Simulated Plasma Profiles Research Articles

Simulated acetaminophen plasma profiles from fixed-dose combination formulations: studies using the flow-through cell dissolution method

The aim of this work was to simulate acetaminophen plasma profiles from two fixed-dose combination formulations (acetylsalicylic acid, acetaminophen, and caffeine of generic vs. reference formulation) and in vitro dissolution data generated by the flow-through cell apparatus (laminar flow of 16 ml/min, 22.6 mm cells and 0.1 M phosphate buffer pH 7.4). Results were compared with in vitro release information of USP apparatus type II (paddle at 100 rpm and 900 ml of same dissolution medium). Dissolved drugs until 60 min were determined with a ratio-derivative spectrophotometric method. To compare dissolution profiles of each drug, dissolution efficiency and mean dissolution time were calculated. To predict in vivo behavior a convolution approach as well as acetaminophen published information were used. Peak plasma concentrations and area under the curve (zero time to infinity) were considered and values of predicted error for these pharmacokinetic parameters were established. When comparing dissolution profiles with Student’s t-tests significant differences were found (p < 0.05). All values of predicted error showed satisfactory results since only data generated by the flow-through cell dissolution method achieved < 10% for each pharmacokinetic parameter. It is important to carried out in vivo studies with used formulations to corroborate the obtained results.

Physiologically Based Pharmacokinetic Modeling of Rosuvastatin to Predict Transporter-Mediated Drug-Drug Interactions

PurposeTo build a physiologically based pharmacokinetic (PBPK) model of the clinical OATP1B1/OATP1B3/BCRP victim drug rosuvastatin for the investigation and prediction of its transporter-mediated drug-drug interactions (DDIs).MethodsThe Rosuvastatin model was developed using the open-source PBPK software PK-Sim®, following a middle-out approach. 42 clinical studies (dosing range 0.002–80.0 mg), providing rosuvastatin plasma, urine and feces data, positron emission tomography (PET) measurements of tissue concentrations and 7 different rosuvastatin DDI studies with rifampicin, gemfibrozil and probenecid as the perpetrator drugs, were included to build and qualify the model.ResultsThe carefully developed and thoroughly evaluated model adequately describes the analyzed clinical data, including blood, liver, feces and urine measurements. The processes implemented to describe the rosuvastatin pharmacokinetics and DDIs are active uptake by OATP2B1, OATP1B1/OATP1B3 and OAT3, active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The available clinical rifampicin, gemfibrozil and probenecid DDI studies were modeled using in vitro inhibition constants without adjustments. The good prediction of DDIs was demonstrated by simulated rosuvastatin plasma profiles, DDI AUClast ratios (AUClast during DDI/AUClast without co-administration) and DDI Cmax ratios (Cmax during DDI/Cmax without co-administration), with all simulated DDI ratios within 1.6-fold of the observed values.ConclusionsA whole-body PBPK model of rosuvastatin was built and qualified for the prediction of rosuvastatin pharmacokinetics and transporter-mediated DDIs. The model is freely available in the Open Systems Pharmacology model repository, to support future investigations of rosuvastatin pharmacokinetics, rosuvastatin therapy and DDI studies during model-informed drug discovery and development (MID3).

Biorelevant in vitro Tools and in silico Modeling to Assess pH-Dependent Drug-drug Interactions for Salts of Weak Acids: Case Example Potassium Raltegravir

BackgroundEarly assessment of pH-dependent drug-drug-interactions (DDIs) for salts of poorly soluble weakly acidic compounds offers various advantages for patient safety, the pharmaceutical industry, and regulatory bodies. Biorelevant media and tests reflecting physiological changes during acid-reducing agent (ARA) co-administration can be used to explore and predict the extent of the pH effect during therapy with ARAs. MethodsSolubility, one-stage and two-stage dissolution of tablets containing potassium raltegravir, the marketed salt form of this poorly soluble, weakly acidic drug, was investigated using biorelevant media specially designed to reflect administration without and during ARA co-therapy. The dissolution data were then converted into parameters suitable for input into an in silico model (Simcyp™) and the simulated plasma profiles were compared with available pharmacokinetic (PK) data from the literature. ResultsDissolution of the potassium raltegravir formulation in media reflecting ARA co-administration, and thus elevated gastric pH, was faster and more complete than in experiments reflecting the low gastric pH observed in the absence of ARA co-administration. Simulations using data from dissolution experiments with ARA media appropriately bracketed the in vivo data for ARA co-administration in healthy volunteers. ConclusionDissolution data from in vitro experiments in biorelevant media reflecting physiological changes due to ARA co-administration provide valuable information about potassium raltegravir's behavior during concomitant ARA therapy. The approach may also be suitable for salts forms of other poorly soluble, weakly acidic drugs.

Rupatadine Oral Solution Titration by Body Weight in Paediatric Patients Suffering from Allergic Rhinitis: A Population Pharmacokinetic Study.

BackgroundAllergic rhinitis (AR) and chronic urticaria, both are treated in children with doses of second generation of antihistamines that have been mostly based on extrapolation of data obtained in adults. The objectives of this work were to develop a model to explain the pharmacokinetics (PK) of rupatadine, a second generation antihistamine, administered to children 2−11 years old and to calculate the non-compartmental PK parameters for two groups of age (2–5 and 6–11 years old) based on the individual Bayesian estimates from the selected model.MethodsData from two PK studies with rupatadine oral solution (1 mg/mL) were pooled: Study A, an extensive blood sampling study performed in 11 children (6–11 years old) who received a single oral dose of rupatadine; and Study B, a sparse blood sampling study in 40 children (2–5 years old) receiving multiple oral doses. A simultaneous population PK model was developed using data available for all children. Using individual Bayesian estimates from the selected model, steady-state plasma concentrations for both studies were simulated and the non-parametric PK parameters were calculated for two age groups: 2–5 years (subgroup I) and 6–11 years (subgroup II).ResultsA two-compartment model with first-order absorption and elimination with clearance depending on body weight, better described the PK of rupatadine for 2–11 year old children. The plasma clearance dependence on weight was linear. The mean (SD) non-compartment PK parameters calculated using simulated plasma profiles at steady state were: Cmax, 2.54 (1.26) vs 1.96 (0.52) ng/mL; AUC0-24h, 10.74 (3.09) vs 10.38 (4.31) ng/mL/h; and t1/2, 12.28 (3.09) vs 15.94 (4.09) h, for children 6–11 and 2–5 years old, respectively.ConclusionsThe PK of rupatadine depends on the weight of paediatric patients but not on their age. The dosage strategy adjusted by body weight in children 2–11 years old (2.5 mL if weight 10–25 kg, and 5 mL if ≥ 25 kg) provides similar exposure between the two groups of age, and to that obtained in adults with the 10 mg dose tablet formulation.

Extemporaneous Compounding and Physiological Modeling of Amlodipine/Valsartan Suspension

Method Amlodipine/valsartan extemporaneous suspension was prepared from available commercial tablets such as Valzadepine®. The dissolution profiles for the extemporaneous preparation and the commercial tablet were determined in different pH media. The physical, chemical, and microbial stability of the compounded formulation was evaluated over one-month period at room temperature. Moreover, in silico modeling using GastroPlus™ software was used to build absorption models for both drugs based on the in vitro dissolution data. The simulated plasma profiles for both active ingredients were compared with the in vivo plasma profiles to examine the similarity of the extemporaneous suspension and the commercial tablets. Results The amlodipine/valsartan extemporaneous suspension was successfully prepared with acceptable organoleptic properties. The suspension was stable for four-week period preserving its physical and chemical features. The release profiles of valsartan and amlodipine from the suspension were similar to those from source tablet Valzadepine®. In silico modeling predicted the similarity of the extemporaneous suspension and the commercial tablets. Conclusion Amlodipine/valsartan extemporaneous suspension could be prepared from available commercial tablets. Moreover, GastroPlus™ can be applied along with the in vitro dissolution in order to affirm similarity in extemporaneous compounding situations.

Prediction of plasma profiles of a weakly basic drug after administration of omeprazole using PBPK modeling

BackgroundOral medicines must release the drug appropriately in the GI tract in order to assure adequate and reproducible absorption. Disease states and co-administration of drugs may alter GI physiology and therefore the release profile of the drug. Acid-reducing agents (ARAs), especially proton pump inhibitors (PPIs), are frequently co-administered during various therapies. As orally administered drugs are frequently poorly soluble weak bases, PPI co-administration raises the risk of pH-induced drug-drug interactions (DDIs) and the potential for changes in the therapeutic outcome. MethodsThis research compared the dissolution data of a poorly soluble weakly basic drug (“PSWB 001”) from capsules in standard fasted state biorelevant media (FaSSGF, FaSSIF V1 and FaSSIF V2), water and recently devised media representing gastric conditions under various levels of PPI co-administration. An in silico simulation model, based on Simcyp software, was developed to compare simulated plasma profiles with clinical data. ResultsPSWB 001 capsules showed rapid and complete dissolution in acidic conditions representing gastric fluids, whereas limited dissolution was observed in deionized water, media representing PPI co-administration and in two biorelevant media representing fluids in the upper small intestine. Buffer capacity and the presence of native surfactants were shown to be important factors in the in vitro dissolution of PSWB 001. The data from in vitro experiments were used in conjunction with the in silico simulation model, which correctly predicted the plasma profiles of PSWB 001 when administered without PPIs, as well as bracketing the PPI effect observed in vivo. ConclusionsRecently developed biorelevant media representing gastric conditions under PPI therapy, combined with PBPK modeling, were able to bracket the observed plasma profiles of PSWB 001. These media may also be useful for predicting PPI effects for other poorly soluble, weakly basic drugs.

Reassessment of steady-state operation in ITER with NBI and EC heating and current drive

One of the three goals of the ITER project is to demonstrate fusion gain Q ≥ 5 in steady-state operation (SSO). A reassessment of the necessary conditions for Q ≥ 5 SSO in ITER has been carried out for steady-state scenarios assuming no internal transport barrier in the core plasma and with the sole use of neutral beam injection (NBI) and electron cyclotron heating and current drive (EC H&CD) as heating and current drive sources in these scenarios. The parametric operational space for SSO in ITER has been reassessed utilizing an inverse evaluation approach that takes into account the baseline design of the NBI and EC H&CD systems with PNBI = 33 MW, PEC = 20 MW and their possible upgrade capabilities included in their design, PNBI ≤ 49.5 MW, and PEC ≤ 30 MW. The optimal operational points from this evaluation approach have been chosen for detailed 1.5-D transport modelling by ASTRA and followed-up by magnetohydrodynamic (MHD) stability analysis to demonstrate the conditions in which the Q = 5 SS goal can be achieved in ITER where the plasma current is fully accounted for by the driven current by NBI and EC H&CD and the self-driven bootstrap current. The ideal MHD stability of plasma configurations with self-consistently simulated plasma profiles and equilibrium for the chosen OPs has been analysed by the KINX code. Using this analysis, the possibility to control the MHD stability of these steady-state plasmas by tailoring the current profile with the flexibility provided by design of the systems for electron cyclotron current drive and neutral beam current drive in ITER has been demonstrated. Issues related to the realization of such scenarios from the point of view of plasma physics, experimental demonstration and design limits of the ITER systems and components is discussed.

On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development.

A small-scale biphasic dissolution setup and a small-scale dissolution-permeation (D-P) setup were evaluated for their usefulness in simulating the luminal precipitation of three lipophilic weak bases—dipyridamole, ketoconazole and itraconazole. The transition from the gastric to intestinal environment was incorporated into both experimental procedures. Emulsification during the biphasic dissolution experiments had a minimal impact on the data, when appropriate risk mitigation steps were incorporated. Precipitation parameters estimated from the in vitro data were inputted into the Simcyp® physiologically based pharmacokinetic (PBPK) modelling software and simulated human plasma profiles were compared with previously published pharmacokinetic data. Average Cmax and AUC values estimated using experimentally derived precipitation parameters from the biphasic experiments deviated from corresponding published actual values less than values estimated using the default simulator parameters for precipitation. The slow rate of transport through the biomimetic membrane in the D-P setup limited its usefulness in forecasting the rates of in vivo precipitation used in the modelling of average plasma profiles.

Towards in vitro in vivo correlation for modified release subcutaneously administered insulins

Therapeutic proteins and peptides are mainly administrated by subcutaneous injection. In vitro release testing of subcutaneous injectables performed using methods that take the structure and environment of the subcutaneous tissue into account may improve predictability of the in vivo behavior and thereby facilitate establishment of in vitro in vivo correlations. The aim of the study was to develop a biopredictive flow-through in vitro release method with a gel-type matrix for subcutaneously administered formulations and to explore the possibility of establishing a level A in vitro in vivo correlation for selected insulin products. A novel gel-based flow-through method with the incorporation of an injection step was used to assess selected commercial insulin formulations with different duration of action (Actrapid®, Mixtard® 30, Insulatard®, Lantus®). The in vitro release method provided the correct rank ordering in relation to the in vivo performance. For the modified release insulins Insulatard® and Lantus®, an in vitro in vivo correlation using non-linear time scaling was established based on the in vitro release data and in vivo subcutaneous absorption data of the 125I-labeled insulins taken from literature. Predicted absorption profiles were constructed using the in vitro in vivo correlation and subsequently converted into simulated plasma profiles. The approach taken may be of wider utility in characterizing injectables for subcutaneous administration.

WB-PBPK approach in predicting zidovudine pharmacokinetics in preterm neonates.

Antiretroviral therapy has been the mainstay of treatment for neonates born to HIV infected mothers. Neonates born prematurely to HIV positive mothers are underdeveloped not only in anatomical terms but also in their physiological systems. Zidovudine, the first antiretroviral drug in clinical therapy for the treatment of HIV has been approved for use in preterm neonates both prophylactically and therapeutically. The present work describes the whole body physiologically based pharmacokinetic (WB-PBPK) model development for zidovudine in preterm neonates of varying gestational ages, to observe the pharmacokinetic behavior of the drug in this vulnerable group of the population. Along with the height, weight, post-natal, and gestational ages of the preterm neonates, metabolic enzymes CYP2A6, CYP2C8, etc. were incorporated for each neonate. The composition of the different organs in terms of water and lipid components, blood flow rates, etc. were specified during simulations according to the gestational ages of these neonates. The following PK parameters were estimated for preterm neonates using simulated plasma profiles: AUC 2686.41 ± 123.49 μmol min/L, Cmax 6.46 ± 0.74 μmol/L, half-life 8.98 ± 2.36 hr, mean residence time 12.23 ± 3.43 hr, and total plasma clearance 1.48 ± 0.19 ml/min/kg in comparison with the observed PK parameters of a clinical study by Mirochknic et al. in preterm neonates with AUC 2020.04 μmol/min/L, Cmax 6.10 μmol/L, and total plasma clearance 1.62 ml/min/kg. PBPK simulations provide an opportunity to visualize the possible impact of physiological maturity levels at varying gestational ages on the pharmacokinetic behavior of zidovudine in preterm neonates.

Prediction of in-vivo pharmacokinetic profile for immediate and modified release oral dosage forms of furosemide using an in-vitro-in-silico-in-vivo approach.

To develop a physiologically based pharmacokinetic (PBPK) model for furosemide immediate release (IR) tablets and modified release (MR) capsules by coupling biorelevant dissolution testing results with pharmacokinetic (PK) and physiologic parameters, and to investigate the key factors influencing furosemide absorption using simulation approaches and the PBPK model. Using solubility, dissolution kinetics, gastrointestinal (GI) parameters and disposition parameters, a PBPK model for furosemide was developed with STELLA software. Solubility and dissolution profiles for both formulations were evaluated in biorelevant and compendial media. The simulated plasma profiles were compared with in-vivo profiles using point estimates of area under plasma concentration-time curve, maximal concentration after the dose and time to maximal concentration after the dose. Simulated plasma profiles of both furosemide IR tablets and MR capsules were similar to the observed in-vivo profile in terms of PK parameters. Sensitivity analysis of the IR tablet model indicated that both the gastric emptying and absorption rate have an influence on the plasma profile. For the MR capsules, the sensitivity analysis suggested that the release rate in the small intestine, gastric emptying and the absorption rate all have an influence on the plasma profile. A predictive model to describe both IR and MR dosage forms containing furosemide was attained. Because sensitivity analysis of the model is able to identify key factors influencing the plasma profile, this in-vitro-in-silico-in-vivo approach could be a useful tool for facilitating formulation development of drug products.

Influence of the physiological variability of fasted gastric pH and tablet retention time on the variability of in vitro dissolution and simulated plasma profiles

The aim of the present study was to show that the physiological variability of fasted gastric pH and tablet gastric retention time contributes to the overall variability of simulated plasma profiles of diclofenac. Those two parameters were implemented into dissolution study and plasma profiles were simulated under assumptions that in vitro dissolution well represents that occurring in vivo, and that absorption profiles are identical to dissolution profiles, as diclofenac is a highly permeable drug. Dissolution experiments were performed using USP 2 apparatus and two consecutive dissolution media, namely, an acidic medium of various pH (ranging from 1–3), where tablets were kept for a certain time (10–200min), and phosphate buffer (pH 6.8). It was shown that the acid pH value and acid retention time of tablets affect in vitro drug release, and consequently also influence the simulated plasma profiles. Lower acid pH resulted in lower plasma peaks at each studied acid retention time. Longer acid retention time caused lower plasma concentrations at lower acid pH values, whereas at pH 3 higher plasma concentrations were noted. Additionally, it was demonstrated that the variability of both parameters represents an important contribution to the overall variability of plasma profiles.

In Vitro–In Vivo Correlation of Efavirenz Tablets Using GastroPlus®

The aim of the present work was to use GastroPlus™ software for the prediction of pharmacokinetic profiles and in vitro-in vivo correlation (IVIVC) as tools to optimize the development of new generic medications. GastroPlus™ was used to simulate the gastrointestinal compartment and was based on the advanced compartmental absorption and transit model. Powder dissolution and efavirenz tablet dissolution studies were carried out to generate data from which correlation was established. The simulated plasma profile, based on the physicochemical properties of efavirenz, was almost identical to that observed in vivo for biobatches A and B. A level A IVIVC was established for the dissolution method obtained for the generic candidate using the Wagner-Nelson (r (2) = 0.85) and for Loo-Riegelman models (r(2) = 0.92). The percentage of fraction absorbed indicated that 0.5% sodium lauryl sulfate may be considered a biorelevant dissolution medium for efavirenz tablets. The simulation of gastrointestinal bioavailability and IVIVC obtained from immediate-release tablet formulations suggests that GastroPlus™ is a valuable in silico method for IVIVC and for studies directed at developing formulations of class II drugs.

Development of coated beads for oral controlled delivery of cefaclor: In vitro evaluation

The aim of the present study was to develop and characterize coated chitosan-alginate beads containing cefaclor as a controlled release delivery system. Coated cefaclor beads were prepared by solvent evaporation techniques. Beads were found to be intact and spherical in shape. Their size range was 1.05 to 2.06. The loading efficiency showed maximum value when the concentration of cefaclor, chitosan and PEG 400 was 10 % (m/V), 0.5 % (m/V) and 2 % (V/V), respectively. Best retardation of cefaclor release from chitosan-alginate beads was achieved by coating with 15 % of shellac in formula F19. A significant antimicrobial activity (p < 0.05) against Staphylococcus aureus and Klebsiella pneumoniae was observed for formula F19 compared to the standard antibiotic disc. Furthermore, the simulated plasma profile showed the superiority of F19 in sustaining drug release for more than 12 h. Therefore, shellac coated chitosan-alginate beads could be considered a successful controlled release oral cefaclor dosage form.

Population Pharmacokinetic/Pharmacodynamic Modeling to Assist Dosing Schedule Selection for Dovitinib

Dovitinib is an oral multitargeted kinase inhibitor with potent activity against receptors for vascular endothelial growth factor, platelet-derived growth factor, and basic fibroblast growth factor. Initial phase 1 to 2 studies of dovitinib using a continuous daily dosing schedule has shown that dovitinib exhibits a prolonged and overproportional increase in dose and exposure relationship above 400 mg/d. To address this, intermittent dosing schedules were explored using a model-based approach. A semi-mechanistic population pharmcokinetic/pharmacodynamic (PD) model was developed from 4 dovitinib phase 1 studies with daily dosing schedules. Autoinduction of cytochrome P450 1A (CYP1A) responsible for dovitinib metabolism was described using an indirect response model. Simulation of dovitinib plasma concentration profiles following 4 intermittent dosing schedules suggested that intermittent dosing could prevent prolonged drug accumulation. Based on the simulated plasma profiles, PD response, and patient compliance, a 5-days-on/2-days-off intermittent dosing schedule was selected for a phase 1 to 2 clinical study. The observed dovitinib plasma concentrations in this study confirmed the model predictions. Furthermore, dovitinib was well tolerated, and antitumor activity was observed as well in this new study. The 5-days-on/2-days-off dosing schedule is currently used in a dovitinib registration trial and other clinical trials.

Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling

To develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK) model of bisoprolol and to simulate its exposure and disposition in healthy adults and patients with renal function impairment. Bisoprolol dispositions in 14 tissue compartments were described by perfusion-limited compartments. Based the tissue composition equations and drug-specific properties such as log P, permeability, and plasma protein binding published in literatures, the absorption and whole-body distribution of bisoprolol was predicted using the 'Advanced Compartmental Absorption Transit' (ACAT) model and the whole-body disposition model, respectively. Renal and hepatic clearances were simulated using empirical scaling methods followed by incorporation into the WB-PBPK model. Model refinements were conducted after a comparison of the simulated concentration-time profiles and pharmacokinetic parameters with the observed data in healthy adults following intravenous and oral administration. Finally, the WB-PBPK model coupled with a Monte Carlo simulation was employed to predict the mean and variability of bisoprolol pharmacokinetics in virtual healthy subjects and patients. The simulated and observed data after both intravenous and oral dosing showed good agreement for all of the dose levels in the reported normal adult population groups. The predicted pharmacokinetic parameters (AUC, C(max), and T(max)) were reasonably consistent (<1.3-fold error) with the observed values after single oral administration of doses ranging from of 5 to 20 mg using the refined WB-PBPK model. The simulated plasma profiles after multiple oral administration of bisoprolol in healthy adults and patient with renal impairment matched well with the observed profiles. The WB-PBPK model successfully predicts the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in diverse normal adult human populations and patients with renal insufficiency.

A case study on the in silico absorption simulations of levothyroxine sodium immediate-release tablets

The aim of this case study was to develop a drug-specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus™ software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration-time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate-release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro-in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets.

Use of mefloquine in children - a review of dosage, pharmacokinetics and tolerability data.

BackgroundUse of anti-malarial medication in children is hampered by a paucity of dosage, pharmacokinetic and tolerability data.MethodsData on the use of mefloquine in children, particularly in young children weighing less than 20 kg, were reviewed using PubMed literature and reports on file.ResultsChemoprophylaxis data: Two studies with a total of 170 children were found. A simulated mefloquine plasma profile showed that doses to achieve protective chemoprophylaxis blood concentration of mefloquine of approximately 620 ng/mL (or 1.67 μmol/L) in children should be at least 5 mg/kg. This simulated plasma profile in children corresponds to that seen in adult travellers using a weekly prophylaxis dose of 250 mg. This reinforces current practice of using weight-based dosage for children. Clearance per body weight is higher in older children. For children who travel to malaria risk areas tablets can be broken and crushed as required. It is necessary to disguise the bitter taste of the drug.Treatment data: Mefloquine treatment (alone or in combination) data are available for more than 6000 children of all age and weight categories. The stereoselectivity and pharmacokinetic profile of mefloquine in children is similar to that observed in adults. There is higher clearance in older children (aged 5-12 years) compared to younger children (aged 6-24 months). Mefloquine treatment is well tolerated in infants (5-12 kg) but vomiting is a problem at high doses. This led to the use of a "split dose" regimen with 15 mg/kg initially, followed 12 hours later by 10 mg/kg.Mefloquine 125 mg has been used as intermittent preventive treatment (IPT) and was found to be efficacious in reducing episodes of malaria in a moderate-transmission setting but vomiting was a problem in 8% of children aged 2-11 months.Mefloquine is also used as a component of artemisinin combination therapy (ACT) in small children. The combination artesunate plus mefloquine is a WHO approved first-line treatment for uncomplicated malaria in Africa.ConclusionCurrently available data provide a scientific basis for the use of mefloquine in small children in the chemoprophylaxis setting and as a part of treatment regimens for children living in endemic areas.

Biorelevant in vitro dissolution testing of products containing micronized or nanosized fenofibrate with a view to predicting plasma profiles

The ability of in vitro biorelevant dissolution tests to predict the in vivo performance of nanosized fenofibrate (Lipidil 145 ONE®) and microsized fenofibrate (Lipidil – Ter®) was evaluated in this study. In vitro dissolution was carried out using USP apparatus 2 (paddle method) with updated biorelevant media to simulate the pre- and postprandial states. Membrane filters with different pore sizes were evaluated for their ability to hold back undissolved, nanosized drug particles. It was shown that filters with pore sizes of 0.1μm and 0.02μm were able to separate molecularly dissolved drug from colloidal and undissolved particles. In vitro results obtained with a suitable filter were used to generate simulated plasma profiles in combination with two different models using STELLA® software: (a) under the assumption of no permeability restrictions to absorption and (b) under the assumption of a permeability restriction. The simulated plasma profiles were compared to in vivo data for the nanosized and the microsized formulation in the fasted and fed states. The first model approach resulted in good correlation for the microsized fenofibrate formulation, but the plasma profile of the formulation containing nanosized fenofibrate was overpredicted in the fasted state. The second model successfully correlated with in vivo data for both formulations, regardless of prandial state. Comparison of simulations with the two models indicates that in the fasted state, absorption of fenofibrate from the nanosized formulation is at least partly permeability-limited, while for the microsized formulation the dissolution of fenofibrate appears to be rate-determining.

Mechanistic Modeling of Hepatic Transport from Cells to Whole Body: Application to Napsagatran and Fexofenadine

A mechanistic model was applied to quantitatively derive the kinetic parameters from in vitro hepatic uptake transport data. These parameters were used as input to simulate in vivo elimination using a fully mechanistic physiologically based pharmacokinetic (PBPK) model. Fexofenadine and napsagatran, both BDDCS class 3 drugs, were chosen as model compounds. In rat, both compounds are hardly metabolized and are eliminated unchanged mostly through biliary excretion. Uptake was estimated in this study based on plated rat hepatocytes, and a mechanistic model was used to derive the active and passive transport parameters, namely Michaelis-Menten uptake parameters (V(maxI) and K(mI,u)) together with passive diffusion (P(dif)) and nonspecific binding. Maximum transport velocity and passive diffusion were scaled to in vivo parameters (J(maxI) and PS(TC)) using hepatocellularity. Biliary excretion, through passive and active transport, was assessed from in vivo studies. These transport parameters were then used as input in a whole body physiologically based model in which the liver compartment was parametrized for the different passive and active transport processes. Each of the processes was linked to the free concentration in the relevant compartment. For napsagatran hepatic uptake, no passive diffusion and no binding were detected in vitro besides the active transport (K(mI,u) = 88.4 +/- 8.1 microM, V(maxI) = 384 +/- 19 pmol/mg/min). Fexofenadine was rapidly taken up into rat hepatocytes (K(mI,u) = 271 +/- 35 microM, V(maxI) = 3162 +/- 274 pmol/mg/min), and some contribution of passive diffusion to the uptake (P(dif) = 2.08 +/- 0.67 microL/mg/min) was observed. For fexofenadine, the biliary export rate was found to be slower than the uptake, leading to drug accumulation in liver. No accumulation was observed for napsagatran where excretion was faster than hepatic uptake. Observed plasma, liver and bile concentration time profiles were compared to PBPK simulations based on scaled in vitro transport kinetic parameters. An uncertainty analysis indicated that for both compounds the scaled in vitro uptake clearance had to be adjusted with an additional empirical scaling factor of 10 to match the plasma and liver concentrations and biliary excretion profiles. Applying this model, plasma clearance (CL(P)) and half-life (t(1/2)), maximum liver concentration (C(maxL)) and fraction excreted in bile (f(bile)) were predicted within 2-fold. In vitro uptake data had most impact on the simulated plasma and biliary excretion profiles, while accurate simulations of liver concentrations required also quantitative estimates of biliary excretion transport. This study indicated that the mechanistic model allowed for accurate evaluation of in vitro experiments; and the scaled kinetic parameters of hepatic uptake transport enabled the prediction of in vivo PK profiles and plasma clearances, using PBPK modeling.