Variability In Pharmacokinetic Parameters Research Articles

Review of the pharmacokinetic properties of nitrofurantoin and nitroxoline

Nitrofurantoin and nitroxoline are oral antibiotics for the treatment or prophylaxis of acute urinary tract infections. New interest in both these drugs is increasing because of the emergence of resistance to other antibiotics, but knowledge of their pharmacokinetics (PK) is lacking since they were developed before the advent of standardized research for drug approval. The aims of this review were to (i) summarize the PK data reported in the literature and (ii) to identify PK knowledge gaps. The current body of PK knowledge of both drugs appears to be poor and mainly based on old studies. Nitrofurantoin PK values were obtained from studies using many variables, e.g. formulations, crystal sizes and analytical methods, resulting in high interindividual variability in PK parameters and no uniform PK profile. Clinical experience and PK data for nitroxoline are even more limited since the drug is registered in only Germany and a few (Eastern European) countries. Clinical studies in relevant patient populations are needed with commercially available nitrofurantoin and nitroxoline formulations at approved dosing regimens to more fully characterize their PK profiles, and to investigate the influence of patient characteristics on these profiles in order to optimize efficacy and avoid toxicity and emergence of resistance. Only with this updated knowledge and efficacy data from well-structured trials can both drugs maintain their antimicrobial activity against uropathogens.

Phenobarbital pharmacokinetics in neonates and infants during extracorporeal membrane oxygenation.

The disposition of drugs is potentially changed due to extracorporeal membrane oxygenation (ECMO) in neonates and infants. The aim of the study was to evaluate the individual pharmacokinetics (PK) of phenobarbital and the effect of PK covariates in neonates and infants undergoing ECMO. Sixteen patients (7 neonates, 9 infants) treated with phenobarbital during ECMO (centrifugal-flow pump circuits) were enrolled in the PK study. Phenobarbital serum concentrations were measured using a fluorescence polarization immunoassay. Individual PK parameters - volume of distribution (Vd) and clearance (CL) were calculated in a one-compartmental pharmacokinetic model. The mean (SD) Vd and CL values in neonates were 0.46 (0.24) L/kg and 8.0 (4.5) mL/h/kg, respectively. Respective values in infants were 0.56 (0.23) L/kg and 8.5 (3.1) mL/h/kg. PK parameters in neonates and infants were not significantly different. We observed high inter-individual variability in PK parameters (coefficients of variation [CV] were 52% and 53% for CL and Vd, respectively). Doses were adjusted based on therapeutic drug monitoring (TDM) in 87.5% patients. Only 50% of the first measured phenobarbital serum concentrations in each patient were within the therapeutic range of 10-40 mg/L, in comparison with 88.6% concentration measured after TDM implementation. Linear regression models showed that both Vd and CL are significantly related with body weight (BW) and length. Median optimal phenobarbital loading dose (LD) and maintenance dose (MD), calculated from pharmacokinetic data, were 15 mg/kg and 4 mg/kg/day, respectively. Body weight was shown to be the main PK covariate of phenobarbital disposition. Subsequent dosing nomograms are provided for phenobarbital dosing during ECMO.

Population Pharmacokinetics of High-Dose Tigecycline in Patients with Sepsis or Septic Shock.

ABSTRACTTigecycline is a glycylcycline often used in critically ill patients as the antibiotic of last resort. The pharmacokinetics (PK) of tigecycline in intensive care unit (ICU) patients can be affected by severe pathophysiological changes so that standard dosing might not be adequate. The aim of this study was to describe population PK of high-dose tigecycline in patients with sepsis or septic shock and evaluate the relationship between individual PK parameters and patient covariates. The study population consisted of 37 adult ICU patients receiving a 200-mg loading dose of tigecycline followed by multiple doses of 100 mg every 12 h. Blood samples were collected at 0.5, 2, 4, 8, and 12 h after dose administration. A two-compartment model with interindividual (IIV) and interoccasion (IOV) variability in PK parameters was used to describe the concentration-time course of tigecycline. The estimated values of mean population PK parameters were 22.1 liters/h and 69.4 liters/h for elimination and intercompartmental clearance, respectively, and 162 liters and 87.9 liters for volume of the central and peripheral compartment, respectively. The IIV and IOV in clearance were less than 20%. The estimated values of distribution volumes were different from previously published values, which might be due to pathophysiological changes in ICU patients. No systematic relationship between individual PK parameters and patient covariates was found. The developed model does not show evidence that individual tigecycline dosing adjustment based on patient covariates is necessary to obtain the same target concentration in patients with sepsis or septic shock. Dosing adjustments should be based on the pathogens, their susceptibility, and PK targets.

Experience of determination of antitumor drugs concentrations as a method of providing the safety of pharmacotherapy

Background. The undesirable side effects in the process of pharmacotherapy are forced to look for ways to prevent them. The most effective means for this is to carry out individual therapeutic drug monitoring. This is especially true for patients who undergo chemotherapy. A narrow therapeutic range of antineoplastic agent concentrations requires an individual approach to the management of each patient. The purpose of this study is to justify the need for therapeutic drug monitoring to provide the safety of antitumor drugs. Methods. Methods for the quantitative determination of the active metabolite of fludarabine, imatinib and gefitinib in human blood plasma have been developed and validated. A study of pharmacokinetics of antitumor drugs: fludarabine - 36 patients, gefitinib - 24 healthy volunteers, imatinib - 24 healthy volunteers. Results and Discussion. The work shows the magnitude of interindividual differences of the pharmacokinetics of various antitumor drugs. High interindividual variability of pharmacokinetic parameters was revealed both in patients and in healthy volunteers. Conclusion. Experience of the Research Laboratory of Toxicology and Drug Monitoring, The Nikiforov Russian Center of Emergency and Radiation Medicine, EMERCOM of Russia on the application of therapeutic drug monitoring showed its relevance and effectiveness for patients undergoing chemotherapy. (For citation: Rodionov GG, Shantyr II, Ushal IE, et al. Experience of determination of antitumor drugs concentrations as a method of providing the safety of pharmacotherapy. Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(1):64-70. doi: 10.17816/RCF16164-70).

Population pharmacokinetics of Rilpivirine in HIV-1-infected patients treated with the single-tablet regimen rilpivirine/tenofovir/emtricitabine.

Rilpivirine, prescribed for the treatment of HIV infection, presents an important inter-individual pharmacokinetic variability. We aimed to determine population pharmacokinetic parameters of rilpivirine in adult HIV-infected patients and quantify their inter-individual variability. We conducted a multicenter, retrospective, and observational study in patients treated with the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. As part of routine therapeutic drug monitoring, rilpivirine concentrations were measured by UPLC-MS/MS. Population pharmacokinetic analysis was performed using NONMEM software. Once the compartmental and random effects models were selected, covariates were tested to explain the inter-individual variability in pharmacokinetic parameters. The final model qualification was performed by both statistical and graphical methods. We included 379 patients, resulting in the analysis of 779 rilpivirine plasma concentrations. Of the observed trough individual plasma concentrations, 24.4% were below the 50ng/ml minimal effective concentration. A one-compartment model with first-order absorption best described the data. The estimated fixed effect for plasma apparent clearance and distribution volume were 9L/h and 321L, respectively, resulting in a half-life of 25.2h. The common inter-individual variability for both parameters was 34.1% at both the first and the second occasions. The inter-individual variability of clearance was 30.3%. Our results showed a terminal half-life lower than reported and a high proportion of patients with suboptimal rilpivirine concentrations, which highlights the interest of using therapeutic drug monitoring in clinical practice. The population analysis performed with data from "real-life" conditions resulted in reliable post hoc estimates of pharmacokinetic parameters, suitable for individualization of dosing regimen.

Pharmacokinetic profile of edaravone: a comparison between Japanese and Caucasian populations

Background: Amyotrophic lateral sclerosis (ALS) affects persons of all races, and there continues to be a need for effective therapies to treat the disease.Objective: To compare the pharmacokinetics (PK) of edaravone between Japanese and Caucasian populations. Methods: Data from five PK studies among Japanese and Caucasian healthy volunteers were pooled and evaluated. In population PK (PPK) modelling, compartment models and other models with linear elimination were evaluated for appropriateness. Covariate effects by race, sex, weight, and age were investigated to explain variability in PK parameters. Simulations of the final PPK model were performed using a virtual population based on ALS clinical trials. Results: The analysis included 86 subjects. A three-compartment model with Michaelis-Menten plus linear elimination was selected as the best fit model. Race was statistically detected as a covariate for the second peripheral volume of distribution (V2), indicating a 26% increase for Caucasian subjects compared to Japanese subjects. However, based on simulation of PPK model for a virtual ALS population, the small difference of V2 was associated with a difference of Ctau around 1 ng/mL after infusion, which was minimal compared to Cmax of approximately 1000 ng/ml. Conclusion: The PPK analyses demonstrated no clinically relevant difference in the PK profiles of edaravone by race, sex, weight, or age.

Within and Between Subject Variability of Oral Midazolam Pharmacokinetic Parameters As Surrogate For Global Cyp3a Function In Female And Male Volunteers

Oral midazolam pharmacokinetic (PK) parameters are considered as a sensitive surrogate for global CYP3A function phenotyping in drug interaction studies. The aim of this evaluation was to estimate sex related differences in pharmakokinetic parameters of oral midazolam and to determine their within and between subject variability. Baseline CYP3A-phenotyping data of a drug interaction study was retrospectively used for evaluation. The study was approved by the institutional ethics committee. After signing informed consent 48 healthy, non-smoking volunteers (24 male, 24 female) were enrolled into the study. Baseline concentration-time data after a 7.5mg tablet of midazolam was determined at study days 1 and 8. PK parameters were evaluated by noncompartmental analysis. No significant differences in Cmax and AUC 0-∞, Cl/F and weight corrected Cl/F between female and male volunteers were observed. T ½ and weight corrected V/F were increased in female volunteers compared to males (p<0.05). Between and within subject variability are illustrated in Table 1:Tabled 1CmaxAUC0-∞FemaleMaleFemaleMaleFemaleMaleFemaleMaleBetween subject CV [%]56.2955.4347.3758.9623.3929.0937.3839.17Within subject CV [%]29.9821.3127.1317.8028.5621.0126.59*14.15CV=coefficient of variation; *p<0.05 compared to male. Open table in a new tab CV=coefficient of variation; *p<0.05 compared to male. Similar rate and extent of midazolam absorption suggest comparable intestinal and hepatic first pass metabolism between sexes. Increased volume of distribution due to different body composition in females needs to be considered as a reason for increased elimination half life. There was an overall trend towards higher within subject variability in pharmacokinetic parameters of midazolam in female volunteers.

Nonlinear mixed-effects models for pharmacokinetic data analysis: assessment of the random-effects distribution.

Nonlinear mixed-effects models are frequently used for pharmacokinetic data analysis, and they account for inter-subject variability in pharmacokinetic parameters by incorporating subject-specific random effects into the model. The random effects are often assumed to follow a (multivariate) normal distribution. However, many articles have shown that misspecifying the random-effects distribution can introduce bias in the estimates of parameters and affect inferences about the random effects themselves, such as estimation of the inter-subject variability. Because random effects are unobservable latent variables, it is difficult to assess their distribution. In a recent paper we developed a diagnostic tool based on the so-called gradient function to assess the random-effects distribution in mixed models. There we evaluated the gradient function for generalized liner mixed models and in the presence of a single random effect. However, assessing the random-effects distribution in nonlinear mixed-effects models is more challenging, especially when multiple random effects are present, and therefore the results from linear and generalized linear mixed models may not be valid for such nonlinear models. In this paper, we further investigate the gradient function and evaluate its performance for such nonlinear mixed-effects models which are common in pharmacokinetics and pharmacodynamics. We use simulations as well as real data from an intensive pharmacokinetic study to illustrate the proposed diagnostic tool.

Relationship between body weight and postmenstrual age in a Korean pediatric population.

Weight is a covariate representative of body size and is known to influence drug disposition. Recently, with increased use of allometric scaling, this variable has become more significant in accounting for variability in pharmacokinetic parameters. In adults, weight can be considered as a time invariant covariate because physical development is complete. As a result, when weight is missing in data, the typical or median value (say, 70 kg) could be imputed. On the contrary, weight continuously changes with age in the pediatric population. In this case, it is more appropriate to consider different median weight for each age group. We constructed a prediction model for weight using postmenstrual age (PMA) with the data consisting of 83,014 Korean pediatric patients. Weight, PMA, and gender information were collected from electronic medical records. Sigmoid models multiplied by exponential or logistic function were tested for basic model structure. Covariate effects on model parameters were then investigated using selection criteria of p < 0.001. All analyses were performed using NONMEM 7.3.0 and R3.2.0. The sigmoid model multiplied by logistic function best described the data and there was a significant difference between boys and girls in model parameters. It is expected that the results obtained in this work can be used for imputation of missing weights in pediatrics when PMA is available. In addition, the developed model can be used for clinical studies in children under 12 years old whose weight change rapidly with age and for model building in dealing with time varying body weight as a covariate.

Influence of B1-Inhomogeneity on Pharmacokinetic Modeling of Dynamic Contrast-Enhanced MRI: A Simulation Study.

ObjectiveTo simulate the B1-inhomogeneity-induced variation of pharmacokinetic parameters on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).Materials and MethodsB1-inhomogeneity-induced flip angle (FA) variation was estimated in a phantom study. Monte Carlo simulation was performed to assess the FA-deviation-induced measurement error of the pre-contrast R1, contrast-enhancement ratio, Gd-concentration, and two-compartment pharmacokinetic parameters (Ktrans, ve, and vp).ResultsB1-inhomogeneity resulted in −23–5% fluctuations (95% confidence interval [CI] of % error) of FA. The 95% CIs of FA-dependent % errors in the gray matter and blood were as follows: −16.7–61.8% and −16.7–61.8% for the pre-contrast R1, −1.0–0.3% and −5.2–1.3% for the contrast-enhancement ratio, and −14.2–58.1% and −14.1–57.8% for the Gd-concentration, respectively. These resulted in −43.1–48.4% error for Ktrans, −32.3–48.6% error for the ve, and −43.2–48.6% error for vp. The pre-contrast R1 was more vulnerable to FA error than the contrast-enhancement ratio, and was therefore a significant cause of the Gd-concentration error. For example, a −10% FA error led to a 23.6% deviation in the pre-contrast R1, −0.4% in the contrast-enhancement ratio, and 23.6% in the Gd-concentration. In a simulated condition with a 3% FA error in a target lesion and a −10% FA error in a feeding vessel, the % errors of the pharmacokinetic parameters were −23.7% for Ktrans, −23.7% for ve, and −23.7% for vp.ConclusionEven a small degree of B1-inhomogeneity can cause a significant error in the measurement of pharmacokinetic parameters on DCE-MRI, while the vulnerability of the pre-contrast R1 calculations to FA deviations is a significant cause of the miscalculation.

High systemic availability of core-crosslinked polymeric micelles after subcutaneous administration

Covalent entrapment of drug molecules within core-crosslinked polymeric micelles (CCPM) represents an attractive approach to improve their therapeutic index. As an alternative to the most commonly employed intravenous (i.v.) route, subcutaneous (s.c.) administration offers the possibility of self-administration and thereby may reduce healthcare costs. The aim of this work was to assess the pharmacokinetic profile and systemic availability of drug-containing CCPM following s.c. injection. We here derivatised dexamethasone (DMS) with three different linkers, which enabled covalent attachment of this drug to the core of CCPM. The obtained DMS-containing CCPM exhibited varying drug release kinetics in vitro. Remarkably, a single dose of DMS-containing CCPM resulted in high systemic availability of about 30% following s.c. injection into the flank of healthy mice, as evidenced by an AUC between 26–37% relative to the AUC attained following i.v. injection. Although different linkers resulted in moderate variations in pharmacokinetic parameters, the overall pharmacokinetic profiles of these i.v. or s.c. administered nanomedicines were not substantially different. Next to DMS, we covalently attached paclitaxel (PTX) to the core of CCPM. Similarly, a single s.c. dose of PTX-containing CCPM resulted in high systemic availability of about 40% compared to i.v. injection and PTX (entrapped plus released) was detected in the blood for at least 3days. Importantly, the systemic availability of s.c. administered drug-containing CCPM is substantially higher than that of other nanoformulations as reported in the literature (e.g. 3% in rodents). These results demonstrate that s.c. administration is a promising route to attain high systemic availability of CCPM, enabling a potentially more patient-friendly and cost-effective treatment approach than the i.v. route.

Pharmacokinetics of oral fludrocortisone in septic shock.

The combination of hydrocortisone and fludrocortisone improved outcomes in septic shock. However, the specific role of fludrocortisone remains controversial and its pharmacokinetics (PK) has never been investigated in septic shock. This study aimed at characterizing the PK of fludrocortisone in septic shock. This was a single-centre ancillary PK study of a large multinational trial of crystalloids versus colloids for acute hypovolemia in intensive care unit (ICU) patients. In 21 adults with septic shock, fludrocortisone plasma concentrations were measured by liquid chromatography-mass spectrometry tandem analysis, before and repeatedly until 18h after an oral dose of 50μg. PK parameters were estimated using a nonlinear mixed-effects modelling. Undetectable plasma concentrations were observed in 7 out of 21 patients. In the remaining 14 patients, plasma fludrocortisone concentrations were best described by a one-compartmental model with first-order absorption, a lag time (Tlag ) before the absorption phase, and first-order elimination. Severity of illness, as quantified by Simplified Acute Physiology Score II, significantly increased Tlag and apparent clearance. There was a large inter-individual variability in PK parameters. The population estimates of PK parameters (inter-individual variability) were: Tlag 0.65h (98%), apparent clearance 40lh-1 (49%) and apparent volume of distribution 78l (75%). Plasma half-life was estimated at 1.35h (95% CI, 0.84-2.03) and area under the curve of plasma concentrations was estimated at 1.25μghl-1 (95% CI, 1.09-1.46). A single oral dose of fludrocortisone yielded undetectable plasma concentrations in one-third of adults with septic shock. Fludrocortisone PK showed a short plasma elimination half-life and a large inter-individual variability.

FVIII-binding IgG modulates FVIII half-life in patients with severe and moderate hemophilia A without inhibitors

AbstractThe substantial variability in pharmacokinetic parameters in hemophilia patients A poses a challenge for optimal treatment with factor VIII (FVIII) products. We investigated the effect of FVIII-specific immunoglobulin G (IgG) on FVIII half-life in a cohort of 42 adult patients with severe and moderate hemophilia A without inhibitors. Fifteen (35.7%) of 42 patients tested positive for FVIII-binding IgG with titers ≥1:20 in the initial antibody screen, 9 of these 15 patients had FVIII-specific antibodies with titers ≥1:40, mostly low-to-moderate-affinity IgG1 and IgG3, and 1 had high-affinity IgG4 and later developed low-titer FVIII inhibitors. His brother with low-to-moderate-affinity IgG1 and IgG3 also later developed low-titer FVIII inhibitors. The presence of FVIII-specific IgG subclass titer ≥1:40 antibodies was significantly associated with shorter FVIII half-life (median, 7.8 hours [interquartile range, 6.6-9.2 hours]) vs 10.4 hours [interquartile range, 8.9-13.8 hours]); the regression coefficient adjusted for log age and log von Willebrand factor (VWF) antigen was −0.32 (P = .004), accounting for 16.9% of the observed variability of FVIII half-life in our cohort. Our data indicate a significant contribution of non-neutralizing FVIII-specific IgG to FVIII half-life reduction in hemophilia A patients. Thus, screening for FVIII-specific IgG could be beneficial in tailoring FVIII prophylactic regimens.

Clinical Pharmacokinetics and Pharmacodynamics of Biologic Therapeutics for Treatment of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with potentially severe clinical manifestation that mainly affects women of child-bearing age. Patients who do not respond to standard-of-care therapies, such as corticosteroids and immunosuppressants, require biologic therapeutics that specifically target a single or multiple SLE pathogenesis pathways. This review summarizes the clinical pharmacokinetic and pharmacodynamic characteristics of biologic agents that are approved, used off-label, or in the active pipeline of drug development for SLE patients. Depending on the type of target, the interacting biologics may exhibit linear (non-specific) or non-linear (target-mediated) disposition profiles, with terminal half-lives varying from approximately 1week to 1month. Biologics given by subcutaneous administration, which offers dosing flexibility over intravenous administration, demonstrated a relatively slow absorption with a time to maximum concentration of approximately 1day to 2weeks and a variable bioavailability of 30-82%. The population pharmacokinetics of monoclonal antibodies were best described by a two-compartment model with central clearance and steady-state volume of distribution ranging from 0.176 to 0.215L/day and 3.60-5.29L, respectively. The between-subject variability in pharmacokinetic parameters were moderate (20-79%) and could be partially explained by body size. The development of linked pharmacokinetic-pharmacodynamic models incorporating SLE disease biomarkers are an attractive strategy for use in dosing regimen simulation and optimization. The relationship between efficacy/adverse events and biologic concentration should be evaluated to improve clinical trial outcomes, especially for biologics in the advanced phase of drug development. New strategies, such as model-based precision dosing dashboards, could be utilized to incorporate information collected from therapeutic drug monitoring into pharmacokinetic/pharmacodynamic models to enable individualized dosing in real time.

Bioavailability of anthocyanins and colonic polyphenol metabolites following consumption of aronia berry extract

A single-dose pharmacokinetic trial was conducted in 6 adults to evaluate the bioavailability of anthocyanins and colonic polyphenol metabolites after consumption of 500mg aronia berry extract. UHPLC-MS methods were developed to quantitate aronia berry polyphenols and their metabolites in plasma and urine. While anthocyanins were bioavailable, microbial phenolic catabolites increased ∼10-fold more than anthocyanins in plasma and urine. Among the anthocyanins, cyanidin-3-O-galactoside was rapidly metabolized to peonidin-3-O-galactoside. Aronia polyphenols were absorbed and extensively metabolized with tmax of anthocyanins and other polyphenol catabolites from 1.0h to 6.33h in plasma and urine. Despite significant inter-individual variation in pharmacokinetic parameters, concentrations of polyphenol metabolites in plasma and urine at 24h were positively correlated with total AUC in plasma and urine (r=0.93, and r=0.98, respectively). This suggests that fasting blood and urine collections could be used to estimate polyphenol bioavailability and metabolism after aronia polyphenol consumption.

Pharmacokinetic analysis of prostate cancer using independent component analysis

Dynamic contrast enhanced (DCE)-MRI combined with pharmacokinetic (PK) modeling of a tumor provides information about its perfusion and vascular permeability. Most PK models require the time course of contrast agent concentration in blood plasma as an input, which cannot be measured directly at the tissue of interest, and is approximated with an arterial input function (AIF). Variability in methods used in estimating the AIF and inter-observer variability in region of interest selection are major sources of discrepancy between different studies. This study had two aims. The first was to determine whether a local vascular input function (VIF) estimated using an adaptive complex independent component analysis (AC-ICA) algorithm could be used to estimate PK parameters from clinical dynamic contrast enhanced (DCE)-MRI studies. The second aim was to determine whether normalizing the input function using its area under the curve would improve the results of PK analysis. AC-ICA was applied to DCE-MRI of 27 prostate cancer patients and the intravascular signal was estimated. This signal was converted into contrast agent concentration to give a local vascular input function (VIF) which was used as the input function for PK analysis. We compared Ktrans values for normal peripheral zone (PZ) and tumor tissues using the local VIF with those calculated using a conventional AIF obtained from the femoral artery. We also compared the Ktrans values obtained from the un-normalized input functions with the KNtrans values obtained after normalizing the AIF and local VIF. Normalization of the input function resulted in smaller variation in PK parameters (KNtrans vs. Ktrans for normal PZ tissue was 0.20±0.04mM.min−1 vs. 0.87±0.54min−1 for local VIF and 0.21±0.07mM.min−1 vs. 0.25±0.29min−1 for AIF) and better separation of the normal and tumor tissues (effect-size of this separation using KNtrans vs. Ktrans was 0.89 vs. 0.75 for local VIF and 0.94 vs. 0.41 for AIF). The AC-ICA and AIF-based analyses provided similar (KNtrans) values in normal PZ tissue of prostate across patients. Normalizing the input function before PK analysis significantly improved the reproducibility of the PK parameters and increased the separation between normal and tumor tissues. Using AC-ICA allows a local VIF to be estimated and the resulting PK parameters are similar to those obtained using a more conventional AIF; this may be valuable in studies where an artery is not available in the field of view.

Population pharmacokinetic‐pharmacodynamic modeling of omecamtiv mecarbil, a cardiac myosin activator, in healthy volunteers and patients with stable heart failure

Data from 3 clinical trials of omecamtiv mecarbil in healthy volunteers and patients with stable heart failure (HF) were analyzed using a nonlinear mixed-effects model to investigate omecamtiv mecarbil's pharmacokinetics and relationship between plasma concentration and systolic ejection time (SET) and Doppler-derived left ventricular outflow tract stroke volume (LVOTSV). Omecamtiv mecarbil pharmacokinetics were described by a linear 2-compartment model with a zero-order input rate for intravenous administration and first-order absorption for oral administration. Oral absorption half-life was 0.62 hours, and absolute bioavailability was estimated as 90%; elimination half-life was approximately 18.5 hours. Variability in pharmacokinetic parameters was not explained by patient baseline characteristics. Omecamtiv mecarbil plasma concentration was directly correlated with increases in SET and LVOTSV between healthy volunteers and patients with HF. The maximum increase from baseline in SET (delta SET) estimated by an Emax model was 137 milliseconds. LVOTSV increased linearly from baseline by 1.6 mL per 100 ng/mL of omecamtiv mecarbil. Model-based simulations for several immediate-release oral dose regimens (37.5, 50, and 62.5 mg dosed every 8, 12, and 24 hours) showed that a pharmacodynamic effect (delta SET ≥20 milliseconds) could be maintained in the absence of excessive omecamtiv mecarbil plasma concentrations.

Gender differences in pharmacokinetics and pharmacodynamics of methadone substitution therapy.

Gender-related differences in the pharmacological effects of drug are an emerging topic. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of methadone, a long-acting opioid agonist that is prescribed as a treatment for opioid dependence and the management of chronic pain.Method: We performed a search in the Medline database from 1990 to 2014 in order to find published literature related to gender differences in pharmacokinetics (PK) and pharmacodynamics (PD) of methadone.Results: None of the studies were carried out with the primary or secondary aim to identify any gender differences in the pharmacokinetic profile of methadone. Importantly; high inter-subjects variability in PK parameters was found also intra female population. The reported differences in volume of distribution could be ascribed to the physiological differences between men and women in body weight and composition, taking into account that the dose of methadone was established irrespective of body weight of patients (Peles and Adelson, 2006). On the other hand, the few studies present in literature found no gender difference in some direct pharmacodynamic parameters. Some reports have suggested that female gender is associated with an increased risk for long-QT-related cardiac arrhythmias in methadone maintenance subjects.Conclusion: Even though it may be too simplistic to expect variability only in one parameter to explain inter-individual variation in methadone response, we believe that a better knowledge of gender-related differences might have significant implications for better outcomes in opioid dependence substitution therapy in women.

Clinical pharmacokinetic and pharmacodynamic profile of lacosamide.

Lacosamide-a third-generation antiepileptic drug available in multiple formulations-was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. In 2014, lacosamide was approved as monotherapy for POS by the US Food and Drug Administration (FDA). A loading dose administration was approved in 2013 by the European Medicines Agency and in 2014 by the FDA. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing and reduction in long-term channel availability without affecting physiological function. Lacosamide is rapidly absorbed, with maximum plasma concentrations reached 0.5-4h after intake. Oral bioavailability is high (100%) for a dose up to 800mg. Bioavailability is irrespective of food intake. Variability in pharmacokinetic parameters is low (coefficients of variation almost all<20%). The pharmacokinetic profile of lacosamide is consistent in healthy subjects and across different patient populations studied. Lacosamide elimination from plasma occurs with a terminal half-life of approximately 13h in young subjects and 14-16h in elderly subjects; this difference does not impact the dose regimen. Lacosamide produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for reduction of seizure frequency can be described by a maximum effect (E max) model. Lacosamide does not induce or inhibit cytochrome P450 enzymes or known drug transporter systems, has low protein binding of less than 15% and, because it has multiple elimination pathways, it has no clinically relevant interactions with commonly prescribed medications.

Safety, tolerability, and pharmacokinetics of SMT C1100, a 2‐arylbenzoxazole utrophin modulator, following single‐ and multiple‐dose administration to healthy male adult volunteers

SMT C1100 is a small molecule utrophin modulator in development to treat Duchenne muscular dystrophy. This study evaluated the safety, tolerability, and pharmacokinetics of SMT C1100 in healthy volunteers. This double‐blind, placebo‐controlled Phase 1 study comprised: Part 1, an escalating, single‐dose with/without fasting involving 50 mg/kg, 100 mg/kg, 200 mg/kg, and 400 mg/kg doses; and Part 2, a multiple 10 day dose evaluation involving 100 mg/kg bid and 200 mg/kg bid doses. Adverse events were recorded. SMT C1100 was absorbed rapidly following single and multiple oral doses, with median tmax attained within 2–3.5 hour across all doses. Considerable variability of pharmacokinetic parameters was noted among subjects. Following single doses, systemic exposure increased in a sub‐proportional manner, with the 8.0‐fold dose increment resulting in 2.7‐ and 2.4‐fold increases in AUC0‐∞ and Cmax, respectively. AUC0‐∞ and Cmax were estimated as 4.2‐ and 4.8‐fold greater, respectively, following food. Systemic exposure reduced upon repeat dosing with steady‐state concentrations achieved within 3–5 days of multiple bid dosing. No serious or severe adverse events were reported. SMT C1100 was safe and well tolerated with plasma concentrations achieved sufficient to cause a 50% increase in concentrations of utrophin in cells in vitro.