The Effect of Inflammatory Bowel Disease and Irritable Bowel Syndrome on Pravastatin Oral Bioavailability: In vivo and in silico evaluation using bottom-up wbPBPK modeling.

The common disorders irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) can modify the drugs' pharmacokinetics via their induced pathophysiological changes. This work aimed to investigate the impact of these two diseases on pravastatin oral bioavailability. Rat models for IBS and IBD were used to experimentally test the effects of IBS and IBD on pravastatin pharmacokinetics. Then, the observations made in rats were extrapolated to humans using a mechanistic whole-body physiologically-based pharmacokinetic (wbPBPK) model. The rat in vivo studies done herein showed that IBS and IBD decreased serum albumin (> 11% for both), decreased PRV binding in plasma, and increased pravastatin absolute oral bioavailability (0.17 and 0.53 compared to 0.01) which increased plasma, muscle, and liver exposure. However, the wbPBPK model predicted muscle concentration was much lower than the pravastatin toxicity thresholds for myotoxicity and rhabdomyolysis. Overall, IBS and IBD can significantly increase pravastatin oral bioavailability which can be due to a combination of increased pravastatin intestinal permeability and decreased pravastatin gastric degradation resulting in higher exposure. This is the first study in the literature investigating the effects of IBS and IBD on pravastatin pharmacokinetics. The high interpatient variability in pravastatin concentrations as induced by IBD and IBS can be reduced by oral administration of pravastatin using enteric-coated tablets. Such disease (IBS and IBD)-drug interaction can have more drastic consequences for narrow therapeutic index drugs prone to gastric degradation, especially for drugs with low intestinal permeability.

Salivary Therapeutic Monitoring of Buprenorphine in Neonates After Maternal Sublingual Dosing Guided by Physiologically Based Pharmacokinetic Modeling.

BACKGROUND: Opioid use disorder (OUD) during pregnancy is associated with high mortality rates and neonatal opioid withdrawal syndrome (NOWS). Buprenorphine, an opioid, is used to treat OUD and NOWS. Buprenorphine active metabolite (norbuprenorphine) can cross the placenta and cause neonatal respiratory depression (EC 50 = 35 ng/mL) at high brain extracellular fluid (bECF) levels. Neonatal therapeutic drug monitoring using saliva decreases the likelihood of distress and infections associated with frequent blood sampling. METHODS: An adult physiologically based pharmacokinetic model for buprenorphine and norbuprenorphine after intravenous and sublingual administration was constructed, vetted, and scaled to newborn and pregnant populations. The pregnancy model predicted that buprenorphine and norbuprenorphine doses would be transplacentally transferred to the newborns. The newborn physiologically based pharmacokinetic model was used to estimate the buprenorphine and norbuprenorphine levels in newborn plasma, bECF, and saliva after these doses. RESULTS: After maternal sublingual administration of buprenorphine (4 mg/d), the estimated plasma concentrations of buprenorphine and norbuprenorphine in newborns exceeded the toxicity thresholds for 8 and 24 hours, respectively. However, the norbuprenorphine bECF levels were lower than the respiratory depression threshold. Furthermore, the salivary buprenorphine threshold levels in newborns for buprenorphine analgesia, norbuprenorphine analgesia, and norbuprenorphine hypoventilation were observed to be 22, 2, and 162 ng/mL. CONCLUSIONS: Using neonatal saliva for buprenorphine therapeutic drug monitoring can facilitate newborn safety during the maternal treatment of OUD using sublingual buprenorphine. Nevertheless, the suitability of using adult values of respiratory depression EC 50 for newborns must be confirmed.

Solvent-free method for masking the bitter taste of azithromycin dihydrate using supercritical fluid technology.

INTRODUCTION AND PURPOSE: The unpleasant extremely bitter taste of the orally administered broad-spectrum antibiotic azithromycin decreases patient compliance, especially in pediatrics. This issue can be overcome by decreasing drug interaction with the tasting buds using insoluble polymers at salivary pH (6.8 - 7.4), like the cationic polymer Eudragit EPO. Supercritical fluid technology is a green synthesis method for preparing pharmaceutical preparations that replace organic solvents with safe supercritical CO2. This study aimed to mask the bitter taste of azithromycin using the supercritical fluid method and a pH-sensitive Eudragit EPO polymer. METHODS: A foaming process was investigated for preparing a formulation (TEST), which comprises treating the polymer with supercritical carbon dioxide (CO2) fluid to prepare a taste-masked dosage form without employing organic solvents or flavors. RESULTS: The use of the supercritical technique at 40 °C and 10 MPa for 2 h allowed the manufacturing of solvent-free polymeric foam with azithromycin dispersions; the average calculated percentage of apparent volume change was 62.5 ± 5.9% with an average pore diameter of 34.879 Å. The formulated sample showed low drug release in simulated salivary fluid while keeping its crystalline nature. Moreover, clinical studies on healthy subjects showed that the formula successfully masked azithromycin's bitter taste. CONCLUSIONS: Overall, it has been shown herein that the supercritical fluid technology foaming method is promising in masking the bitter taste of bitter ingredients.

The In Vitro, In Vivo, and PBPK Evaluation of a Novel Lung-Targeted Cardiac-Safe Hydroxychloroquine Inhalation Aerogel.

Hydroxychloroquine (HCQ) was repurposed for COVID-19 treatment. Subtherapeutic HCQ lung levels and cardiac toxicity of oral HCQ were overcome by intratracheal (IT) administration of lower HCQ doses. The crosslinker-free supercritical fluid technology (SFT) produces aerogels and impregnates them with drugs in their amorphous form with efficient controlled release. Mechanistic physiologically based pharmacokinetic (PBPK) modeling can predict the lung's epithelial lining fluid (ELF) drug levels. This study aimed to develop a novel HCQ SFT formulation for IT administration to achieve maximal ELF levels and minimal cardiac toxicity. HCQ SFT formulation was prepared and evaluated for physicochemical, in vitro release, pharmacokinetics, and cardiac toxicity. Finally, the rat HCQ ELF concentrations were predicted using PBPK modeling. HCQ was amorphous after loading into the chitosan-alginate nanoporous microparticles (22.7±7.6 µm). The formulation showed a zero-order release, with only 40% released over 30 min compared to 94% for raw HCQ. The formulation had a tapped density of 0.28 g/cm3 and a loading efficiency of 35.3±1.3%. The IT administration of SFT HCQ at 1 mg/kg resulted in 23.7-fold higher bioavailability, fourfold longer MRT, and eightfold faster absorption but lower CK-MB and LDH levels than oral raw HCQ at 4 mg/kg. The PBPK model predicted 6 h of therapeutic ELF levels for IT SFT HCQ and a 100-fold higher ELF-to-heart concentration ratio than oral HCQ. Our findings support the feasibility of lung-targeted and more effective SFT HCQ IT administration for COVID-19 compared to oral HCQ with less cardiac toxicity. Graphical abstract.

Evaluating the Pharmacokinetics of Fentanyl in the Brain Extracellular Fluid, Saliva, Urine, and Plasma of Newborns from Transplacental Exposure from Parturient Mothers Dosed with Epidural Fentanyl Utilizing PBPK Modeling.

BACKGROUND AND OBJECTIVE: Fentanyl can mitigate the mother and newborn complications resulting from labor pain. However, fentanyl shows a narrow therapeutic index between its respiratory depressive and analgesic effects. Thus, prenatally acquired high fentanyl levels in the newborn brain extracellular fluid (bECF) may induce respiratory depression which requires therapeutic drug monitoring (TDM). TDM using saliva and urine in newborns can reduce the possibility of infections and distress associated with TDM using blood. The objective of this study was to develop  a physiologically based pharmacokinetic (PBPK) model to predict fentanyl concentrations in different newborn tissues due to intrauterine exposure. METHODS: A fentanyl PBPK model in adults after intravenous and epidural administration was built, validated, and scaled to pregnancy and newborn populations. The dose that the newborn received transplacentally at birth was calculated using the pregnancy model. Then, the newborn bECF, saliva, plasma, and urine concentrations after such a dose were predicted using the newborn PBPK model. RESULTS: After a maternal epidural dose of fentanyl 245 µg, the predicted newborn plasma and bECF levels were below the toxicity thresholds. Furthermore, the salivary threshold levels in newborns for fentanyl analgesic and respiratory depression effects were estimated to be 0.39 and 14.7-18.2 ng/ml, respectively. CONCLUSION: The salivary TDM of fentanyl in newborns can be useful in newborns exposed to intrauterine exposure from parturient females dosed with epidural fentanyl. However, newborn-specific values of µ-opioid receptors IC50 for respiratory depression are needed.

The Analysis of Pethidine Pharmacokinetics in Newborn Saliva, Plasma, and Brain Extracellular Fluid After Prenatal Intrauterine Exposure from Pregnant Mothers Receiving Intramuscular Dose Using PBPK Modeling.

BACKGROUND AND OBJECTIVE: Pethidine (meperidine) can decrease labor pain-associated mother's hyperventilation and high cortisol-induced newborn complications. However, prenatal transplacentally acquired pethidine can cause side effects in newborns. High pethidine concentrations in the newborn brain extracellular fluid (bECF) can cause a serotonin crisis. Therapeutic drug monitoring (TDM) in newborns' blood distresses them and increases infection incidence, which can be overcome by using salivary TDM. Physiologically based pharmacokinetic (PBPK) modeling can predict drug concentrations in newborn plasma, saliva, and bECF after intrauterine pethidine exposure. METHODS: A healthy adult PBPK model was constructed, verified, and scaled to newborn and pregnant populations after intravenous and intramuscular pethidine administration. The pregnancy PBPK model was used to predict the newborn dose received transplacentally at birth, which was used as input to the newborn PBPK model to predict newborn plasma, saliva, and bECF pethidine concentrations and set correlation equations between them. RESULTS: Pethidine can be classified as a Salivary Excretion Classification System class II drug. The developed PBPK model predicted that, after maternal pethidine intramuscular doses of 100 mg and 150 mg, the newborn plasma and bECF concentrations were below the toxicity thresholds. Moreover, it was estimated that newborn saliva concentrations of 4.7 µM, 11.4 µM, and 57.7 µM can be used as salivary threshold concentrations for pethidine analgesic effects, side effects, and the risk for serotonin crisis, respectively, in newborns. CONCLUSION: It was shown that saliva can be used for pethidine TDM in newborns during the first few days after delivery to mothers receiving pethidine.

In vitro-in vivo extrapolation of bexarotene metabolism in the presence of chronic kidney disease and acute kidney injury in rat using physiologically based pharmacokinetic modeling and extrapolation to human.

Renal impairment can affect the elimination of hepatically metabolized drugs. Bexarotene (BXT) used for cutaneous T-cell lymphoma is highly bound in plasma and metabolized by CYP3A4. The BXT European Medicine Agency and Food and Drug Administration packages recommended the evaluation of renal impairment on BXT metabolism. The plasma protein binding of BXT can be changed in patients with renal dysfunction due to hypoalbuminemia and accumulation of uremic toxins. In vitro, microsomal stability and plasma protein binding studies were pursued. A preclinical pharmacokinetic study was pursued in control, chronic kidney disease (CKD), and acute kidney injury (AKI) rats. A BXT physiologically based pharmacokinetic (PBPK) model that utilized in vitro-in vivo extrapolation of metabolism was established and verified in healthy rats, customized to CKD and AKI rats, and extrapolated to healthy human subjects and those with CKD stages 3, 4, and 5. In vitro studies showed that AKI and CKD significantly increased the BXT fraction unbound in plasma (from 0.011 to 0.018 and 0.022, respectively) and decreased intrinsic clearance (from 4.1 to 2.5, and 2.2 mL/min/g liver, respectively). This could explain the reduced in vivo clearance observed in CKD rats (from 0.4 to 0.28 L/h/kg) and the 1.3-fold increase in BXT exposure. Changes in BXT disposition in AKI rats were not straightforward due to simultaneous changes in BXT distribution. The human PBPK model predicted an increased BXT exposure by 2-fold in CKD patients, suggesting the need for dose reduction and drug monitoring. The reduced BXT metabolism due to renal impairment is especially relevant in cancer patients with CKD.

The investigation of the complex population-drug-drug interaction between ritonavir-boosted lopinavir and chloroquine or ivermectin using physiologically-based pharmacokinetic modeling.

OBJECTIVES: Therapy failure caused by complex population-drug-drug (PDDI) interactions including CYP3A4 can be predicted using mechanistic physiologically-based pharmacokinetic (PBPK) modeling. A synergy between ritonavir-boosted lopinavir (LPVr), ivermectin, and chloroquine was suggested to improve COVID-19 treatment. This work aimed to study the PDDI of the two CYP3A4 substrates (ivermectin and chloroquine) with LPVr in mild-to-moderate COVID-19 adults, geriatrics, and pregnancy populations. METHODS: The PDDI of LPVr with ivermectin or chloroquine was investigated. Pearson's correlations between plasma, saliva, and lung interstitial fluid (ISF) levels were evaluated. Target site (lung epithelial lining fluid [ELF]) levels of ivermectin and chloroquine were estimated. RESULTS: Upon LPVr coadministration, while the chloroquine plasma levels were reduced by 30, 40, and 20%, the ivermectin plasma levels were increased by a minimum of 425, 234, and 453% in adults, geriatrics, and pregnancy populations, respectively. The established correlation equations can be useful in therapeutic drug monitoring (TDM) and dosing regimen optimization. CONCLUSIONS: Neither chloroquine nor ivermectin reached therapeutic ELF levels in the presence of LPVr despite reaching toxic ivermectin plasma levels. PBPK modeling, guided with TDM in saliva, can be advantageous to evaluate the probability of reaching therapeutic ELF levels in the presence of PDDI, especially in home-treated patients.

Insights into the mapping of green synthesis conditions for ZnO nanoparticles and their toxicokinetics.

Research on ZnO nanoparticles (NPs) has broad medical applications. However, the green synthesis of ZnO NPs involves a wide range of properties requiring optimization. ZnO NPs show toxicity at lower doses. This toxicity is a function of NP properties and pharmacokinetics. Moreover, NP toxicity and pharmacokinetics are affected by the species type and age of the animals tested. Physiologically based pharmacokinetic (PBPK) modeling offers a mechanistic platform to scrutinize the colligative effect of the interplay between these factors, which reduces the need for in vivo studies. This review provides a guide to choosing green synthesis conditions that result in minimal toxicity using a mechanistic tool, namely PBPK modeling.

Enhancing Atorvastatin In Vivo Oral Bioavailability in the Presence of Inflammatory Bowel Disease and Irritable Bowel Syndrome Using Supercritical Fluid Technology Guided by wbPBPK Modeling in Rat and Human.

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are common disorders that can change the body's physiology and drugs pharmacokinetics. Solid dispersion (SD) preparation using supercritical fluid technology (SFT) has many advantages. Our study aimed to explore the effect of IBS and IBD on atorvastatin (ATV) pharmacokinetics, enhance ATV oral bioavailability (BCS II drug) using SFT, and analyze drug-disease-formulation interaction using a whole-body physiologically based pharmacokinetic (wbPBPK) model in rat and human. A novel ATV formulation was prepared using SFT and characterized in vitro and in vivo in healthy, IBS, and IBD rats. The resulting ATV plasma levels were analyzed using a combination of conventional and wbPBPK approaches. The novel formulation increased ATV solubility by 20-fold and resulted in a zero-order release of up to 95%. Both IBS and IBD increased ATV exposure after oral and intravenous administration by more than 30%. The novel SFT formulation increased ATV bioavailability by 28, 14, and 18% in control, IBD, and IBD rat groups and resulted in more consistent exposure as compared to raw ATV solution. Higher improvements in ATV bioavailability of more than 2-fold upon receiving the novel SFT formulation were predicted by the human wbPBPK model as compared to receiving the conventional tablets. Finally, the established wbPBPK model could describe ATV ADME in the presence of IBS and IBD after oral administration of raw ATV and using the novel SFT formula and can help scale the optimized ATV dosing regimens in the presence of IBS and IBD from rats to humans.

The Development of a PBPK Model for Atomoxetine Using Levels in Plasma, Saliva and Brain Extracellular Fluid in Patients with Normal and Deteriorated Kidney Function.

BACKGROUND: Atomoxetine is a treatment for attention-deficit hyperactivity disorder. It inhibits Norepinephrine Transporters (NET) in the brain. Renal impairment can reduce hepatic CYP2D6 activity and atomoxetine elimination which may increase its body exposure. Atomoxetine can be secreted in saliva. OBJECTIVE: The objective of this work was to test the hypothesis that atomoxetine saliva levels (sATX) can be used to predict ATX brain Extracellular Fluid (bECF) levels and their pharmacological effects in healthy subjects and those with End-Stage Renal Disease (ESRD). METHODS: The pharmacokinetics of atomoxetine after intravenous administration to rats with chemically induced acute and chronic renal impairments were investigated. A physiologically-based pharmacokinetic (PBPK) model was built and verified in rats using previously published measured atomoxetine levels in plasma and brain tissue. The rat PBPK model was then scaled to humans and verified using published measured atomoxetine levels in plasma, saliva, and bECF. RESULTS: The rat PBPK model predicted the observed reduced atomoxetine clearance due to renal impairment in rats. The PBPK model predicted atomoxetine exposure in human plasma, sATX and bECF. Additionally, it predicted that ATX bECF levels needed to inhibit NET are achieved at 80 mg dose. In ESRD patients, the developed PBPK model predicted that the previously reported 65% increase in plasma exposure in these patients can be associated with a 63% increase in bECF. The PBPK simulations showed that there is a significant correlation between sATX and bECF in human. CONCLUSION: Saliva levels can be used to predict atomoxetine pharmacological response.

Physiologically-based pharmacokinetic model for alectinib, ruxolitinib, and panobinostat in the presence of cancer, renal impairment, and hepatic impairment.

Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity that can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically-based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model-predicted plasma exposures in patients with different health conditions within average 2-fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively, in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively, in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non-small cell lung cancer, moderate HIP, and severe HIP at 1-, 1.5-, and 1.8-fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP.

Development and Evaluation of Cocoa Butter Taste Masked Ibuprofen Using Supercritical Carbon Dioxide.

Masking the unpleasant taste of the pharmaceutically active ingredients plays a critical role in patient acceptance, particularly for children. This work's primary objective was the preparation of taste-masked ibuprofen microparticles using cocoa butter with the assistance of supercritical fluid technology. Microparticles were prepared by dissolving ibuprofen in melted cocoa butter at 40 °C. The solution was then introduced into a supercritical fluid unit and processed at 10 MPa CO2 pressure for 30 min. The product was collected after depressurizing the system. The effect of the drug to cocoa butter ratio and the supercritical fluid units' configuration on product quality was evaluated and compared with the sample prepared by a conventional method. Physicochemical characterization of the prepared product, including particle size, crystallinity, entrapment efficiency, in vitro drug release, and product taste using a human volunteer panel was conducted. The produced microparticles were in the range of 1.42 to 15.28 µm. The entrapment efficiency of the formulated microparticles ranged from 66 to 81%. The drug:polymer ratio, the configuration of the supercritical fluid unit, and the method of preparation were found to have a critical role in the formulation of ibuprofen microparticles. Taste evaluation using human volunteers showed that microparticles containing 20% drug and processed with supercritical fluid technology were capable of masking the bitter taste of ibuprofen. In conclusion, the dispersion of ibuprofen in cocoa butter using supercritical fluid technology is a a promising innovative method to mask the bitter taste of ibuprofen.

Saliva versus Plasma Therapeutic Drug Monitoring of Gentamicin in Jordanian Preterm Infants. Development of a Physiologically-Based Pharmacokinetic (PBPK) Model and Validation of Class II Drugs of Salivary Excretion Classification System.

Gentamicin has proven to be a very successful treatment for bacterial infection, but it also can cause adverse effects, especially ototoxicity, which is irreversible. Therapeutic drug monitoring (TDM) in saliva is a more convenient non-invasive alternative compared to plasma. A physiologically-based pharmacokinetic (PBPK) model of gentamicin was built and validated using previously-published plasma and saliva data. The validated model was then used to predict experimentally-observed plasma and saliva gentamicin TDM data in Jordanian pediatric preterm infant patients measured using sensitive LCMS/MS method. A correlation was established between plasma and saliva exposures. The developed PBPK model predicted previously reported gentamicin levels in plasma, saliva and those observed in the current study. A good correlation was found between plasma and saliva exposures. The PBPK model predicted that gentamicin in saliva is 5-7 times that in plasma, which is in agreement with observed results. Saliva can be used as an alternative for TDM of gentamicin in preterm infant patients. Exposure to gentamicin in plasma and saliva can reliably be predicted using the developed PBPK model in patients.

Preparation of Hybrid Alginate-Chitosan Aerogel as Potential Carriers for Pulmonary Drug Delivery.

This study aims to prepare hybrid chitosan-alginate aerogel microparticles without using additional ionic crosslinker as a possible pulmonary drug delivery system. The microparticles were prepared using the emulsion gelation method. The effect of the mixing order of the biopolymer within the emulsion and the surfactant used on final particle properties were investigated. Physicochemical characterizations were performed to evaluate particle size, density, morphology, surface area, surface charge, and the crystallinity of the preparation. The developed preparation was evaluated for its acute toxicity in adult male Sprague-Dawley rats. Measurements of zeta potential suggest that the surface charge depends mainly on the surfactant type while the order of biopolymer mixing has less impact on the surface charge. Chitosan amphiphilic properties changed the hydrophilic-lipophilic balance (HLB) of the emulsifying agents. The specific surface area of the prepared microparticles was in the range of (29.36-86.20) m2/g with a mesoporous pore size of (12.48-13.38) nm and pore volume of (0.09-0.29) cm3/g. The calculated aerodynamic diameter of the prepared particles was in the range of (0.17-2.29 µm). Toxicity studies showed that alginate-chitosan carrier developed herein caused mild lung inflammation with some renal and hepatic toxicities.

Development, In Vitro Characterization, and In Vivo Toxicity Evaluation of Chitosan-Alginate Nanoporous Carriers Loaded with Cisplatin for Lung Cancer Treatment.

Polysaccharide-based aerogels are promising drug carriers. Being nanoporous with a high specific surface area allows their use as a drug vehicle for various delivery routes. Intratracheal and intravenous administration of free cisplatin causes toxicity in the rat liver, lungs, and kidneys. In this work, microspherical particles based on alginate-chitosan without a traditional crosslinker were evaluated for targeted delivery of cisplatin by intratracheal administration. The aerogel particles were prepared using the emulsion gelation method, followed by supercritical carbon dioxide extraction. Loading of cisplatin on the prepared porous particles was performed by impregnation using supercritical fluid technology. The prepared carrier and the loaded drug were evaluated for drug content, release, and in vivo acute and subacute toxicity. Cisplatin was successfully loaded (percent drug loading > 76%) on the prepared carrier (particle size = 0.433 ± 0.091 µm) without chemically interacting with the carrier and without losing its crystal form. Sixty percent of cisplatin was released within 2 h, and the rest was loaded inside the polymer pores and had a sustained first-order release over 6 h. Loading cisplatin on the carrier developed herein reduced the cisplatin lung toxicity but increased the liver toxicity after intratracheal administration with nephrotoxicity being proportional to cisplatin dose in case of carrier-loaded cisplatin. Moreover, loading cisplatin on the carrier significantly reduced mortality rate and prevented weight loss in rats as compared to free cisplatin in subacute studies after intratracheal administration. Thus, the developed carrier showed high potential for targeted delivery of cisplatin for lung cancer treatment by inhalation. Graphical abstract.

The development of a population physiologically based pharmacokinetic model for mycophenolic mofetil and mycophenolic acid in humans using data from plasma, saliva, and kidney tissue.

BACKGROUND: Mycophenolic acid (MPA) is used widely to prevent graft rejection in kidney-transplant patients. Therapeutic drug monitoring (TDM) in plasma requires an invasive procedure that is inconvenient, especially in pediatric patients. TDM in saliva is a more convenient non-invasive alternative compared with plasma. METHODS: A population physiologically based pharmacokinetic (Pop-PBPK) model of mycophenolate mofetil (MMF) and MPA with enterohepatic recycling was built and verified using previously published plasma, saliva, and kidney biopsy data in healthy and kidney-transplant adult patients. The verified model was then used to predict experimentally observed plasma and saliva MMF and MPA TDM data in Jordanian pediatric kidney transplant patients measured using LC-MS/MS. A correlation was established between plasma and saliva exposures in pediatrics. RESULTS: The developed LCMS was sensitive to both MMF and MPA in plasma and saliva. The developed Pop-PBPK model predicted well the previously reported MMF and MPA levels in plasma, saliva, and kidney tissue and those observed in the current study (more than 75% of observed data points were within 90% predictive interval of population simulations). A statistically significant correlation was found between plasma and saliva exposures for both MMF (Pop-PBPK predicted and observed) and MPA (Pop-PBPK predicted). CONCLUSION: Both MPA and MMF can be classified as class III compounds in the Salivary Excretion Classification System. Saliva is an alternative body fluid to plasma that can be used for TDM of MPA and MMF in kidney-transplant patients in pediatrics. Exposure to MPA and MMF in plasma, saliva, and kidney tissue was reliably predicted using the developed Pop-PBPK model.

Optimization of Drugs Pharmacotherapy During Pregnancy Using Physiologically Based Pharmacokinetic Models - An Update.

BACKGROUND: Clinical studies during pregnancy are rare due to ethical and practical limitations. Giving pregnant females the same dosing regimen used in adult males or nonpregnant females is inappropriate. Pregnancy physiologically-based pharmacokinetic modeling is a powerful tool that can be used to refine pharmacotherapy during pregnancy. OBJECTIVE: This work provides a review of the current status of application of physiologically based pharmacokinetic models in developing dosing regimens in pregnant women. METHODS: A structured search was done on Scholar Google, Science Direct and PubMed. The articles searched were those providing physiological, anatomical and biochemical data needed for pregnancy physiologically-based pharmacokinetic models or utilizing these models to evaluate the effect of pregnancy on drugs pharmacokinetics. Key words used for search include: PBPK and pregnancy, pharmacokinetic during pregnancy, ethics of pregnancy studies. The found articles were evaluated in terms of main pharmacokinetic features of the drug that were affected by pregnancy, the structure of the model, the software platform used and quality of predicted maternal and fetal exposure. RESULTS: Pregnancy physiologically-based pharmacokinetic models can be used to optimize effective and safe dosing regimens needed during pregnancy. Different model structures have been successfully used for this purpose using different modeling software. CONCLUSION: More work is needed to fill the gaps in knowledge needed to more accurately and mechanistically simulate simultaneous exposure of the pregnant mother and her fetus/ embryo to drugs using pregnancy physiologicallybased pharmacokinetic modeling approach.

Sublingual spray drug delivery of ketorolac-loaded chitosan nanoparticles.

INTRODUCTION: The aim of this study was to investigate ketorolac (KT) systemic absolute bioavailability after sublingual (SL) administration in vivo to conscious rabbits. Furthermore, the study investigated the potential use of chitosan nanoparticles as a delivery system to enhance the systemic bioavailability of KT following SL administration. METHODS: Ketorolac-loaded chitosan nanoparticles were prepared through ionotropic gelation of chitosan with tripolyphosphate anions. The KT-nanoparticles were administered SL as a spray to rabbits and KT plasma concentration at predetermined time points was compared to SL spray administration of KT in solution. The concentrations of KT in plasma were analyzed by ultra-performance liquid chromatography mass spectroscopy (UPLC/MS). RESULTS: KT-loaded chitosan nanoparticles significantly (p < .05) enhanced systemic absorption with 97% absolute bioavailability as compared to 70% after SL administration of KT solution. CONCLUSIONS: The results of the present study suggest that SL absorption of KT illustrated flip-flop kinetics with prolonged persistence in the body compared to intravenous administration. Formulation of KT as chitosan nanoparticles has increased its systemic bioavailability after SL spray administration. The new delivery system could be an attractive approach for the delivery of KT.

Delivery of Peptidic Gonadotropin Releasing Hormone Antagonists.

GnRH antagonists have several clinical applications in prostate cancer, regulation of ovulation induction in females, breast cancer, male contraception and others. Antagonists differ from natural GnRH decapeptide in having five or more amino acid substitutions, whereas most of the antagonists are available as subcutaneous (SC) formula for injection some are formulated as a depot formulation for sustained release (e.g., Cetrorelix, Degarelix). Systemic delivery of cetrorelix acetate by intratracheal route can be achieved using dry powder for inhalation of the adhesive mixture when the powder deposition reaches stage four. The oral route for systemic delivery of peptide without its degradation can be achieved using gastrointestinal permeation enhancement technology GIPET® provided by acyline.