Analysis Of Pharmacokinetic Data Research Articles

Influence of Escherichia coli lipopolysaccharide induced fever on the plasma kinetics of cefquinome in buffalo calves

The pharmacokinetic behavior of cefquinome was studied in healthy and febrile buffalo calves after single intramuscular administration (2 mg/kg). The fever was induced with Escherichia coli lipopolysaccharide (1 μg/kg, IV). The drug concentration in plasma was detected by HPLC method. Pharmacokinetic analysis of disposition data indicated that intramuscular administration data were best described by one-compartment open model. At 2.5 min, concentrations of cefquinome in healthy and febrile animals were 2.21±0.38 and 2.52±0.38 μg/ml, respectively, and drug was detected up to 24 h. The peak plasma levels of cefquinome in febrile buffalo calves (7.70±0.46μg.ml-1) and healthy buffalo calves (6.70±0.46μg.ml-1) were achieved at 45 min and 30 min, respectively. The absorption half life (t1/2ka) of cefquinome was similar in healthy and febrile buffalo calves. Drug distribution was altered by fever as febrile animals showed volume of distribution (0.37±0.07L/kg) lower than healthy animal (0.69±0.04 L/ kg). Total body clearances in healthy and febrile animals were 0.09 and 0.04 L/kg/h, respectively. To maintain minimum therapeutic concentration of 0.1 mg/ml, a satisfactory dosage regimen of cefquinome in healthy and febrile buffalo calves would be 2.8 mg/kg and 1.2 mg/kg body weight, respectively, to be repeated at 24 h intervals.

Subcutaneous Bioavailability of Taspoglutide at 3 Different Injection Sites in Healthy Overweight/Obese Subjects

PurposeTaspoglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist that has >90% homology with the endogenous GLP-1 while retaining equivalent potency. Once-weekly subcutaneous injections with taspoglutide demonstrated meaningful antihyperglycemic and weight loss effects in patients with type 2 diabetes. The present study was performed to compare the relative bioavailability of taspoglutide injected subcutaneously in the abdomen, upper arm, and thigh. MethodsHealthy overweight/obese subjects were randomized in an open-label, 3-way crossover study. A single 20-mg dose of taspoglutide was injected subcutaneously on 3 occasions in the abdomen, upper arm, or thigh. Each injection was separated by a 12-week washout period. Blood was sampled up to 12 weeks for the pharmacokinetic evaluation of taspoglutide. FindingsSixty subjects were randomized into the study (mean age, 45.5 years; body weight, 97.6 kg; and body mass index, 31.4 kg/m2). AUClast values (geometric mean) for subcutaneous injections in the abdomen, upper arm, and thigh were 44.2, 61.2, and 50.0 ng·h/mL, respectively. The geometric mean ratio (relative bioavailability) for the upper arm versus the abdomen was 1.41 (90% CI: 1.22–1.62) and for the thigh versus the abdomen was 1.13 (90% CI: 0.98–1.31). Corresponding Cmax values for subcutaneous injections in the abdomen, upper arm, and thigh were 0.268, 0.382, and 0.341 ng/mL, respectively, and the geometric mean ratio for the upper arm versus the abdomen was 1.43 (90% CI: 1.24–1.64) and for the thigh versus the abdomen was 1.27 (90% CI: 1.10–1.46). Decreases in taspoglutide exposure were observed with each subsequent period. AUClast values (geometric mean across injections sites) for periods 1, 2, and 3 were 97.2, 42.6, and 31.5 ng·h/mL, respectively. The geometric mean ratio for period 2 versus 1 was 0.44 (90% CI: 0.38–0.50) and for period 3 versus 1 was 0.32 (90% CI: 0.27–0.37). Analysis of pharmacokinetic data after first injection only (period 1) showed comparable AUClast across the 3 injection sites and lower initial Cmax after injection into the abdomen compared with the other 2 injection sites. Overall, taspoglutide was well tolerated by most subjects in all 3 injection sites, with a lower incidence of nausea and vomiting when injected in the abdomen. ImplicationsRegardless of a pronounced period effect, relative bioavailability of taspoglutide was different across injection sites, with the lowest exposure and incidence of nausea and vomiting seen after administration in the abdomen. In the absence of comparable bioavailability, taspoglutide was recommended to be injected into the abdomen.

Incorporation of stochastic variability in mechanistic population pharmacokinetic models: handling the physiological constraints using normal transformations.

The utilisation of physiologically-based pharmacokinetic models for the analysis of population data is an approach with progressively increasing impact. However, as we move from empirical to complex mechanistic model structures, incorporation of stochastic variability in model parameters can be challenging due to the physiological constraints that may arise. Here, we investigated the most common types of constraints faced in mechanistic pharmacokinetic modelling and explored techniques for handling them during a population data analysis. An efficient way to impose stochastic variability on the parameters of interest without neglecting the underlying physiological constraints is through the assumption that they follow a distribution with support and properties matching the underlying physiology. It was found that two distributions that arise through transformations of the normal, the logit-normal generalisation and the logistic-normal, are excellent for such an application as not only they can satisfy the physiological constraints but also offer high flexibility during characterisation of the parameters' distribution. The statistical properties and practical advantages/disadvantages of these distributions for such an application were clearly displayed in the context of different modelling examples. Finally, a simulation study clearly illustrated the practical gains of the utilisation of the described techniques, as omission of population variability in physiological systems parameters leads to a biased/misplaced stochastic model with mechanistically incorrect variance structure. The current methodological work aims to facilitate the use of mechanistic/physiologically-based models for the analysis of population pharmacokinetic clinical data.

Population pharmacokinetic modeling and noncompartmental analysis demonstrated bioequivalence between metformin component of metformin/vildagliptin fixed‐dose combination products and metformin immediate‐release tablet sourced from various countries

Metformin is the first-line pharmacotherapy choice for treating type-2 diabetes mellitus, alone or in combination with other antidiabetic drugs. During the development of immediate-release (IR) metformin containing novel fixed-dose combination (FDC) products, several health-authorities require sponsors to demonstrate bioequivalence between FDC products and the country-sourced metformin for market approval. Eight bioequivalence studies that compared metformin/vildagliptin FDC product (test) to metformin IR tablet sourced from various countries (reference) were conducted. A population pharmacokinetic (PPK) analysis of pooled metformin concentration-time data was performed to evaluate whether country-sourced metformin is a significant covariate. The PPK analysis demonstrated that there was no clinically relevant effect of metformin source or race/ethnicity on metformin pharmacokinetics. Also, noncompartmental analysis conducted showed that 90%CI of geometric mean ratios of test to reference metformin formulations, calculated for maximum-concentration and exposure parameters, were within the 80%-125% criteria, indicating comparable metformin exposure regardless of the country-sourced metformin IR formulation. These results are consistent with the biopharmaceutics properties of metformin and provide scientific evidence that after assessing in vitro dissolution of novel FDC formulation, additional bioequivalence studies with multiple countries' reference products may not be required once bioequivalence is established with 1 country-sourced IR metformin formulation.

Abstract P5-19-17: Final results of the phase I "HIT" study: A multicenter phase I-II study evaluating trastuzumab administered by intrathecal injection for leptomeningeal meningitis of HER2+ metastatic breast cancer (MBC)

Abstract Metastatic breast cancer (MBC) is the leading non hematologic cause of leptomeningeal metastases (LM), associated with a poor prognosis. Amongst breast cancer (BC) subtypes, HER2+ tumors present a high LM incidence. Intravenous (IV) trastuzumab (T) has improved survival of MBC patients but better control of central nervous system (CNS) disease is needed. The main physiopathological hypothesis for intracranial recurrences is the low level of T in cerebrospinal fluid (CSF) due to his high molecular weight (148kD). Intraventricular (via Ommaya port) or intrathecal (IT) T administration would permit LM progression control through high therapeutic T concentrations in the CSF. This prospective trial, sponsored by Institut Curie, was the first Phase I-II study to investigate the safety and efficacy of IT T administration for HER2+ LM in BC. The final results of the Phase I cohort are reported herein. Methods: LM diagnosis was based on either CSF with HER2+ cytology or clinical/MRI imagings of meningitis. Adequate organs functions for all patients were required. The T IT (or via Ommaya port) injections were given on weekly basis during 8 weeks. We used a Fibonacci dose escalation design, 4 dose levels (DL) (30-150mg). The objectives of this phase I were to investigate the maximum tolerated dose (MTD) and the recommend dose (DR) of T. A pharmacokinetic (PK) data analysis was performed. We targeted a concentration in the CSF close to the residual serum concentration (30µg/mL) achieved with standard IV schedule. Results: Starting May 2011, 19 patients were included, with 16 evaluable for toxicity (three had not received the treatment) treated in 4 DL (30-150mg). Twelve patients were evaluable for PK and 210 samples T concentrations available (103 in the LCR and 107 in the serum). The MTD was not reached and the treatment appears to have been well tolerated by the patients. Neither Grade ≥3 toxicity nor neurological toxicity related to IT T was observed. The T target-concentration in the CSF was reached at DL4 and the recommended T dose for the Phase II trial is 150 mg. Five patients have experimented a evident clinical benefit and received more than 8 weekly injections with an average of 23 [12-40]. Extended data on clinical outcome and PK will be presented. Conclusion: Intraventricular or IT injections appears to be safe at the dose of 150 mg and possibly effective. The Phase II study will investigate the efficacy of the recommended dose on neurological progression-free survival at 2 months in 19 patients. This trial was performed with Roche funding. Citation Format: Maya Gutierrez, Emmanuelle Mouret Fourme, Emilie Le Rhun, Olivier Tredan, Veronique Dieras, Patricia Tresca, Fawzia Mefti, Isabelle Turbiez, Sophie Taillibert, Céline Desvignes, Gilles Paintaud. Final results of the phase I "HIT" study: A multicenter phase I-II study evaluating trastuzumab administered by intrathecal injection for leptomeningeal meningitis of HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-17.

Pharmacokinetics of pazufloxacin in buffalo calves after single subcutaneous administration

The pharmacokinetics and urinary excretion of pazufloxacin was investigated in buffalo calves following a single subcutaneous administration (5 mg/kg b.wt.). Pharmacokinetic analysis of disposition data indicated that subcutaneous administration data were best described by 1-compartment open model. The peak plasma levels of pazufloxacin were 1.12±0.05 μg/ml at 45 min and the drug was detected up to 16 h. The absorption half-life and elimination half-life were 0.26±0.04 h and 3.01±0.18h, respectively. The apparent volume of distribution and total body clearance were 2.96±0.20 L/kg and 0.67±0.02 L/kg/h, respectively. The urinary excretion of pazufloxacin in 24 h was 23.8±2.30 % of total administrated dose. From the data of surrogate markers (AUC/MIC, Cmax/MIC), it was determined in the buffalo calves that when administered by the subcutaneous route at 5 mg/kg, pazufloxacin is likely to be effective against bacterial isolates with MIC < 0.05 μg/ml.

Recombinant full-length factor VIII (FVIII) and extended half-life FVIII products in prophylaxis--new insight provided by pharmacokinetic modelling.

The pharmacokinetics (PK) of extended half-life factor VIII (FVIII) products might allow longer dosing intervals in prophylaxis, potentially affecting its efficacy. We used published population PK models of a recombinant full-length FVIII (rAHF-PFM) and a recombinant B-domain-deleted FVIII Fc fusion product (rFVIIIFc) to assess the time spent weekly with FVIII levels below 3IUdL(-1) or above 10IUdL(-1) . These FVIII levels were chosen based on the observation that trough levels of 1IUdL(-1) may not be sufficient in all patients. This approach was applied to a simulated population of 1000 severe haemophilia A subjects with dosing regimens included in the prescribing information or evaluated in clinical trials. FVIII levels remained ≥3IUdL(-1) in 57% of patients treated with rAHF-PFM 30IUkg(-1) every 48h compared with 41.1%, 18.3%, 0.9% and 0% of patients treated with rFVIIIFc 30IUkg(-1) every 72h, 50IUkg(-1) every 96h or 120h and 65IUkg(-1) every 168h respectively. Patients on rAHF-PFM 30IUkg(-1) every 48h spent more time weekly with FVIII levels above 10IUdL(-1) than those on rFVIIIFc 50IUkg(-1) every 96h or 120h, and 65IUkg(-1) every 168h. In conclusion, PK modelling indicates that choice and dosing intervals of standard and extended half-life FVIII products require careful evaluation of individual PK to allow more time at protective levels, especially in patients with active lifestyles.

Population pharmacokinetics of ketamine in children with heart disease

This study aims at developing a population pharmacokinetic model for ketamine in children with cardiac diseases in order to rationalize an effective 2-h anesthetic medication, personalized based on cardiac function and age. Twenty-one children (6 months to 18 years old) were enrolled in this prospective, open label study. Ketamine 2mg/kg IV was administered and blood samples were then collected over 8h for ketamine assay. Pharmacokinetic data analysis using NONMEM, was undertaken. Ketamine pharmacokinetics was adequately described by a two-compartment linear disposition model. Typical population parameters were: total clearance: 60.6×(weight/70)0.75L/h, intercompartmental clearance: 73.2×(weight/70)0.75L/h, central distribution volume: 57.3×(weight/70)L, and peripheral distribution volume: 152×(weight/70)L. Ketamine clearance in children with pre-existing congenital heart disease was comparable to values reported in healthy subjects. Computer simulations indicated that an initial loading dose of ketamine 2mg/kg IV over 1min followed by a constant rate infusion of 6.3mg/kg/h for 29min, 4.5mg/kg/h from 30 to 80min, and 3.9mg/kg/h from 80 to 120min achieves and maintains anesthetic plasma level for 2h in children 1 year or older (weight ≥10kg).

The use of error-category mapping in pharmacokinetic model analysis of dynamic contrast-enhanced MRI data

This study introduces the use of ‘error-category mapping’ in the interpretation of pharmacokinetic (PK) model parameter results derived from dynamic contrast-enhanced (DCE-) MRI data.Eleven patients with metastatic renal cell carcinoma were enrolled in a multiparametric study of the treatment effects of bevacizumab. For the purposes of the present analysis, DCE-MRI data from two identical pre-treatment examinations were analysed by application of the extended Tofts model (eTM), using in turn a model arterial input function (AIF), an individually-measured AIF and a sample-average AIF. PK model parameter maps were calculated. Errors in the signal-to-gadolinium concentration ([Gd]) conversion process and the model-fitting process itself were assigned to category codes on a voxel-by-voxel basis, thereby forming a colour-coded ‘error-category map’ for each imaged slice.These maps were found to be repeatable between patient visits and showed that the eTM converged adequately in the majority of voxels in all the tumours studied. However, the maps also clearly indicated sub-regions of low Gd uptake and of non-convergence of the model in nearly all tumours. The non-physical condition ve ≥1 was the most frequently indicated error category and appeared sensitive to the form of AIF used.This simple method for visualisation of errors in DCE-MRI could be used as a routine quality-control technique and also has the potential to reveal otherwise hidden patterns of failure in PK model applications.

Pharmacokinetics of injectable, long-acting nevirapine for HIV prophylaxis in breastfeeding infants.

Mother-to-child transmission (MTCT) of HIV-1 remains a global health problem. The World Health Organization (WHO) recommendations advise the administration of a once-daily, oral, prophylactic regimen of the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) from birth until 4 to 6 weeks of age for infants born to HIV-infected mothers in regions without access to safe and nutritionally adequate alternatives to breast milk. A critical factor driving the successful implementation of the WHO guidelines involves sustaining high adherence to the frequent dosing. With these challenges in mind, we have developed the first injectable, sustained-release NVP formulations with the goal of providing, for 6 weeks or longer, preventative plasma drug levels from a single subcutaneous administration at birth. The long-acting NVP consists of large (>50 μm), monodisperse NVP particles coated with biocompatible polymers that control the drug release kinetics. Two lead formulations exhibiting burst-free, sustained-release kinetics for up to 75 days in vitro were developed. Subsequent in vivo studies in rats demonstrated no toxicity related to the formulations. Rat plasma NVP concentrations were above the analytical assay's limit of quantification for up to 28 days. Pharmacokinetic analysis of the rat plasma NVP concentration-time data allowed absorption rate constants to be calculated. These data then were used to simulate infant NVP exposure from a single injected dose (<200 mg) of our long-acting formulations, demonstrating preliminary feasibility of the technology to maintain safe, preventative NVP plasma levels (0.2 to 3.0 μg ml(-1)) for 6 weeks or longer.

Optimizing anticancer drug treatment in pregnant cancer patients: pharmacokinetic analysis of gestation-induced changes for doxorubicin, epirubicin, docetaxel and paclitaxel

Pregnant patients with cancer are increasingly treated with anticancer drugs, although the specific impact of pregnancy-induced physiological changes on the pharmacokinetics (PK) of anticancer drugs and associated implications for optimal dose regimens remains unclear. Our objectives were to quantify changes in PK during pregnancy for four frequently used anticancer agents doxorubicin, epirubicin, docetaxel and paclitaxel, and to determine associated necessary dose adjustments. A pooled analysis of PK data was carried out for pregnant (Pr) and nonpregnant (NPr) patients for doxorubicin (n = 16 Pr/59 NPr), epirubicin (n = 14 Pr/57 NPr), docetaxel (n = 3 Pr/32 NPr) and paclitaxel (n = 5 Pr/105 NPr). Compartmental nonlinear mixed effect models were used to describe the PK and gestational effects. Subsequently, we derived optimized dose regimens aiming to match to the area under the concentration-time curve (AUC) in nonpregnant patients. The effect of pregnancy on volumes of distribution for doxorubicin, epirubicin, docetaxel and paclitaxel were estimated as fold-change of <1.32, <2.08, <1.37 and <4.21, respectively, with adequate precision [relative standard error (RSE) <37%]. For doxorubicin, no gestational effect could be estimated on clearance (CL). For epirubicin, docetaxel and paclitaxel, a fold-change of 1.1 (RSE 9%), 1.19 (RSE 7%) and 1.92 (RSE 21%) were, respectively, estimated on CL. Calculated dose adjustment requirements for doxorubicin, epirubicin, docetaxel and paclitaxel were +5.5%, +8.0%, +16.9% and +37.8%, respectively. Estimated changes in infusion duration were marginal (<4.2%) except for paclitaxel (-21.4%). Clinicians should be aware of a decrease in drug exposure during pregnancy and should not a priori reduce dose. The decrease in exposure was most apparent for docetaxel and paclitaxel which is supported by known physiological changes during pregnancy. The suggested dose adaptations should only be implemented after conduct of further confirmatory studies of the PK during pregnancy.

A Review Study on the Efficacy of Quantitative DCE-MRI in Breast Lesion Diagnosis

: Breast cancer is the most common cancer among women, for which a successful treatment depends in part, on early diagnosis. Accurate differentiation of lesions may greatly affect the outcome of treatment. In this regard, anatomical along with physiological MR imaging modalities, such as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), diffusion weighted imaging (DWI), and magnetic resonance spectroscopy (MRS) which provide accurate, repeatable and noninvasive physiological biomarkers of tumor growth, have been increasingly used as secondary characterizing tools to ultrasonography (US) and mammography. The aim of this study is to present a thorough review on available scholarly works, especially where quantitative DCE-MRI has been employed for diagnostic decisions on breast cancer, concluding if the modality is either necessary for better sensitivity/specificity, or for a reliable surgery/treatment planning. US and mammography are the conventional screening modalities for breast cancer diagnosis. The overall sensitivity of mammography is 70%90%. However, this sensitivity is variable and can range from as high as 80%98% in women with fatty breast tissue to as low as 30%48% in women with dense breast tissue. Sonographic classification of benign and malignant tumors has a high sensitivity of as high as 98% but a low specificity of about 32%. The low specificity of mammography and US methods and the need for extracting biomarkers, has led to rising interest in employing physiological MR imaging methods for characterizing breast cancers. DCE-MR images can be analyzed in a semi-quantitative (non-model-abased) or quantitative (model-based) approach. The sensitivity and specificity of semi-quantitative DCE-MRI in detecting breast cancer reaches 88.1% and 67.7%, respectively. While it has been proved that DCE-MR imaging features could be useful to noninvasively distinguish highly aggressive breast carcinomas, they are not as useful in discriminating benign from malignant non-mass lesions (such as DCIS). On the other hand, the pharmacokinetic (or model-based) analysis of DCE-MRI can be useful in monitoring and predicting response to therapy, as the changes in tumor vascularization in responder patients precede changes in tumor size, and may better describe tumor response to therapy. Pharmacokinetic model analysis of DCE-MRI data provided a sensitivity and specificity of 100% and 78%, respectively. In comparison with semi-quantitative DCE-MRI, Quantitative DCE-MRI has significantly improved the sensitivity and specificity of breast cancer diagnosis. Other physiological MR imaging alternatives like DW-MRI and MRS have also been employed for breast cancer diagnosis. In a pooled analysis on clinical breast MRS gathered from five independent centers around the world, the sensitivity and specificity of breast MRS were 83% and 85%, respectively. In a study on 78 patients (110 lesions), the sensitivity and specificity of DWI in detection of malignant and benign lesions was reported at 86%. Although the sensitivity and specificity of imaging could be influenced by the selected values of ADC cut-off, the ADC-values may still be used to characterize breast lesions. The diagnosis of breast cancer is a very challenging issue, as early detection may allow for conservative surgery as an alternative to mastectomy. Although mammography and US allow earlier detection of cancers and have been shown to improve the survival of women with breast cancer, with a relatively high sensitivity in women older than 50 years, monitoring the breast cancer is limited by low specificity. DCE-MRI is a powerful imaging tool that has shown utility in delineating the extent of disease in patients with known breast cancer and in screening women at high risk for breast cancer. Semi-quantitative DCE-MRI has high sensitivity but only moderate specificity, because of an overlap between benign and malignant lesions, independent of breast density, tumor type, and menopausal status. Quantitative analysis of DCE-MRI is used by many researchers for detecting and evaluating breast diseases and is a means of increasing the specificity of breast MR examination. MRS of the breast has been proposed as an adjunct to the anatomical MRI examination to improve the specificity of distinguishing malignant from benign breast tumors, however, MRS alone is not suitable in lactating women. Nevertheless, many studies have reported that DWI-MRI may help to differentiate between benign and malignant lesions with good specificity. These findings suggest that incorporating MRS and DW-MRI may increase the overall specificity of quantitative analysis of breast DCE-MRI.

Parameter Estimation of Population Pharmacokinetic Models with Stochastic Differential Equations: Implementation of an Estimation Algorithm

Population pharmacokinetic (PPK) models play a pivotal role in quantitative pharmacology study, which are classically analyzed by nonlinear mixed-effects models based on ordinary differential equations. This paper describes the implementation of SDEs in population pharmacokinetic models, where parameters are estimated by a novel approximation of likelihood function. This approximation is constructed by combining the MCMC method used in nonlinear mixed-effects modeling with the extended Kalman filter used in SDE models. The analysis and simulation results show that the performance of the approximation of likelihood function for mixed-effects SDEs model and analysis of population pharmacokinetic data is reliable. The results suggest that the proposed method is feasible for the analysis of population pharmacokinetic data.

Key differences between Venlafaxine XR and Desvenlafaxine: An analysis of pharmacokinetic and clinical data

Venlafaxine XR and its major active metabolite, desvenlafaxine, are serotonin-norepinephrine reuptake inhibitors. Both are FDA-approved for the treatment of major depressive disorder and have essentially the same pharmacologic and pharmacokinetic profiles; however, the recommended dosing is notably different. The FDA approved recommended starting and maintenance dose for desvenlafaxine is 50 mg daily, while venlafaxine XR requires titration from 37.5 mg daily to the maintenance dose of 150 - 225 mg daily. The dose recommendation for desvenlafaxine is based on results from 8-week acute-phase clinical trials, but complete therapeutic response is not always achieved in this short time period. Venlafaxine XR relies on CYP2D6 for conversion to desvenlafaxine while desvenlafaxine has no significant metabolism by CYP2D6 at recommended doses. Both venlafaxine XR and desvenlafaxine have limited clinically significant drug interactions. The most striking difference between the two products is cost.

Oral Liquid Formulation of Etravirine for Enhanced Bioavailability

Aim: Etravirine is the first drug in the second generation of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). Despite its use in clinical management of HIV infected patients, the drug has very limited bioavailability due to low water solubility and low gastrointestinal permeability. The majority of currently available anti-AIDS drugs in the U.S. market are in solid dosage forms. There is a need of introducing an oral liquid dosage formulation, especially for those AIDS patients who are often unable to swallow a pill. Methods: Co-solvent formulations of etravirine were prepared using 1-methyl-2-pyrrolidinone, Labrasol, and water after evaluating the etravirine solubility in various solvents. A long term stability study was carried out to examine the physical stability of an optimal oral formulation of etravirine. Pharmacokinetic studiesof etravirine were conducted in rats to evaluate bioavailability of the drug. Four groups of jugular vein-cannulated male Sprague- Dawley rats were orally administered etravirine dosage forms such asetravirine solution in DMSO (2.5 mg/kg), commercial etravirine tablets (200 mg/kg), and an optimized liquid formulation (25 mg/kg and 50 mg/kg), respectively. Serial blood samples were collected at predetermined time points. Plasma samples were analyzed for etravirine concentration using a validated LC-MS/MS assay. Pharmacokinetic and statistical data analysis was performed using WinNonlin and Systat. Results: A co-solvent dosage formulation of etravirine was developed containing 5 mg/mL of etravirine dissolved in 3.5% 1-methyle 2-pyrrolidinone, 46.5% Labrasol, and 50% water. The formulation was found to be stable after 21 months storage at room temperature. The drug formulation was successfully administered to rats without any signs of acute toxicity. Pharmacokinetic study showed over 40-times superior oral bioavailability of the formulation as compared with the marketed Intelence® Tablet formulation. Conclusion: A stable co-solvent liquid solution formulation of etravirine was developed with significantly improved oral bioavailability for potential clinical application.

Pharmacokinetics Of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Pediatric Subjects With Hemophilia A: An Interim Analysis Of The Kids A-LONG Study

IntroductionProphylactic factor VIII (FVIII) administration is the standard of care for patients with severe hemophilia A; however, frequent injections are required to maintain protective factor levels. To reduce injection frequency, we developed a long-lasting recombinant FVIII Fc fusion protein (rFVIIIFc) consisting of one rFVIII molecule covalently linked to the Fc domain of immunoglobulin G1 (IgG1). rFVIIIFc had a 1.53-fold higher half-life and a 36% reduction in clearance (CL) versus FVIII (Advate®) in a phase 3 study of adults and adolescents (J Thromb Haemost. 2013;11[2]:169). The Kids A-LONG study (NCT01458106) was designed to investigate the pharmacokinetics (PK), safety, and efficacy of rFVIIIFc in pediatric subjects with hemophilia A who were previously treated with FVIII products. The objective of this planned interim analysis was to determine the PK parameters of rFVIIIFc in pediatric subjects and compare these parameters to those of the subjects' prescribed FVIII products. MethodsThis multi-center, open-label, phase 3 study is currently enrolling previously-treated subjects aged<12 years with severe hemophilia A (≤1 IU/dL endogenous FVIII), at least 50 exposure days (EDs) to FVIII products, and no history of or current inhibitors to FVIII. Subjects are stratified into two age cohorts (<6 years and 6 to<12 years). All subjects are started on a twice-weekly rFVIIIFc prophylactic regimen 25 IU/kg on day 1 and 50 IU/kg on day 4 with subsequent dosing adjustment based on PK data and bleeding frequency. The primary endpoint is the incidence of inhibitor development. A sequential PK analysis is performed to compare the PK parameters of rFVIIIFc with that of the prescribed FVIII product. Subjects undergo a washout period of at least 72 hours before receiving the first dose of either FVIII or rFVIIIFc. For FVIII PK analysis, subjects receive 50 IU/kg of their currently prescribed FVIII product with sampling at baseline and at 4 additional time points after for up to 48 hours. For rFVIIIFc PK assessment, subjects receive 50 IU/kg rFVIIIFc, with sampling prior to rFVIIIFc administration and at 5 additional time points after for up to 72 hours. PK parameters were derived from FVIII activity-over-time profiles estimated by the non-compartmental analysis using the PK data analysis software Phoenix™ WinNonlin 6.2.1.51. FVIII activity was measured by the one-stage clotting assay calibrated against a commercially available FVIII plasma standard. A data cut-off date of 8 February 2013 was used to report PK data in this interim analysis. ResultsAt the time of this analysis, 52 subjects were enrolled and received at least one dose of FVIII and/or rFVIIIFc. Of 37 subjects with evaluable PK profiles, 30 received both FVIII and rFVIIIFc. For PK assessment of FVIII, 7 different FVIII products were used, of which Advate ®, Haemosolvate®, and Kogenate FS® were the most common. A comparison of PK parameters for rFVIIIFc versus FVIII for both age cohorts demonstrated that rFVIIIFc had a longer half-life (∼1.5 fold increase) and a lower CL (30% to 50% reduction) than FVIII (Table 1). ConclusionIn comparison to currently available FVIII products, rFVIIIFc had an extended half-life and reduced CL in children. These results are in agreement with those previously observed in adults and adolescents. The final analysis of the Kids A-LONG study will provide additional PK information and evaluate the safety and efficacy of rFVIIIFc in children. Disclosures:Young:Novo Nordisk: Consultancy, Honoraria; Biogen Idec, Baxter, Kedrion: Consultancy. Mahlangu:Bayer, Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Research Funding. Brown:Novo Nordisk, Biogen Idec, Baxter: Membership on an entity's Board of Directors or advisory committees. Valentino:Baxter, Bayer, Biogen Idec, GTC Biotherapeutics, Inspiration Biopharmaceuticals, Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liesner:Bayer, Baxter, Novo Nordisk, Pfizer: Consultancy, Sponsorship Other; Octapharma: Consultancy, Research Funding, Sponsorship, Sponsorship Other; Inspiration Biopharmaceuticals: Research Funding. Dong:Biogen Idec: Employment, Equity Ownership. Diao:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Nugent:Biogen Idec: Employment, Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership. Allen:Biogen Idec: Employment, Equity Ownership.

Pharmacokinetics Of Recombinant Factor IX Fc Fusion Protein (rFIXFc) In Pediatric Subjects With Hemophilia B: An Interim Analysis Of The Kids B-LONG Study

IntroductionProphylaxis with factor IX (FIX) is the optimal treatment for patients with hemophilia B; however, due to the short half-life of currently available FIX products, frequent injections may be required to prevent bleeding episodes. To prolong half-life and reduce injection frequency, a long-acting recombinant FIX Fc fusion protein (rFIXFc) consisting of one rFIX molecule covalently linked to the Fc domain of immunoglobulin G1 (IgG1) was developed. In a phase 3 study in adults and adolescents, rFIXFc had a 2.43-fold increase in half-life and 50% reduction in clearance (CL) compared with FIX (BeneFIX®) (J Thromb Haemost. 2013;11[2]:241). The Kids B-LONG study (NCT01440946) was designed to evaluate the pharmacokinetics (PK), safety, and efficacy of rFIXFc prophylaxis in previously treated pediatric subjects with hemophilia B. The objective of this planned interim analysis was to determine the PK parameters of rFIXFc in subjects enrolled in Kids B-LONG and compare these parameters to their pre-study FIX PK parameters. MethodsThis multicenter, open-label, phase 3 study is currently enrolling previously treated subjects aged<12 years with severe hemophilia B (≤2 IU/dL endogenous FIX), at least 50 exposure days (EDs) to FIX products, and no inhibitors to FIX. Subjects are stratified into two age cohorts (<6 and 6 to<12 years of age). A weekly prophylactic regimen of 50-60 IU/kg of rFIXFc is administered to all subjects, with subsequent dose and interval adjustments based upon PK data and bleeding frequency. Subjects will continue treatment until they achieve 50 EDs. The primary endpoint is the incidence of inhibitor formation. A sequential PK analysis is performed to compare the PK parameters of rFIXFc with that of pre-study FIX products. PK sampling of pre-study FIX occurs at baseline prior to first dose of FIX (50 IU/kg) and at 5 additional time points through 48 hours. PK sampling of rFIXFc occurs prior to first dose of 50 IU/kg rFIXFc and at 7 additional time points through 168 hours following the first dose; a washout period of 96 hours is required before the first dose of both pre-study FIX and rFIXFc. Plasma FIX activity is measured using the one-stage clotting assay calibrated against a commercially available FIX plasma standard and the FIX activity-over-time profiles are analyzed by non-compartmental analysis (NCA) using the PK data analysis software Phoenix™ WinNonlin 6.2.1.51. A data cut-off date of 23 April 2013 was used to report PK data in this interim analysis. ResultsAt the time of this interim analysis, 24 subjects were enrolled and had received at least one dose of pre-study FIX and/or rFIXFc. Of 18 subjects with evaluable PK profiles, 15 had complete PK profiles for both pre-study FIX (BeneFIX®, Haemosolvex®, or Alphanine®) and rFIXFc. A comparison of PK parameters for rFIXFc versus FIX for both age cohorts is presented in Table 1. rFIXFc had a more than 3-fold prolongation in half-life and a more than 60% reduction in CL compared to the FIX products.Table 1PK of FIX products and rFIXFc in pediatric subjects (Geometric mean [95% CI])Half-life (hr)CL (mL/dL/kg)IR (IU/dL per IU/kg)Vss (mL/kg)< 6 yrsFIX (pre-study) n=518.1 (15.6 - 20.9)11.8 (9.27 - 15.0)0.525 (0.447 - 0.617)293 (247 - 348)rFIXFc (on-study) n=663.6 (42.1 – 96.2)4.36 (3.56 – 5.34)0.593 (0.494 - 0.711)344 (276 - 429)rFIXFc/FIX Ratio n=43.70 (2.56 - 5.34)0.385 (0.280 - 0.529)1.13 (0.981 - 1.31)1.21 (1.18 - 1.25)6 to<12 yrsFIX (pre-study) n=1317.8 (16.0 – 19.8)8.76 (7.35 - 10.5)0.638 (0.502 - 0.812)217 (165 - 286)rFIXFc (on-study) n=1370.4 (61.0 - 81.3)3.51 (3.01 – 4.09)0.718 (0.612 - 0.841)290 (237 - 354)rFIXFc/FIX Ratio n=113.99 (3.36 - 4.74)0.386 (0.322 - 0.462)1.16 (0.942 - 1.42)1.31 (0.992 - 1.74) ConclusionIn comparison to currently available FIX products, rFIXFc had a prolonged half-life and reduced CL in pediatric subjects, which was similar to previous observations in adults and adolescents. The final analysis of the Kids B-LONG study will provide further PK information and evaluate the safety and efficacy of rFIXFc in children. Disclosures:Fischer:Biogen Idec, Baxter, Novo Nordisk, Bayer: Membership on an entity's Board of Directors or advisory committees; Baxter, Bayer, Novo Nordisk, Pfizer: Research Funding. Kulkarni:Biogen Idec, Novo Nordisk, Baxter : Membership on an entity's Board of Directors or advisory committees. Ragni:Biogen Idec: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, Smith Kline Glaxo, Tacere Benitec: Consultancy; Baxter, Bayer, Biogen Idec, Bristol Myers Squibb, CSL Behring, Merck, Novo Nordisk, Pfizer, Smith Kline Glaxo: Research Funding. Rangarajan:Baxter, Pfizer: Research Funding; Biogen Idec : Membership on an entity's Board of Directors or advisory committees. Dong:Biogen Idec: Employment, Equity Ownership. Li:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment, Equity Ownership. Nugent:Biogen Idec: Employment, Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership. Allen:Biogen Idec: Employment, Equity Ownership.

Combined Analysis of Pharmacokinetic and Efficacy Data of Preclinical Studies with Statins Markedly Improves Translation of Drug Efficacy to Human Trials

Correct prediction of human pharmacokinetics (PK) and the safety and efficacy of novel compounds based on preclinical data, is essential but often fails. In the current study, we aimed to improve the predictive value of ApoE*3Leiden (E3L) transgenic mice regarding the cholesterol-lowering efficacy of various statins in humans by combining pharmacokinetic with efficacy data. The efficacy of five currently marketed statins (atorvastatin, simvastatin, lovastatin, pravastatin, and rosuvastatin) in hypercholesterolemic patients (low-density lipoprotein ≥ 160 mg/dl) was ranked based on meta-analysis of published human trials. Additionally, a preclinical combined PK efficacy data set for these five statins was established in E3L mice that were fed a high-cholesterol diet for 4 weeks, followed by 6 weeks of drug intervention in which statins were supplemented to the diet. Plasma and tissue levels of the statins were determined on administration of (radiolabeled) drugs (10 mg/kg p.o.). As expected, all statins reduced plasma cholesterol in the preclinical model, but a direct correlation between cholesterol lowering efficacy of the different statins in mice and in humans did not reach statistical significance (R(2) = 0.11, P < 0.57). It is noteworthy that, when murine data were corrected for effective liver uptake of the different statins, the correlation markedly increased (R(2) = 0.89, P < 0.05). Here we show for the first time that hepatic uptake of statins is related to their cholesterol-lowering efficacy and provide evidence that combined PK and efficacy studies can substantially improve the translational value of the E3L mouse model in the case of statin treatment. This strategy may also be applicable for other classes of drugs and other preclinical models.

Gender-related pharmacokinetics and absolute bioavailability of diosbulbin B in rats determined by ultra-performance liquid chromatography-tandem mass spectrometry

Ethnopharmacological relevanceDiosbulbin B (DB) is the main constituent of furano-norditerpenes in Dioscorea bulbifera Linn., which is widely distributed in China and was usually used as a remedy for sore throat, struma and tumor. Owing to its potential antitumor activity, DB has been considered as a promising candidate for drug development. Aim of the studyTo study the pharmacokinetic properties and excretion of DB in rats by a sensitive UPLC–MS/MS method. Absolute bioavailability and gender-related pharmacokinetic properties, as well as excretion fractions of DB in urine and feces after oral and intravenous administrations would be addressed for the first time. Materials and methodsSprague–Dawley rats were administrated orally (32mg/kg) and intravenously (0.5mg/kg) of DB, respectively. The concentrations of DB in rat plasma were determined by a sensitive and well-validated LC–MS/MS method. Main pharmacokinetic parameters including area under the plasma concentration–time curve (AUC), elimination half time (t1/2), mean residence time (MRT), apparent volume of distribution (Vd) and clearance rate (CL) were estimated using a non-compartmental pharmacokinetics data analysis software. Urine and feces of rats were collected within 48h after oral administration (32mg/kg) and detected by UPLC–MS/MS and HPLC, respectively. ResultsThe standard curves of DB in rat plasma and urine showed good linearity in the concentration range of 1.0–515ng/mL in the method, with acceptable selectivity, precisions, recoveries, and stability. The oral absolute bioavailability of DB in female rats was 2.0%, significantly higher than that of males (0.3%) (p<0.05). Female rats demonstrated longer t1/2 and MRT (p<0.01), bigger Vd and higher CL (p<0.05) than males after intravenous administration of DB. Bigger but no significant difference in excretion fractions of urine and feces in female rats were observed, comparing to those in males. ConclusionA simple and sensitive UPLC–MS/MS method was developed to determine the pharmacokinetic profiles of DB in rats, as well as the excretion in rat urine. Gender exerted a significant influence on the pharmacokinetics and bioavailability of DB in rats. Female rats showed significantly better absorption of DB than males after oral administration.

Method of variability optimization in pharmacokinetic data analysis

For many drugs administered per os, high variability in the concentration–time (C–T) values from first sampling to the phase of distribution may cause difficulty in pharmacokinetic analysis. Therefore, the aim of this study was to propose a method of transformation of C–T data, which would allow significantly reducing the standard deviation (SD) value of observed concentrations, without a statistically significant influence on the value of the mean for each sampling point in group. In the presented study, the lowest value of relative standard deviation of concentrations observed in the elimination phase and the value of precision of the used analytical method, were used to optimize the arithmetic, geometric means, median, and the value of SD obtained after single oral administration of itraconazole in human subjects. Non-compartmental modeling was used to estimate pharmacokinetic parameters. The analysis of SD pharmacokinetic parameters after C–T value optimization indicated more than twice the lower value of SD. After transforming the itraconazole data, lower variability of concentration data gives more selective pharmacokinetics profile in absorption and early distribution phase.