte Carlo Simulation

Aztreonam (AZM) is a monobactam antibiotic with a high level of activity against gram-negative micro-organisms, including Pseudomonas aeruginosa. We evaluated AZM pharmacokinetics and pharmacokinetic-pharmacodynamic relationships in patients with cystic fibrosis (CF) and healthy subjects. Pharmacokinetic data in eight CF patients and healthy subjects that were matched for age, gender, weight, and height were obtained and analyzed by using the nonparametric adaptive grid algorithm. Probabilities of target attainment using percentages of time of unbound concentration above the MIC (fT>MIC) were obtained by using a Monte Carlo simulation. AZM total body clearance was significantly higher in CF patients (100.1 +/- 17.1 versus 76.2 +/- 7.4 ml/min in healthy subjects; P < 0.01). The pharmacokinetic parameter estimates for terminal half-life (1.54 +/- 0.17 h [mean +/- the standard deviation]) and volume of distribution (0.20 +/- 0.02 liters/kg in patients with CF patients were not different from those in healthy subjects. Monte Carlo simulations with a target of a fT>MIC of 50 to 60% at a dose of 1,000 mg every 8 h indicated a clinical breakpoint of 4 mg/liter and 1 to 2 mg/liter for healthy subjects and CF patients, respectively. This study using matched controls showed that AZM total body clearance and not the volume of distribution is higher in CF patients as a result of increased renal clearance. Pharmacokinetic parameter estimates in healthy subjects resulted in a clinical susceptibility breakpoint of < or =4 mg/liter for a dose of 1,000 mg every 8 h. Patients suspected of having high clearance rates, such as CF patients, should be monitored closely, with dosing regimens adjusted accordingly.

Population pharmacokinetics of darbepoetin alfa in healthy subjects

To develop and evaluate a population pharmacokinetic (PK) model of the long-acting erythropoiesis-stimulating protein, darbepoetin alfa in healthy subjects. PK profiles were obtained from 140 healthy subjects receiving single intravenous and/or single or multiple subcutaneous doses of darbepoetin alfa (0.75-8.0 microg kg(-1), or either 80 or 500 microg). Data were analysed by a nonlinear mixed-effects modelling approach using NONMEM software. Influential covariates were identified by covariate analysis emphasizing parameter estimates and their confidence intervals, rather than stepwise hypothesis testing. The model was evaluated by comparing simulated profiles (obtained using the covariate model) to the observed profiles in a test dataset. The population PK model, including first-order absorption, two-compartment disposition and first-order elimination, provided a good description of data. Modelling indicated that for a 70-kg human, the observed nearly twofold disproportionate dose-exposure relationship at the 8.0 microg kg(-1)-dose relative to the 0.75 microg kg(-1)-dose may reflect changing relative bioavailability, which increased from approximately 48% at 0.75 microg kg(-1) to 78% at 8.0 microg kg(-1). The covariate analysis showed that increasing body weight may be related to increasing clearance and central compartment volume, and that the absorption rate constant decreased with increasing age. The full covariate model performed adequately in a fixed-effects prediction test against an external dataset. The developed population PK model describes the inter- and intraindividual variability in darbepoetin alfa PK. The model is a suitable tool for predicting the PK response of darbepoetin alfa using clinically untested dosing regimens.