Higher Plasma Drug Concentrations Research Articles

A long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis

Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb) and is a major cause of morbidity and mortality. Successful treatment requires strict adherence to drug regimens for prolonged periods of time. Long-acting (LA) delivery systems have the potential to improve adherence. Here, we show the development of LA injectable drug formulations of the anti-TB drug rifabutin made of biodegradable polymers and biocompatible solvents that solidifies after subcutaneous injection. Addition of amphiphilic compounds increases drug solubility, allowing to significantly increase formulation drug load. Solidified implants have organized microstructures that change with formulation composition. Higher drug load results in smaller pore size that alters implant erosion and allows sustained drug release. The translational relevance of these observations in BALB/c mice is demonstrated by (1) delivering high plasma drug concentrations for 16 weeks, (2) preventing acquisition of Mtb infection, and (3) clearing acute Mtb infection from the lung and other tissues.

Prednisolone and dexamethasone are systemically absorbed after topical application of ophthalmic suspensions in healthy dogs.

To quantify plasma concentrations of prednisolone and dexamethasone (peripheral and jugular) and cortisol following topical ophthalmic application of 1% prednisolone acetate and 0.1% dexamethasone to healthy adult dogs. 12 purpose-bred Beagles. Dogs received 1 drop of 1% prednisolone acetate (n = 6) or neomycin polymyxin B dexamethasone (ie, 0.1% dexamethasone; 6) ophthalmic suspension in both eyes every 6 hours for 14 days. Blood samples (peripheral and jugular) were collected on days 0, 1, 7, and 14 and analyzed for plasma prednisolone and dexamethasone concentrations. Plasma cortisol concentrations were measured at the beginning of the study and following topical drug administration. Both drugs demonstrated systemic absorption. Prednisolone was detected on days 1, 7, and 14 (median plasma concentration, 24.80 ng/mL; range, 6.20 to 74.00 ng/mL), and dexamethasone was detected on days 1, 7, and 14 (2.30 ng/mL; 0 to 17.70 ng/mL). Neither prednisolone nor dexamethasone were detected in plasma samples on day 0 (baseline). Sampling from the jugular vein resulted in higher plasma drug concentrations than from a peripheral vein when samples from each day were combined. Plasma cortisol concentrations were significantly lower than baseline following 14 days of treatment with topical prednisolone acetate and dexamethasone. Prednisolone and dexamethasone are detected in the plasma of healthy dogs following topical ophthalmic administration 4 times/d with prednisolone concentrations being close to a physiologic dose of orally administered prednisolone. Additional research is needed to evaluate the systemic absorption of these medications in dogs with ocular inflammation.

Relationship of Prolactin Concentrations to Steady-State Plasma Concentrations of Aripiprazole in Patients With Schizophrenia.

Aripiprazole is regarded as the first-line antipsychotic medication. Long-term aripiprazole therapy can cause hypoprolactinemia, which may result from its activity as a dopamine agonist. However, there is little information on hypoprolactinemia and steady-state aripiprazole concentrations. The subjects included 66 male and 177 female patients diagnosed with schizophrenia who were treated with aripiprazole. The plasma concentrations of aripiprazole and dehydroaripiprazole and the plasma concentration of prolactin were measured using high-performance liquid chromatography and enzyme immunoassay, respectively. A prolactin concentration of <5 ng/mL was defined as hypoprolactinemia. Fifty-two of the 66 male patients (79%) and 58 of the 177 female patients (33%) had hypoprolactinemia. There were significant inverse correlations between plasma prolactin levels and plasma concentrations of aripiprazole (rs = -0.447, P < 0.001) and the active moiety (aripiprazole plus dehydroaripiprazole) (rs = -0.429, P < 0.001) in men. In women, significant inverse correlations were also found between plasma prolactin levels and plasma concentrations of aripiprazole (rs = -0.273, P < 0.01) and the active moiety (rs = -0.275, P < 0.01). These findings suggest that lower prolactin levels are, to some extent, associated with higher plasma drug concentrations in male and female patients with schizophrenia treated with aripiprazole.

Biodegradable nanoparticulate co-delivery of flavonoid and doxorubicin: Mechanistic exploration and evaluation of anticancer effect in vitro and in vivo

The proposed study involves delivering drug/bioactive using a single nanoplatform based on poly lactic-co-glycolic acid (PLGA) for better efficacy, synergistic effect, and reduced toxicity. PLGA was conjugated to doxorubicin (D1), and this conjugate was used for encapsulation of naringenin (D2) to develop naringenin loaded PLGA-doxorubicin nanoparticles (PDNG). The PDNG NPs were 165.4 ± 4.27 nm in size, having 0.112 ± 0.035 PDI, with -10.1 ± 2.74 zeta potential. The surface morphology was confirmed through transmission electron microscopy (TEM) and atomic force microscopy (AFM). The in vitro studies revealed that PDNG NPs exhibited selective anticancer potential in breast cancer cells, and induced apoptosis with S-phase inhibition via an increase in intrinsic reactive oxygen species (ROS) and altering the mitochondrial potential. The results also signified the efficient uptake of nanoparticles encapsulated drugs by cells besides elevating the caspase level suggesting programmed cell death induction upon treatment. In vivo studies results revealed better half-life (27.35 ± 1.58 and 11.98 ± 1.21 h for doxorubicin and naringenin) with higher plasma drug concentration. In vivo biodistribution study was also in accordance with the in vitro studies and in line with the in vivo pharmacokinetic. In vivo tumor regression assay portrayed that the formulation PDNG halts the tumor growth and lessen the tumor volume with the stable bodyweight of the mice. Conclusively, the dual delivery approach was beneficial and highly effective against tumor-induced mice.

Explaining anaesthetic hysteresis with effect-site equilibration

BackgroundAnaesthetic induction occurs at higher plasma drug concentrations than emergence in animal studies. Some studies find evidence for such anaesthetic hysteresis in humans, whereas others do not. Traditional thinking attributes hysteresis to drug equilibration between plasma and the effect site. Indeed, a key difference between human studies showing anaesthetic hysteresis and those that do not is in how effect-site equilibration was modelled. However, the effect-site is a theoretical compartment in which drug concentration cannot be measured experimentally. Thus, it is not clear whether drug equilibration models with experimentally intractable compartments are sufficiently constrained to unequivocally establish evidence for the presence or absence of anaesthetic hysteresis. MethodsWe constructed several models. One lacked hysteresis beyond effect-site equilibration. In another, neuronal dynamics contributed to hysteresis. We attempted to distinguish between these two systems using drug equilibration models. ResultsOur modelling studies showed that one can always construct an effect-site equilibration model such that hysteresis collapses. So long as the concentration in the effect-site cannot be measured directly, the correct effect-site equilibration model and the one that erroneously collapses hysteresis are experimentally indistinguishable. We also found that hysteresis can naturally arise even in a simple network of neurones independently of drug equilibration. ConclusionsEffect-site equilibration models can readily collapse hysteresis. However, this does not imply that hysteresis is solely attributable to the kinetics of drug equilibration.

Anti-SARS-CoV-2 Potential of Artemisinins In Vitro.

The discovery of novel drug candidates with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potential is critical for the control of the global COVID-19 pandemic. Artemisinin, an old antimalarial drug derived from Chinese herbs, has saved millions of lives. Artemisinins are a cluster of artemisinin-related drugs developed for the treatment of malaria and have been reported to have multiple pharmacological activities, including anticancer, antiviral, and immune modulation. Considering the reported broad-spectrum antiviral potential of artemisinins, researchers are interested in whether they could be used to combat COVID-19. We systematically evaluated the anti-SARS-CoV-2 activities of nine artemisinin-related compounds in vitro and carried out a time-of-drug-addition assay to explore their antiviral mode of action. Finally, a pharmacokinetic prediction model was established to predict the therapeutic potential of selected compounds against COVID-19. Arteannuin B showed the highest anti-SARS-CoV-2 potential with an EC50 of 10.28 ± 1.12 μM. Artesunate and dihydroartemisinin showed similar EC50 values of 12.98 ± 5.30 μM and 13.31 ± 1.24 μM, respectively, which could be clinically achieved in plasma after intravenous administration. Interestingly, although an EC50 of 23.17 ± 3.22 μM was not prominent among the tested compounds, lumefantrine showed therapeutic promise due to high plasma and lung drug concentrations after multiple dosing. Further mode of action analysis revealed that arteannuin B and lumefantrine acted at the post-entry step of SARS-CoV-2 infection. This research highlights the anti-SARS-CoV-2 potential of artemisinins and provides leading candidates for anti-SARS-CoV-2 drug research and development.

Women and Heart Failure: Heart Drugs and Dosages

Several studies have documented higher plasma drug concentrations with the same medication doses in women than in men, but guideline-recommended doses

Development of microparticles coated with poly-γ-glutamic acid to improve oral absorption of a poorly water-soluble drug

Novel microparticles coated with poly-γ-glutamic acid (PGA) were developed to improve the oral absorption of indomethacin (IM), a poorly water-soluble drug. Microparticles containing γ-IM (IMbulk-PGA) or crystal polymorph α-IM (IMpolymorph-PGA) were prepared. Additionally, microparticles were prepared containing α-IM without PGA (IMpolymorph without PGA). IMbulk-PGA and IMpolymorph-PGA exhibited better drug retention properties on mucin disks. Drug release rates from IMpolymorph-PGA and IMpolymorph without PGA were higher than from IM bulk powder, and drug release from IMbulk-PGA was also improved. Drug release from IMbulk-PGA could be improved with the use of Tween 80. In addition, PGA may influence the ionization of IM or affect specific molecular interactions. After the microparticles were administered orally to mice, IMbulk-PGA and IMpolymorph-PGA increased the plasma drug concentration more rapidly compared with IM bulk powder, but IMpolymorph without PGA did not increase the plasma drug concentration. It was considered that IMbulk-PGA and IMpolymorph-PGA rapidly reached the intestinal membrane through the mucus layer and IM was absorbed quickly. Because IMbulk-PGA and IMpolymorph-PGA showed a rapid increase in plasma drug concentration, IMbulk-PGA and IMpolymorph-PGA could be useful preparations to improve the gastrointestinal absorption of IM. Furthermore, IMbulk-PGA may maintain higher plasma drug concentrations than IMpolymorph-PGA.

DEVELOPMENT OF STABLE NANOSUSPENSION LOADED ORAL FILMS OF GLIMEPIRIDE WITH IMPROVED BIOAVAILABILITY

Objective: In the present work attempt has been made to stabilize optimized nanosuspensions of glimepiride by solidification using a novel Oral Thin Film (OTF) formulation.Methods: Nanosuspensions were characterized for particle size, zeta potential as well as in vitro dissolution profile. As nanosuspensions are prone to destabilization by Ostwald’s ripening or agglomeration/aggregation, OTF formulation as a novel approach for stabilization through solidification of optimized nanosuspension was attempted. OTF formulation method is a simple, easy and scalable method for the preparation of solid oral dosage form. Prepared formulations were evaluated for physicochemical parameters like folding endurance, disintegration time, tensile strength, in vitro drug release, in vivo bioavailability and stability.Results: The mean particle size of the nanoparticles in OTF was found to be 57.2 nm. It was observed from the results of in vivo bioavailability studies that high plasma drug concentrations(Cmax) were achieved for nanosuspension loaded OTF (NSOTF) i.e. 4900 ng/ml as compared to marketed oral formulation (Cmax-2900 ng/ml). Results of the stability studies indicated that nanosize of the particles was retained even after 3 mo of the study.Conclusion: Therefore it can be concluded that OTF formulation has a potential for stabilization of nanosuspensions.

Syk Inhibition Induces Platelet Dependent Peri-islet Hemorrhage in the Rat Pancreas.

Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is an important signaling enzyme downstream of immunoreceptors containing an intracellular immunoreceptor tyrosine activating motif (ITAM). These receptors encompass a wide variety of biological functions involved in autoimmune disease pathogenesis. There has been considerable interest in the development of inhibitors of the Syk pathway for the treatment of rheumatoid arthritis and systemic lupus erythematosus. We report that Syk inhibition mechanistically caused peri-islet hemorrhages and fibrin deposition in the rat pancreas and that this finding is due to a homeostatic functional defect in platelets. In more limited studies, similar lesions could not be induced in mice, dogs, and cynomolgus monkeys at similar or higher plasma drug concentrations. Irradiation-induced thrombocytopenia caused a phenotypically similar peri-islet pancreas lesion and the formation of this lesion could be prevented by platelet transfusion. In addition, Syk inhibitor-induced lesions were prevented by the coadministration of prednisone. A relatively greater sensitivity of rat platelets to Syk inhibition was supported by functional analyses demonstrating rat-specific differences in response to convulxin, a glycoprotein VI agonist that signals through Syk. These data demonstrate that the Syk pathway is critical in platelet-endothelial cell homeostasis in the peri-islet pancreatic microvasculature in rats.

Formulation, development and optimization of raloxifene-loaded chitosan nanoparticles for treatment of osteoporosis

Context: Osteoporosis (OP) is a disease of skeletal system and is associated with fragility fracture at the hip, spine and wrist. Various drugs have been used to treat OP. One of them is raloxifene hydrochloride (RLX), a second-generation selective estrogen receptor modulator (SERM) approved by the USFDA. RLX possesses only 2% absolute bioavailability (BA) by oral route due to its extensive first-pass metabolism.Objective: The purpose of the current research work was to develop and evaluate RLX-loaded chitosan nanoparticles (CS-NPs) for treatment of OP with enhanced BA.Materials and methods: The RLX-loaded CS-NPs were prepared by gelation of CS with tripolyphosphate (TPP) by ionic cross-linking. Formulation was optimized and in vitro drug release and in vivo study were performed.Results and discussions: CS-NPs were formed by the ionic gelation method. The particle size, entrapment efficiency and loading efficiency varied from 216.65 to 1890 nm, 32.84 to 97.78% and 23.89 to 62.46%, respectively. Release kinetics showed diffusion-controlled and Fickian release pattern. In vivo study indicated higher plasma drug concentration with NPs administered intranasally as compared to drug suspension administered through oral route (p < 0.05). A significantly higher drug concentration in plasma was achieved in 10 min after nasal administration with respect to oral administration.Conclusion: The results suggest that RLX-loaded CS-NPs have better BA and would be a promising approach for intranasal (i.n.) delivery of RLX for the treatment of OP.

Methylprednisolone in Neonatal Cardiac Surgery: Reduced Inflammation Without Improved Clinical Outcome

Corticosteroids are widely used in pediatric open-heart surgery to reduce systemic inflammatory response and to mediate possible cardioprotective effects. However, the optimal dosing of corticosteroids is unknown and their administration varies considerably between different institutions. Forty neonates undergoing open-heart surgery were randomized in a double-blind fashion equally into 2 groups. After the induction of anesthesia, 1 group received 30 mg/kg intravenous methylprednisolone and the other a placebo. Concentrations in plasma of interleukin 6 (IL-6), IL-8, IL-10, free methylprednisolone and total methylprednisolone were obtained for the following: (1) at anesthesia induction before the study drug was administered; (2) 30 minutes on cardiopulmonary bypass; (3) 5 minutes after protamine administration; and (4) 6 hours after weaning from cardiopulmonary bypass. Troponin T was measured at time points T1, T3, T4, and also at 6:00 on the first postoperative morning. Physiological and clinical outcome parameters were also recorded. Intravenous methylprednisolone resulted in high plasma drug concentrations that peaked at T2. Methylprednisolone significantly lowered concentrations of proinflammatory cytokines IL-6 and IL-8 and raised levels of anti-inflammatory IL-10. No significant differences in troponin T levels were detected. Blood glucose levels were significantly higher in the methylprednisolone group, and patients in this group received more often insulin therapy than controls. No significant differences were observed in other clinical or physiological outcome measurements. Intravenous 30 mg/kg methylprednisolone administered before cardiopulmonary bypass resulted in high effective plasma drug concentrations and a decreased inflammatory response. However, no cardioprotective effect or better clinical outcome was noticed.

Does chronic alcohol use by HIV-infected patients on d4T/3TC/NVP drug regimen effect the HIV viral load and what is the therapeutic window of the drugs, CD4+ count and WBC count in patients with high viral load during the 9 months period of follow up?

The study investigated the effects of chronic alcohol use on HIV viral load in HIV-infected patients on d4T/3TC/ NVP drug regimen during 9 months follow up period. It also determined plasma drug concentrations of d4T, 3TC and NVP; CD4 + and WBC counts for patients with high HIV viral load. A case-control study using repeated measures with serial measurements was used. A total of 41 patients (20 alcohol group and 21 control group) were screened for alcohol use using WHO AUDIT tool and chronic alcohol use biomarkers. Blood sampling was done at 3 month intervals for a period of 9 months. HIV viral load was determined using Roche Amplicor HIV-1 monitor test, version 1.5 (Amplicor). The d4T, 3TC and NVP concentrations were determined by Shimadzu Class-VPTM HPLC Chromatography data system version 6.1. The CD4 + cell count was determined using FACSCalibur flow cytometer. T he WBC was determined using automated hematological Coulter CBC-5 Hematology Analyzer system. Results show that % patients with HIV viral load ≥400 copies/ml in control group was highest (23.8%, n=5) at 3 month while in chronic alcohol use group, it was at 0 month (35%, n=7) for both WHO AUDIT tool and chronic alcohol-use biomarkers groups. Generally patients with high viral load ≥400 copies/ml was observed in chronic alcohol use as compared to control group in both WHO AUDIT tool and biomarkers group despite of patients having high steady state d4T, 3TC and NVP plasma drug concentrations in circulation that is available to suppress HIV virus. The high viral load could be associated with the emergence of resistance of the HIV virus and these patients generally had a low CD4 + cell count. Some of these patients had no detectable d4T plasma drug concentrations in circulation and most of them with high viral load had sub-therapeutic NVP plasma drug concentrations in their blood circulation. Chronic ethanol use by HIV-infected patients on d4T/3TC/NVP drug regimen increased HIV viral load and the patients with high viral load had sub-therapeutic NVP plasma drug concentrations and some with undetectable d4T drug concentrations in their blood circulation.

A potent preparation method combining neutralization with microfluidization for rebamipide nanosuspensions and its in vivo evaluation

Backgrounds: Rebamipide (REB) is classified as a Biopharmaceutics Classification System (BCS) Class-IV compound with poor aqueous solubility and poor permeability. The local concentration in the mucosa makes REB exhibiting the therapeutic activities, and the strategy of increasing the dissolution rate has the possibility to improve the oral gastrointestinal (GI) distribution when using REB nanosuspensions.Objective: The purpose of this work was to prepare REB nanosuspensions (REB-NSs) by combining neutralization with microfluidization to improve its dissolution rate and orally pharmacokinetic properties.Methods: The feasibility of using acid-base neutralization and microfluidization to prepare REB-NSs was studied, and the preparation was optimized by central composite design (CCD). Physical states were characterized by using some technical methods, while the plasma drug concentration and GI distribution in rodents were determined.Results: The experimental results identified a formulation with 10 mg/mL REB, 0.9% (w/v) Lutrol F127, and 0.6% (w/v) Kollidon 90F. The dissolution rate of the dried REB-NSs was faster than that of Mucosta® tablets in different media, and the pharmacokinetic study showed a slight increase (1.3-fold and 1.1-fold) in the AUC0–12 h compared with unprocessed conventional suspensions (CSs) and solutions. Also, the GI distribution of REB-NSs improved compared with REB-CSs, and this would be preferable to assist in protecting GI mucosa.Conclusion: The REB-NSs prepared by the combining method exhibited a higher plasma drug concentration and superior GI distribution, thereby demonstrating positive results for preparing nanosuspensions of local effective BCS IV drugs with pH dependence such as REB by this method.

An approach for rapid development of nasal delivery of analgesics—Identification of relevant features, in vitro screening and in vivo verification

Drug delivery via the nasal route is gaining increasing interest over the last two decades as an alternative to oral or parenteral drug administration. In the current study an approach for rapid identification of relevant features, screening and in vivo verification of potential therapeutic agents for nasal delivery was carried out using “analgesic agents” as an example. Four such drug candidates (rizatriptan, meloxicam, lornoxicam and nebivolol) were initially identified as potentially viable agents based on their therapeutic use and physicochemical characteristics. An in vitro screening was then carried out using the Calu-3 cell line model. Based on the in vitro screening results and the reported pharmacokinetic and the stability data, meloxicam was predicted to be the most promising drug candidate and was subsequently verified using an in vivo animal model. The in vivo results showed that nasal administration of meloxicam was comparable to its intravenous administration, with respect to plasma drug concentration and AUC 0–2 h . In addition, nasal absorption of meloxicam was much more rapid with higher plasma drug concentration and AUC 0–2 h than that of oral administration. The current approach appears to be capable of developing “analgesic agents” suitable for nasal delivery. Further studies are needed to prove the clinical advantage of the specific selected agent, meloxicam, by nasal administration in patients.

Pharmacological Issues of Linezolid

Linezolid is the first oxazolidinone agent introduced into clinical practice for use against Gram-positive bacteria that are resistant to beta-lactams and glycopeptides, including methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). An optimal antibacterial effect is achieved when plasma drug concentrations are above the minimum inhibitory concentration (MIC) [T>MIC] for the entire length of treatment and the ratio between the area under the plasma concentration-time curve (AUC) and the MIC (AUC/MIC) is greater than 100, as is most commonly obtained with administration of the standard dosage of linezolid 600 mg twice daily. A wide tissue distribution, including the CNS and respiratory tract, nearly linear pharmacokinetics and good tolerability are additional characteristics of linezolid. However, variability in the drug pharmacokinetics associated with clinical conditions (e.g. sepsis, burn injuries, end-stage renal disease, cystic fibrosis), haemodialysis and/or young age may lower the T>MIC and the AUC/MIC ratio, thus impairing both antibacterial activity and prevention of mutants. In most cases, changes in the dosage or in the schedule of administration (e.g. an additional [third] daily dose) may improve the effectiveness of linezolid. It is worth noting that linezolid could affect its own metabolism as a result of protein synthesis inhibition in mitochondria, and this could lead to high plasma concentrations and an increased risk of non-negligible toxicities. The latter may be reported during long-term administration of linezolid or in the presence of some pathological conditions (e.g. renal disease or kidney transplantation) associated with high plasma drug concentrations. Therefore, treatment optimization should be considered a requirement for more effective and tolerable use of the drug, particularly in special populations.

Therapeutic Drug Monitoring of Posaconazole: a Monocentric Study with 54 Adults

Posaconazole is a potent broad-spectrum triazole antifungal. Little is known about the prevalence and risk factors for low plasma posaconazole concentrations (PPCs). We retrospectively reviewed all adult patients whose PPCs were measured after at least 5 days of treatment between April 2006 and July 2008 at the Hôpital Necker Enfants Malades. A low PPC was defined as a concentration lower than 500 ng/ml. Fifty-four patients were included: 36 receiving prophylactic (200 mg three times a day) and 18 receiving curative (400 mg twice a day) posaconazole therapy. The prevalence of low PPCs was 44% (16/36) in the prophylaxis group and 22% (4/18) in the curative-treatment group. In the prophylaxis group, low PPCs tended to be more frequent in cases of digestive disease (62.5% versus 30%; P = 0.051) and were significantly more frequent among patients with diarrhea (71.4% versus 27%; P = 0.009) or mucositis (100% versus 33%; P = 0.004). In the curative-treatment group, low PPCs were significantly more frequent in cases of diarrhea (75% versus 7%; P = 0.018). In the prophylaxis group, the only two patients who subsequently developed invasive fungal infections exhibited low PPCs. The only adverse event was hepatotoxicity for 2/54 patients (3.7%), which was not related to high plasma drug concentrations. In conclusion, low PPC is common, significantly more frequent in cases of diarrhea or mucositis, and potentially associated with subsequent invasive fungal infection. Therapeutic drug monitoring of posaconazole is therefore mandatory for immunosuppressed adults, at least for those with gastrointestinal disorders.

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.

A first-in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors

3516 Background: Aberrant Hh signaling pathway activation has been implicated in a variety of cancers via both Hh ligand-independent and ligand-dependent overexpression. GDC-0449 is a first-in-human, first-in-class, potent systemic inhibitor of Hh signal transduction. Methods: Refractory solid tumor pts were enrolled in a 3+3 ph I study to evaluate safety, tolerability and pharmacokinetics/pharmacodynamics (PK/PD). GDC-0449 was administered orally as a single dose on Day 1 with a 1-week PK break, and then once daily continuously (cycle 1=35 days). Surrogate tissues were assessed for the expression of Hh downstream target gene, Gli1. Results: 19 pts were treated: 150 mg/day (n=7), 270 mg/day (n=9), and 540 mg/day (n=3); median pt age 63 yrs (range 39–84) with ECOG performance status 0–2. There have been no dose-limiting toxicities. Reversible drug-related Gr 3 hyponatremia and fatigue (1 each) were reported. One partial response (150 mg) in basal cell carcinoma (BCC) and 2 stable disease (270 mg) in BCC and adenocystic carcinoma were seen. Unexpectedly high plasma drug concentrations at the 150 and 270 mg dose levels led to the expansion of those cohorts. GDC-0449 PK properties showed a prolonged terminal half-life and drug accumulation, which resulted in surprisingly similar mean steady state plasma concentrations (30–35 μM) across dose levels. Gli1 was down modulated >2-fold in skin biopsies from 11 of 14 pts analyzed. Conclusions: The Hh antagonist GDC-0449 was evaluated at 3 dose levels and demonstrated a unique PK profile. Continuous oral dosing at 150 mg/day demonstrated safety, effective PK concentrations, PD activity, an objective response and clinical benefit, and was selected for ph II studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology

Safety, Tolerability, Pharmacokinetics, and Aβ Levels After Short-term Administration of R-flurbiprofen in Healthy Elderly Individuals

To evaluate the safety and tolerability and pharmacokinetic properties of R-flurbiprofen (Tarenflurbil) in normal elderly individuals and to determine the effect of the drug on amyloid beta 42 (Abeta42) levels, we conducted a double-blind, placebo-controlled study of 48 healthy subjects aged 55 to 80. Three successive cohorts were randomized to doses of 400, 800, or 1600 mg/d, or placebo, given as 2 divided doses for 21 days. Blood and cerebrospinal fluid were collected for pharmacokinetic studies and measurement of Abeta levels at baseline and on day 21. R-flurbiprofen was well-tolerated at all 3 doses. The compound penetrated the blood-brain barrier in a dose-dependent manner. From baseline to 21 days, comparisons between study groups revealed no significant differences in changes of cerebrospinal fluid Abeta42 levels and no significant differences in changes of plasma Abeta42 levels at the time of trough drug level at 21 days of treatment. Further analysis of drug concentration-response for plasma samples showed that at the time of peak plasma concentration, higher plasma drug concentration was related to lower Abeta42 plasma levels (P=0.016). R-flurbiprofen had an excellent safety profile and showed dose-dependent central nervous system penetration. Exploratory analyses of plasma Abeta and peak drug levels suggested a short-term effect in plasma that warrants independent verification. The safety, tolerability, and pharmacokinetic profile of R-flurbiprofen in these older individuals support the ongoing studies of this compound in patients with Alzheimer disease.