Potential of pharmacogenetics in minimizing drug therapy problems in cystic fibrosis.

BACKGROUND: With advancements in CF drug development, people with cystic fibrosis (PwCF) now take a median of seven medications daily, increasing treatment complexity, risk of drug therapy problems (DTPs), and interference with treatment goals. Given that some of these DTPs can be prevented with preemptive pharmacogenetic testing, the overall goal of this study was to test the clinical utility of a multi-gene pharmacogenetics (PGx) panel in potentially reducing DTPs in PwCF. METHODS: A population based retrospective study of patients with CF was conducted at the University of Utah Health Care System. The patients were genotyped for CYP450 enzymes using a pharmacogenomic assay, and their drug utilization information was obtained retrospectively. This pharmacogenomic information was combined with clinical guidelines to predict the number of actionable PGx interventions in this patient cohort. RESULTS: A total of 52 patients were included in this study. In the patient sample, a minimum of one order of actionable PGx medication was observed in 75 % of the cases. Results revealed that 4.2 treatment modifications per 10 patients can be enabled with the help of a PGx intervention in this patient population. Additionally, our findings suggest that polymorphisms in CYP2D6 and CYP2C19 are most likely to be the primary contributors to DTP's within PwCF. CONCLUSION: This study provides evidence that the PGx panel has the potential to help alleviate the clinical burden of DTPs in PwCF and can assist in informing pharmacotherapy recommendations. Future research should validate these findings and evaluate which subgroups of PwCF would most benefit from pharmacogenetic testing.

Effectiveness of atropine in managing sialorrhea: A systematic review and meta-analysis.

OBJECTIVES: To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling. MATERIALS AND METHODS: We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale. RESULTS: A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes. CONCLUSION: Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.

Pharmacokinetic Modeling Using Real-World Data to Optimize Unfractionated Heparin Dosing in Pediatric Patients on Extracorporeal Membrane Oxygenation and Evaluate Target Achievement-Clinical Outcomes Relationship.

Unfractionated heparin (UFH) is a commonly used anticoagulant for pediatric patients undergoing extracorporeal membrane oxygenation (ECMO), but evidence is lacking on the ideal dosing. We aimed to (1) develop a population pharmacokinetic (PK) model for UFH, measured through anti-factor Xa assay; (2) optimize UFH starting infusions and dose titrations through simulations; and (3) explore UFH exposure-clinical outcomes relationship. Data from 218 patients admitted to Utah's Primary Children's Hospital were retrospectively collected. A 1-compartment PK model with time-varying clearance (CL) adequately described UFH PK. Weight on CL and volume of distribution and ECMO circuit change on CL were significant covariates. The typical estimates for initial CL and first-order rate constant to reach steady-state CL were 0.57 L/(h·10 kg) and 0.02/h. Comparable to non-ECMO patients, the typical steady-state CL was 0.81 L/(h·10 kg). Simulations showed that a 75 IU/kg UFH bolus dose followed by starting infusions of 25 and 20 IU/h/kg for patients aged younger than 6 years and 6 years or older, respectively, achieved the therapeutic target in 56.6% of all patients, whereas only 3.1% exceeded the target. The proposed UFH titration schemes achieved the target in more than 90% of patients while less than 0.63% were above the target after 24 and 48 hours of treatment. The median intensive care unit survival time in patients within and below the target at 24 hours was 136 and 66 hours, respectively. In conclusion, PK model of UFH was developed for pediatric patients on ECMO. The proposed UFH dosing scheme attained the anti-factor Xa target rapidly and safely.

Population pharmacokinetics and target attainment analysis of vancomycin after intermittent dosing in adults with cystic fibrosis.

Vancomycin is the first-line agent to treat pulmonary infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis (PwCF). However, there is no consensus on vancomycin initial dosing in this population among health institutions, and there is a large variability in initial dosing across the United States. In this study, we characterized the pharmacokinetics (PK) of vancomycin in PwCF using a population PK approach. The clinical PK data to develop the population PK model were obtained from vancomycin therapeutic monitoring data from PwCF undergoing treatment for infections due to MRSA. The population PK model was then used to perform comprehensive Monte Carlo simulations to evaluate the probability of target attainment (PTA) of 12 different initial dosing scenarios. The area under the curve to minimum inhibitory concentration (MIC) ratio ≥400 mg*h/L and <650 mg*h/L were used as efficacy and toxicity targets for PTA analysis. A total of 181 vancomycin plasma concentrations were included in the analysis. A one-compartment model with first-order elimination best described the data. Weight significantly influenced the vancomycin PK (P < 0.05). In the final model, clearance was estimated as 5.52 L/h/70 kg, and the volume of distribution was 31.5 L/70 kg. The PTA analysis showed that at MIC = 1 µg/mL, doses 1,500 q8h and 2,000 q12h showed the highest %PTA in achieving both efficacy and toxicity targets. The PTA results from this study may potentially inform the initial dosing regimens of vancomycin to treat pulmonary infections due to MRSA in PwCF.

Pharmacokinetics of intranasal amiloride in healthy volunteers.

Anxiety and panic disorders are the most common mental illnesses in the United States and lack effective treatment options. Acid-sending ion channels (ASICs) in the brain were shown to be associated with fear conditioning and anxiety responses and therefore are potential targets for treating panic disorder. Amiloride is an inhibitor of the ASICs in the brain and was shown to reduce panic symptoms in preclinical animal models. An intranasal formulation of amiloride will be highly beneficial to treat acute panic attacks due to advantages such as the rapid onset of action and patient compliance. The aim of this single-center, open-label trial was to evaluate the basic pharmacokinetics (PKs) and safety of amiloride after intranasal administration in healthy human volunteers at three doses (0.2, 0.4, and 0.6 mg). Amiloride was detected in plasma within 10 min of intranasal administration and showed a biphasic PK profile with an initial peak within 10 min of administration followed by a second peak between 4 and 8 h of administration. The biphasic PKs indicate an initial rapid absorption via the nasal pathway and later slower absorption by non-nasal pathways. Intranasal amiloride exhibited a dose-proportional increase in the area under the curve and did not exhibit any systemic toxicity. These data indicate that intranasal amiloride is rapidly absorbed and safe at the doses evaluated and can be further considered for clinical development as a portable, rapid, noninvasive, and nonaddictive anxiolytic agent to treat acute panic attacks.

Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19: Mechanistic Insights from a Whole-Body Infection Dynamics Model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen of immense public health concern. Efforts to control the disease have only proven mildly successful, and the disease will likely continue to cause excessive fatalities until effective preventative measures (such as a vaccine) are developed. To develop disease management strategies, a better understanding of SARS-CoV-2 pathogenesis and population susceptibility to infection are needed. To this end, mathematical modeling can provide a robust in silico tool to understand COVID-19 pathophysiology and the in vivo dynamics of SARS-CoV-2. Guided by ACE2-tropism (ACE2 receptor dependency for infection) of the virus and by incorporating cellular-scale viral dynamics and innate and adaptive immune responses, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body (respiratory tract, gut, liver, spleen, heart, kidneys, and brain). Following parameter quantification with in vivo and clinical data, we used the model to simulate viral load progression in a virtual patient with varying degrees of compromised immune status. Further, we ranked model parameters through sensitivity analysis for their significance in governing clearance of viral load to understand the effects of physiological factors and underlying conditions on viral load dynamics. Antiviral drug therapy, interferon therapy, and their combination were simulated to study the effects on viral load kinetics of SARS-CoV-2. The model revealed the dominant role of innate immunity (specifically interferons and resident macrophages) in controlling viral load, and the importance of timing when initiating therapy after infection.

Predicting Resolvin D1 Pharmacokinetics in Humans with Physiologically-Based Pharmacokinetic Modeling.

Sjögren's syndrome (SS) is an autoimmune disease with no effective treatment options. Resolvin D1 (RvD1) belongs to a class of lipid-based specialized pro-resolving mediators that showed efficacy in preclinical models of SS. We developed a physiologically-based pharmacokinetic (PBPK) model of RvD1 in mice and optimized the model using plasma and salivary gland pharmacokinetic (PK) studies performed in NOD/ShiLtJ mice with SS-like features. The predictive performance of the PBPK model was also evaluated with two external datasets from the literature reporting RvD1 PKs. The PBPK model adequately captured the observed concentrations of RvD1 administered at different doses and in different species. The PKs of RvD1 in virtual humans were predicted using the verified PBPK model at various doses (0.01-10 mg/kg). The first-in-human predictions of RvD1 will be useful for the clinical trial design and translation of RvD1 as an effective treatment strategy for SS.

Innate immunity plays a key role in controlling viral load in COVID-19: mechanistic insights from a whole-body infection dynamics model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen of immense public health concern. Efforts to control the disease have only proven mildly successful, and the disease will likely continue to cause excessive fatalities until effective preventative measures (such as a vaccine) are developed. To develop disease management strategies, a better understanding of SARS-CoV-2 pathogenesis and population susceptibility to infection are needed. To this end, physiologically-relevant mathematical modeling can provide a robust in silico tool to understand COVID-19 pathophysiology and the in vivo dynamics of SARS-CoV-2. Guided by ACE2-tropism (ACE2 receptor dependency for infection) of the virus, and by incorporating cellular-scale viral dynamics and innate and adaptive immune responses, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body (respiratory tract, gut, liver, spleen, heart, kidneys, and brain). Following calibration with in vivo and clinical data, we used the model to simulate viral load progression in a virtual patient with varying degrees of compromised immune status. Further, we conducted global sensitivity analysis of model parameters and ranked them for their significance in governing clearance of viral load to understand the effects of physiological factors and underlying conditions on viral load dynamics. Antiviral drug therapy, interferon therapy, and their combination was simulated to study the effects on viral load kinetics of SARS-CoV-2. The model revealed the dominant role of innate immunity (specifically interferons and resident macrophages) in controlling viral load, and the importance of timing when initiating therapy following infection.

Pharmacokinetics of nanotechnology-based formulations in pediatric populations.

The development of therapeutics for pediatric use has advanced in the last few decades. However, off-label use of adult medications in pediatrics remains a significant clinical problem. Furthermore, the development of therapeutics for pediatrics is challenged by the lack of pharmacokinetic (PK) data in the pediatric population. To promote the development of therapeutics for pediatrics, the United States Pediatric Formulation Initiative recommended the investigation of nanotechnology-based delivery systems. Therefore, in this review, we provided comprehensive information on the PK of nanotechnology-based formulations from preclinical and clinical studies in pediatrics. Specifically, we discuss the relationship between formulation parameters of nanoformulations and PK of the encapsulated drug in the context of pediatrics. We review nanoformulations that include dendrimers, liposomes, polymeric long-acting injectables (LAIs), nanocrystals, inorganic nanoparticles, polymeric micelles, and protein nanoparticles. In addition, we describe the importance and need of PK modeling and simulation approaches used in predicting PK of nanoformulations for pediatric applications.

Pharmacokinetics of oral therapeutics delivered by dendrimer-based carriers.

Introduction: Dendrimers showed promise as carriers for oral delivery due to their nanoscale size and transepithelial permeability across the gut epithelium. However, for the successful approval of dendrimer-based oral therapeutics for human use, it is essential to understand their pharmacokinetics. The knowledge of pharmacokinetics of drugs delivered with dendrimers within the context of oral delivery of therapeutics will help in the design of clinical trials, and development of dosage regimens. Areas covered: This review summarizes the pharmacokinetic aspects of dendrimer and dendrimer-drug complexes after oral administration. We discussed the influence of size, core chemistry, surface charge, surface chemistry, and modification on the pharmacokinetics of dendrimers and dendrimer-drug complexes. Furthermore, we also discussed studies involving alternative dosage forms such as matrix tablets containing dendrimers, dendrimers encapsulated in lipid nanostructures, and chitosan anchored-dendrimers. Expert opinion: From the studies, it is evident that dendrimers significantly improve the oral bioavailability of drugs with poor biopharmaceutical properties. However, further in vivo studies are needed to establish the relationship between the properties of dendrimers and oral pharmacokinetics of dendrimer-drug complexes and conjugates.

Biopharmaceutical Characterization and Oral Efficacy of a New Rapid Acting Antidepressant Ro 25-6981.

Ro 25-6981 is a highly potent and selective blocker of N-methyl-d-aspartate receptors that has been shown to possess both rapid and sustained antidepressant activity. In the present study, we report the biopharmaceutical characterization of Ro 25-6981 by evaluating gastrointestinal stability, transepithelial permeability, stability in human liver microsomes, and in silico metabolic prediction. Moreover, in vivo efficacy of Ro 25-6981 after oral administration was evaluated in animal models of depression. When mixed with 5 different simulated gastrointestinal fluids, no loss of parent compound was observed after 6 h, indicating compound stability in the gastrointestinal environment. At the tested concentrations, Ro 25-6981 was shown to have transepithelial permeability with apparent permeability (Papp) values comparable to highly permeable drugs. Ro 25-6981 was metabolized within 30 min in human liver microsomes, and the metabolic prediction data showed glucuronidation and sulfation as potential metabolic pathways. The in vivo efficacy data suggested that Ro 25-6981, when administered orally at 30 mg/kg, exhibits antidepressant-like activity following oral administration with efficacy comparable to traditional antidepressants that is both dose- and time-dependent. Overall, due to optimal gastrointestinal stability, oral permeability, and oral efficacy, Ro 25-6981 can be a potential therapeutic option for the treatment of depression.

Pediatric oral formulation of dendrimer-N-acetyl-l-cysteine conjugates for the treatment of neuroinflammation.

N-Acetyl-l-cysteine (NAC) commonly used as an antidote in acetaminophen poisoning has shown promise in the treatment of neurological disorders such as cerebral palsy (CP). However, NAC suffers from drawbacks such as poor oral bioavailability and suboptimal blood-brain-barrier (BBB) permeability limiting its clinical success. It was previously demonstrated that intravenous administration of dendrimer-NAC (D-NAC) conjugates have shown significant promise in the targeted treatment of neuroinflammation, in multiple preclinical models. Development of an oral formulation of D-NAC may open new administrative routes for this compound. Here, we report the gastrointestinal stability, in vitro transepithelial permeability, and in vivo oral absorption and pharmacokinetics in rats of a pediatric formulation of D-NAC containing Capmul MCM (glycerol monocaprylate) as a penetration enhancer. D-NAC was stable for 6 h in all five simulated gastrointestinal fluids with no signs of chemical degradation. The apparent permeability (Papp) of D-NAC increased 9-fold in the formulation containing Capmul. The area under the curve [AUC]0-∞ of D-NAC with Capmul increased by 47% when compared to D-NAC alone. These results indicate that an oral pediatric formulation containing D-NAC and Capmul can be an effective option for the treatment of neuroinflammation.

Stability of extemporaneously prepared preservative-free prochlorperazine nasal spray.

PURPOSE: The stability of an extemporaneously prepared preservative-free prochlorperazine 5-mg/mL nasal spray was evaluated. METHODS: The preservative-free prochlorperazine nasal spray was prepared by adding 250 mg of prochlorperazine edisylate to 50 mL of citrate buffer in a low-density polyethylene nasal spray bottle. A stability-indicating high-performance liquid chromatography (HPLC) method was developed and validated using the major degradant prochlorperazine sulfoxide and by performing forced-degradation studies. For chemical stability studies, 3 100-µL samples of the preservative-free prochlorperazine from 5 nasal spray bottles stored at room temperature were collected at days 0, 20, 30, 45, and 60 and were assayed in triplicate using the stability-indicating HPLC method. Microbiological testing involved antimicrobial effectiveness testing based on United States Pharmacopeia (USP) chapter 51 and quantitative microbiological enumeration of aerobic bacteria, yeasts, and mold based on USP chapter 61. Samples for microbiological testing were collected at days 0, 30, and 60. RESULTS: The stability-indicating HPLC method clearly identified the degradation product prochlorperazine sulfoxide without interference from prochlorperazine. All tested solutions retained over 90% of the initial prochlorperazine concentration for the 60-day study period. There were no detectable changes in color, pH, and viscosity in any sample. There was no growth of bacteria, yeast, and mold for 60 days in all samples tested. CONCLUSION: An extemporaneously prepared preservative-free nasal spray solution of prochlorperazine edisylate 5 mg/mL was physically, chemically, and microbiologically stable for 60 days when stored at room temperature in low-density polyethylene bottles.

Penetration and pharmacokinetics of non-steroidal anti-inflammatory drugs in rat prostate tissue.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) involves inflammation of the prostate and affects the quality of life of men of all ages. It is well reported in clinical studies that the treatment for CP/CPPS using nonsteroidal anti-inflammatory drugs (NSAIDs) produced favorable outcomes. However, currently, there are no guidelines on choice of the NSAIDs for the treatment of CP/CPPS. Therefore, in the current research study, we evaluated the prostate tissue penetration of four NSAIDs in rats to provide guidance on choice of NSAIDs for the treatment of CP/CPPS. METHODS: Male Sprague-Dawley rats were administered orally with four NSAIDs viz. celecoxib, diclofenac, ibuprofen, and naproxen at 500 mg/kg dose. The animals were then sacrificed at various time points, and their prostate tissues were harvested. The NSAIDs were then extracted from the prostate tissues using liquid extraction technique, and their concentration in prostate tissue was quantified using high-performance liquid chromatography (HPLC). The prostate tissue penetration and related pharmacokinetic parameters were evaluated by non-compartmental analysis. RESULTS: The HPLC method for quantifying NSAIDs in prostate tissue resulted in single, sharp peaks without any interference and all validation parameters were within limits. Celecoxib showed the highest area under the curve (AUC) [146.50 ± 2.75 µg/mL*h] of all NSAID's. A two-factor analysis of variance (ANOVA) with replication indicated an overall statistically significant difference in the pharmacokinetic parameters for celecoxib, diclofenac, ibuprofen, and naproxen. CONCLUSIONS: This study for the first time reported the relative prostate tissue penetration of four NSAIDs. The pharmacokinetic data indicated that celecoxib has the highest penetration and retention in rat prostate tissues. Therefore, celecoxib may be considered as a better choice for the treatment CP/CPPS involving NSAIDs.

Omega-3 Fatty Acid Grafted PAMAM-Paclitaxel Conjugate Exhibits Enhanced Anticancer Activity in Upper Gastrointestinal Cancer Cells.

Upper Gastrointestinal Cancers (UGCs) are a leading cause of cancer-related deaths worldwide. Paclitaxel (PTX) is frequently used for the treatment of UGCs; however, low bioavailability, reduced solubility, and dose-dependent toxicity impede its therapeutic use. PAMAMG4.0 -NH2 -DHA is synthesized by linking amine-terminated fourth-generation poly(amidoamine) (PAMAMG4.0 -NH2 ) dendrimers with omega-3 fatty acid docosahexaenoic acid (DHA). Next, PAMAMG4.0 -NH2 -DHA-PTX (DHATX) and PAMAMG4.0 -NH2 -PTX (PAX) conjugates are synthesized by subsequent covalent binding of PTX with PAMAMG4.0 -NH2 -DHA and PAMAMG4.0 -NH2 , respectively. 1 H-NMR and MALDI-TOF analyses are performed to confirm conjugation of DHA to PAMAMG4.0 -NH2 and PTX to PAMAMG4.0 -NH2 -DHA. The cell viability, clonogenic cell survival, and flow cytometry analyses are used to determine the anticancer activity of PTX, PAX, and DHATX in UGC cell lines. The in vitro data indicate that treatment with DHATX is significantly more potent than PTX or PAX at inhibiting cellular proliferation, suppressing long-term survival, and inducing cell death in UGC cells.

Poly(amido amine) dendrimers in oral delivery.

Poly(amidoamine) (PAMAM) dendrimers have been extensively investigated for oral delivery applications due to their ability to translocate across the gastrointestinal epithelium. In this Review, we highlight recent advances in the evaluation of PAMAM dendrimers as oral drug delivery carriers. Specifically, toxicity, mechanisms of transepithelial transport, models of the intestinal epithelial barrier including isolated human intestinal tissue model, detection of dendrimers, and surface modification are discussed. We also highlight evaluation of various PAMAM dendrimer-drug conjugates for their ability to transport across gastrointestinal epithelium for improved oral bioavailability. In addition, current challenges and future trends for clinical translation of PAMAM dendrimers as carriers for oral delivery are discussed.

Pharmacokinetic modeling of therapies for systemic lupus erythematosus.

With the increasing use of different types of therapies in treating autoimmune diseases such as systemic lupus erythematosus (SLE), there is a need to utilize pharmacokinetic (PK) strategies to optimize the clinical outcome of these treatments. Various PK analysis approaches, including population PK modeling and physiologically based PK modeling, have been used to evaluate drug PK characteristics and population variability or to predict drug PK profiles in a mechanistic manner. This review outlines the PK modeling of major SLE therapies including immunosuppressants (methotrexate, azathioprine, mycophenolate and cyclophosphamide, among others) and immunomodulators (intravenous immunoglobulin). It summarizes the population PK modeling, physiologically based PK modeling and model-based individualized dosing strategies to improve the therapeutic outcomes in SLE patients.

Clinical pharmacokinetics of inhaled antimicrobials.

Administration of inhaled antimicrobials affords the ability to achieve targeted drug delivery into the respiratory tract, rapid entry into the systemic circulation, high bioavailability and minimal metabolism. These unique pharmacokinetic characteristics make inhaled antimicrobial delivery attractive for the treatment of many pulmonary diseases. This review examines recent pharmacokinetic trials with inhaled antibacterials, antivirals and antifungals, with an emphasis on the clinical implications of these studies. The majority of these studies revealed evidence of high antimicrobial concentrations in the airway with limited systemic exposure, thereby reducing the risk of toxicity. Sputum pharmacokinetics varied widely, which makes it challenging to interpret the result of sputum pharmacokinetic studies. Many no vel inhaled antimicrobial therapies are currently under investigation that will require detailed pharmacokinetic studies, including combination inhaled antimicrobial therapies, inhaled nanoparticle formulations of several antibacterials, inhaled non-antimicrobial adjuvants, inhaled antiviral recombinant protein therapies and semi-synthetic inhaled antifungal agents. Additionally, the development of new inhaled delivery devices, particularly for mechanically ventilated patients, will result in a pressing need for additional pharmacokinetic studies to identify optimal dosing regimens.

Punctal plug: a medical device to treat dry eye syndrome and for sustained drug delivery to the eye.

Punctal plugs (PPs) are miniature medical implants that were initially developed for the treatment of dry eyes. Since their introduction in 1975, many PPs made from different materials and designs have been developed. PPs, albeit generally successful, suffer from drawbacks such as epiphora and suppurative canaliculitis. To overcome these issues intelligent designs of PPs were proposed (e.g. SmartPLUG™ and Form Fit™). PPs are also gaining interest among pharmaceutical scientists for sustaining drug delivery to the eye. This review aims to provide an overview of PPs for dry eye treatment and drug delivery to treat a range of ocular diseases. It also discusses current challenges in using PPs for ocular diseases.