Over the past few decades, physiologically based biopharmaceutics modeling (PBBM) has demonstrated its utility in both new drug and generic product development. Applications of PBBM for fed bioequivalence study waivers is an upcoming area. Recently Innovation & Quality (IQ) consortium demonstrated utility of PBBM to avoid repeat food effect studies for new drugs. In the similar lines, the current manuscript aims to discuss role of PBBM in generic fed bioequivalence study waivers. Generic industry practices related to PBBM model development to predict fed bioequivalence was portrayed with special emphasis on fed bio-predictive media. Media that can simulate fed bioequivalence study outcome were discussed from practical perspective. In-depth analysis, collating the data from 36 products was performed to understand predictability of PBBM for fed bioequivalence. Cases where PBBM was successful to predict fed bioequivalence was correlated with BCS class, formulation category and type of food effect. Further, two case studies were presented wherein fed bioequivalence study waiver obtained with PBBM approach. Lastly, future direction in terms of fed bioequivalence study waivers, regulatory perspectives and best practices for PBBM were portrayed. Overall, this article paves a way to utilize PBBM for generic fed bioequivalence study waivers.
Biopharmaceutics , Drugs, Generic , Therapeutic Equivalency , Solubility , Models, Biological
Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten physiochemically diverse medicines. First, PBPK models were developed for "non-lactating" adult individuals in PK-Sim/MoBi v9.1 (Open Systems Pharmacology). The PBPK models predicted the area-under-the-curve (AUC) and maximum concentrations (Cmax) in plasma within a two-fold error. Next, the PBPK models were extended to include lactation physiology. Plasma and human milk concentrations were simulated for a three-months postpartum population, and the corresponding AUC-based milk-to-plasma (M/P) ratios and relative infant doses were calculated. The lactation PBPK models resulted in reasonable predictions for eight medicines, while an overprediction of human milk concentrations and M/P ratios (>2-fold) was observed for two medicines. From a safety perspective, none of the models resulted in underpredictions of observed human milk concentrations. The present effort resulted in a generic workflow to predict medicine concentrations in human milk. This generic PBPK model represents an important step towards an evidence-based safety assessment of maternal medication during lactation, applicable in an early drug development stage.
Sildenafil is a potent vasodilator and phosphodiesterase type five inhibitor, commercially known as Revatio® and approved for the treatment of pulmonary arterial hypertension. Maternal administration of sildenafil during pregnancy is being evaluated for antenatal treatment of several conditions, including the prevention of pulmonary hypertension in fetuses with congenital diaphragmatic hernia. However, determination of a safe and effective maternal dose to achieve adequate fetal exposure to sildenafil remains challenging, as pregnancy almost always is an exclusion criterion in clinical studies. Physiologically-based pharmacokinetic (PBPK) modelling offers an attractive approach for dose finding in this specific population. The aim of this study is to exploit physiologically-based pharmacokinetic modelling to predict the required maternal dose to achieve therapeutic fetal exposure for the treatment congenital diaphragmatic hernia. A full-PBPK model was developed for sildenafil and N-desmethyl-sildenafil using the Simcyp simulator V21 platform, and verified in adult reference individuals, as well as in pregnant women, taking into account maternal and fetal physiology, along with factors known to determine hepatic disposition of sildenafil. Clinical pharmacokinetic data in mother and fetus were previously obtained in the RIDSTRESS study and were used for model verification purposes. Subsequent simulations were performed relying either on measured values for fetal fraction unbound (fu = 0.108) or on values predicted by the simulator (fu = 0.044). Adequate doses were predicted according to the efficacy target of 15 ng/mL (or 38 ng/mL) and safety target of 166 ng/mL (or 409 ng/mL), assuming measured (or predicted) fu values, respectively. Considering simulated median profiles for average steady state sildenafil concentrations, dosing regimens of 130 mg/day or 150 mg/day (administered as t.i.d.), were within the therapeutic window, assuming either measured or predicted fu values, respectively. For safety reasons, dosing should be initiated at 130 mg/day, under therapeutic drug monitoring. Additional experimental measurements should be performed to confirm accurate fetal (and maternal) values for fu. Additional characterization of pharmacodynamics in this specific population is required and may lead to further optimization of the dosing regimen.
This study aimed to examine specific niches and usage for the aztreonam/amoxicillin/clavulanate combination and to use population pharmacokinetic simulations of clinical dosing regimens to predict the impact of this combination on restricting mutant selection. The in vitro susceptibility of 19 New-Delhi metallo-ß-lactamase (NDM)-producing clinical isolates to amoxicillin/clavulanate and aztreonam alone and in co-administration was determined based on the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC). The fractions of a 24-h duration that the free drug concentration was within the mutant selection window (fTMSW) and above the MPC (fT>MPC) in both plasma and epithelial lining fluid were determined from simulations of 10,000 subject profiles based on regimens by renal function categories. This combination reduced the MIC of aztreonam and amoxicillin/clavulanate to values below their clinical breakpoint in 7/9 K. pneumoniae and 8/9 E. coli, depending on the ß-lactamase genes detected in the isolate. In the majority of the tested isolates, the combination resulted in fT>MPC > 90% and fTMSW < 10% for both aztreonam and amoxicillin/clavulanate. Clinical dosing regimens of aztreonam and amoxicillin/clavulanate were sufficient to provide mutant restriction coverage for MPC and MIC ≤ 4 mg/L. This combination has limited coverage against NDM- and extended-spectrum ß-lactamase co-producing E. coli and K. pneumoniae and is not effective against isolates carrying plasmid-mediated AmpC and KPC-2. This study offers a potential scope and limitations as to where the aztreonam/amoxicillin/clavulanate combination may succeed or fail.
Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant Acinetobacter baumannii at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit in vitro synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of A. baumannii harboring OXA-23, respectively, in order to derive the fraction of time over the 24-h wherein the free drug concentration was within the mutant selection window (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) from simulated pharmacokinetic profiles. The combination of these three antibiotics can confer susceptibility in multi-drug resistant A. baumannii and reduce the opportunity for bacteria to develop further resistance. Clinical intravenous dosing regimens of amikacin, polymyxin-B, and sulbactam were predicted to optimize fTMSW and fT>MPC from drug exposures in the blood. Mean fT>MPC were ≥ 60% and ≥ 80% for amikacin and polymyxin-B, whereas mean fTMSW was reduced to <30% and <15%, respectively, in the triple antibiotic combination. Due to the low free drug concentration of amikacin and polymyxin-B simulated in the epithelial lining fluid, the two predicted pharmacodynamic parameters in the lung after intravenous administration were not optimal even in the combination therapy setting.
AIMS: The aim of this work is the development of a mechanistic physiologically-based pharmacokinetic (PBPK) model using in vitro to in vivo extrapolation to conduct a drug-drug interaction (DDI) assessment of treosulfan against two cytochrome p450 (CYP) isoenzymes and P-glycoprotein (P-gp) substrates. METHODS: A PBPK model for treosulfan was developed de novo based on literature and unpublished clinical data. The PBPK DDI analysis was conducted using the U.S. Food and Drug Administration (FDA) DDI index drugs (probe substrates) midazolam, omeprazole and digoxin for CYP3A4, CYP2C19 and P-gp, respectively. Qualified and documented PBPK models of the probe substrates have been adopted from an open-source online model database. RESULTS: The PBPK model for treosulfan, based on both in vitro and in vivo data, was able to predict the plasma concentration-time profiles and exposure levels of treosulfan applied for a standard conditioning treatment. Medium and low potentials for DDI on CYP3A4 (maximum area under the concentration-time curve ratio (AUCRmax = 2.23) and CYP2C19 (AUCRmax = 1.6) were predicted, respectively, using probe substrates midazolam and omeprazole. Treosulfan was not predicted to cause a DDI on P-gp. CONCLUSION: Medicinal products with a narrow therapeutic index (eg, digoxin) that are substrates for CYP3A4, CYP2C19 or P-gp should not be given during treatment with treosulfan. However, considering the comprehensive treosulfan-based conditioning treatment schedule and the respective pharmacokinetic properties of the concomitantly used drugs (eg, half-life), the potential for interaction on all evaluated mechanisms would be low (AUCR < 1.25), if concomitantly administered drugs are dosed either 2 hours before or 8 hours after the 2-hour intravenous infusion of treosulfan.
Cytochrome P-450 CYP3A , Midazolam , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Busulfan/analogs & derivatives , Cytochrome P-450 CYP2C19 , Cytochrome P-450 CYP3A/metabolism , Digoxin , Drug Interactions , Humans , Midazolam/pharmacokinetics , Models, Biological , Omeprazole , Pharmaceutical Preparations
OBJECTIVES: Ceftazidime/avibactam is not active against MBL-producing bacteria. Combining ceftazidime/avibactam or avibactam with aztreonam can counter the resistance of MBL-producing Enterobacterales. The aim of this study was to evaluate whether the addition of avibactam could reduce or close the mutant selection window (MSW) of aztreonam in Escherichia coli and Klebsiella pneumoniae harbouring MBLs; MSW is a pharmacodynamic (PD) parameter for the selection of emergent resistant mutants. METHODS: In vitro susceptibility of 19 clinical isolates to ceftazidime/avibactam, aztreonam alone, and in co-administration (aztreonam/ceftazidime/avibactam and aztreonam/avibactam) was determined, as well as the mutant prevention concentration (MPC). The fraction of time within 24 h that the free drug concentration was within the MSW (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) in both plasma and epithelial lining fluid (ELF) were determined from simulations of 10â000 profiles. The joint PTA was used to derive a joint cumulative fraction of response (CFR). RESULTS: All isolates were resistant to ceftazidime/avibactam or aztreonam. Combining aztreonam and avibactam or ceftazidime/avibactam resulted in synergistic bactericidal activities against all isolates. Synergism was primarily due to the aztreonam/avibactam combination. For aztreonam/avibactam dosing regimens evaluated in clinical trials, fT>MPC values were >90% and >80%, whereas fTMSW measures were <10% and <20% in plasma and ELF, respectively. The CFR was 100% for aztreonam/avibactam against the collection of clinical isolates. CONCLUSIONS: Effective antimicrobial combination optimized the PD parameters measuring selection for emergent mutants by increasing fT>MPC and reducing fTMSW.
Aztreonam , Klebsiella pneumoniae , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Azabicyclo Compounds/pharmacology , Aztreonam/pharmacology , Ceftazidime/pharmacology , Drug Combinations , Escherichia coli/genetics , Klebsiella pneumoniae/genetics , Microbial Sensitivity Tests , Serine , beta-Lactamases/genetics
AIMS: The objective of the current study was to evaluate paediatric dosing regimens for meropenem plus fosfomycin that generate sufficient coverage against multidrug-resistant bacteria. METHODS: The physiologically based pharmacokinetic (PBPK) models of meropenem and fosfomycin were developed from previously published pharmacokinetic studies in five populations: healthy subjects of Japanese origin, and healthy adults, geriatric, paediatric and renally impaired of primarily Caucasian origins. Pharmacodynamic (PD) analyses were carried out by evaluating dosing regimens that achieved a ≥90% joint probability of target attainment (PTA), which was defined as the minimum of the marginal probabilities to achieve the target PD index of each antibiotic. For meropenem, the percentage of time over a 24-hour period wherein the free drug concentration was above the minimum inhibitory concentration (fT > MIC) of at least 40% was its PD target. The fosfomycin PD index was described by fAUC/MIC of at least 40.8. RESULTS: For coadministration consisting of 20 mg/kg meropenem q8h as a 3-hour infusion and 35 mg/kg fosfomycin q8h also as a 3-hour infusion in a virtual paediatric population between 1 month and 12 years of age with normal renal function and a corresponding body weight between 3 and 50 kg, a joint PTA ≥ 90% is achieved at MICs of 16 and 64 mg/L for meropenem and fosfomycin coadministration, respectively, against Klebsiella pneumoniae and Pseudomonas aeruginosa. CONCLUSION: The current study identified potentially effective paediatric dosing regimens for meropenem plus fosfomycin coadministration against multidrug-resistant bacteria.
Fosfomycin , Pediatrics , Adult , Aged , Anti-Bacterial Agents/pharmacology , Child , Fosfomycin/pharmacology , Humans , Meropenem , Microbial Sensitivity Tests , Monte Carlo Method
AIMS: Pregnancy is associated with physiological changes that alter the pharmacokinetics (PK) of drugs. The aim of this study was to predict the PK of ziprasidone in pregnant women. METHODS: A full physiologically-based pharmacokinetic (PBPK) model of ziprasidone was developed and validated for the non-pregnant population (healthy adults, paediatrics, geriatrics), and this was extended to the pregnant state to assess the change in PK profile of ziprasidone throughout pregnancy. RESULTS: The PBPK model successfully predicted the ziprasidone disposition in healthy adult volunteers, wherein the predicted and observed AUC, Cmax and tmax were within the fold-difference of 0.94-1.09, 0.89-1.40 and 0.80-1.08, respectively. The paediatric and geriatric population, also showed predicted AUC, Cmax and tmax within a two-fold range of the observed values. The simulated exposure in pregnant women using a p-PBPK model showed no significant difference when compared to non-pregnant women. CONCLUSIONS: The PBPK model predicted the impact of physiological changes during pregnancy on PK and exposure of ziprasidone, suggesting that dose adjustment is not necessary in this special population.
Antipsychotic Agents/pharmacokinetics , Computer Simulation , Models, Biological , Piperazines/pharmacokinetics , Thiazoles/pharmacokinetics , Adult , Age Factors , Aged , Antipsychotic Agents/administration & dosage , Area Under Curve , Caco-2 Cells , Child , Dose-Response Relationship, Drug , Drug Dosage Calculations , Female , Healthy Volunteers , Humans , Mental Disorders/drug therapy , Piperazines/administration & dosage , Pregnancy , Pregnancy Complications/drug therapy , Thiazoles/administration & dosage
INTRODUCTION: The objective of this study was to compare three capsaicin extraction methods: Shoxlet, Ultrasound-assisted Extraction (UAE), and Shaker-assisted Extraction (SAE) from Habanero pepper, CNPH 15.192. MATERIALS AND METHODS: The different parameters evaluated were alcohol degree, time extraction, and solid-solvent ratio using response surface methodology (RSM). RESULTS: The three parameters found significant (p < 0.05) were for UAE and solvent concentration and extraction time for SAE. The optimum conditions for the capsaicin UAE and SAE were similar 95% alcohol degree, 30 minutes and solid-liquid ratio 2 mg/mL. The Soxhlet increased the extraction in 10-25%; however, long extraction times (45 minutes) degraded 2% capsaicin. CONCLUSION: The extraction of capsaicin was influenced by extraction method and by the operating conditions chosen. The optimized conditions provided savings of time, solvent, and herbal material. Prudent choice of the extraction method is essential to ensure optimal yield of extract, thereby making the study relevant and the knowledge gained useful for further exploitation and application of this resource. SUMMARY: Habanero pepper, line CNPH 15.192, possess capsaicin in higher levels when compared with others speciesHigher levels of ethanolic strength are more suitable to obtain a higher levels of capsaicinBox-Behnken design indicates to be useful to explore the best conditions of ultrasound assisted extraction of capsaicin. Abbreviations used: Nomenclature UAE: Ultrasound-assisted Extraction; SAE: Shaker-assisted Extraction.
Ultraviolet B (UVB) irradiation may cause oxidative stress- and inflammation-dependent skin cancer and premature aging. Pyrrolidine dithiocarbamate (PDTC) is an antioxidant and inhibits nuclear factor-κB (NF-κB) activation. In the present study, the mechanisms of PDTC were investigated in cell free oxidant/antioxidant assays, in vivo UVB irradiation in hairless mice and UVB-induced NFκB activation in keratinocytes. PDTC presented the ability to scavenge 2,2'-azinobis-(3-ethyl benzothiazoline-6-sulfonic acid) radical (ABTS), 2,2-diphenyl-1-picryl-hydrazyl radical (DPPH) and hydroxyl radical (OH); and also efficiently inhibited iron-dependent and -independent lipid peroxidation as well as chelated iron. In vivo, PDTC treatment significantly decreased UVB-induced skin edema, myeloperoxidase (MPO) activity, production of the proinflammatory cytokine interleukin-1ß (IL-1ß), matrix metalloproteinase-9 (MMP-9), increase of reduced glutathione (GSH) levels and antioxidant capacity of the skin tested by the ferric reducing antioxidant power (FRAP) and ABTS assays. PDTC also reduced UVB-induced IκB degradation in keratinocytes. These results demonstrate that PDTC presents antioxidant and anti-inflammatory effects in vitro, which line up well with the PDTC inhibition of UVB irradiation-induced skin inflammation and oxidative stress in mice. These data suggest that treatment with PDTC may be a promising approach to reduce UVB irradiation-induced skin damages and merits further pre-clinical and clinical studies.
Antioxidants/pharmacology , Edema/etiology , Oxidative Stress/drug effects , Pyrrolidines/pharmacology , Skin/radiation effects , Thiocarbamates/pharmacology , Ultraviolet Rays , Animals , Antioxidants/chemistry , Cell Line , Female , Glutathione/metabolism , Humans , I-kappa B Proteins/metabolism , Interleukin-1beta/metabolism , Male , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Hairless , Oxidative Stress/radiation effects , Peroxidase/metabolism , Pyrrolidines/chemistry , Thiocarbamates/chemistry
This study aimed to impact of different extraction methods on the quality of Dipteryx alata Vogel, Fabaceae, extracts from fruits. The major compounds found were the lipids 38.9% (w/w) and proteins 26.20% (w/w). The residual moisture was 7.20% (w/w), total fiber 14.50% (w/w), minerals 4.10% (w/w) and carbohydrate 9.10 % (w/w). The species studied has great potential in producing oil, but the content and type of fatty acids obtained is dependent on the method of extraction. The Blingh & Dyer method was more selective for unsaturated fatty acids and Shoxlet method was more selective for saturated fatty acids. The tannin extraction by ultrasound (33.70 % w/w) was 13.90% more efficient than extraction by decoction (29 % w/w).
A 2³ full factorial design was used to assess the impact of spraying air flow rate (30-50 L/min), drying air inlet temperature (90-150 ºC) and extract feed rate (4-6 g/min) on the quality of Eugenia dysenterica DC., Myrtaceae, spray-dried extracts. Response surface methodology (RSM) was applied to analyze the significance of the effects of process factors on product quality and to obtain fitted equations to predict dry powder properties. Powder yields were satisfactory, ranging from 34.64 to 63.92%. The dried products showed moisture contents and water activities below 5% and 0.5, respectively. The recuperation ratios of total polyphenols, tannins and flavonoids ranged from 88.66 to 99.07%, 70.38 to 81.87% and 74.51 to 98.68%, respectively. Additionally, in some conditions the parameters related to dry products flowability and compressibility varied over a range acceptable for pharmaceutical purposes. RSM proved that studied factors significantly affected most of the quality indicators at different levels. The spray drying technology is an attractive and promising alternative for the development of intermediate phytopharmaceutical products of E. dysenterica.
