Effect of Activated Charcoal on Apixaban Pharmacokinetics in Healthy Subjects

Background

Activated charcoal is commonly used to manage overdose or accidental ingestion of medicines. This study evaluated the effect of activated charcoal on apixaban exposure in human subjects.

Methods

This was an open-label, three-treatment, three-period, randomized, crossover study of single-dose apixaban (20 mg) administered alone and with activated charcoal given at 2 or 6 h post-dose to healthy subjects. Blood samples for assay of plasma apixaban concentration were collected up to 72 h post-dose. Pharmacokinetic parameters, including peak plasma concentration (C _max), time to C _max (T _max), area under the concentration–time curve from time 0 to infinity (AUC_INF), and terminal half-life (T _½), were derived from apixaban plasma concentration–time data. A general linear mixed-effect model analysis of C _max and AUC_INF was performed to estimate the effect of activated charcoal on apixaban exposure.

Results

A total of 18 subjects were treated and completed the study. AUC_INF for apixaban without activated charcoal decreased by 50 and 28 %, respectively, when charcoal was administered at 2 and 6 h post-dose. Apixaban C _max and T _max were similar across treatments. The mean T _½ for apixaban alone (13.4 h) decreased to ~5 h when activated charcoal was administered at 2 or 6 h post-dose. Overall, apixaban was well tolerated in this healthy population, and most adverse events were consistent with the known profile of activated charcoal.

Conclusion

Administration of activated charcoal up to 6 h after apixaban reduced apixaban exposure and facilitated the elimination of apixaban. These results suggest that activated charcoal may be useful in the management of apixaban overdose or accidental ingestion.     

Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Effects of Nasal Spray Suspension Particle Size and Properties

Purpose

The objective of this study was to use a recently developed nasal dissolution, absorption, and clearance (DAC) model to evaluate the extent to which suspended drug particle size influences nasal epithelial drug absorption for a spray product.

Methods

Computational fluid dynamics (CFD) simulations of mucociliary clearance and drug dissolution were used to calculate total and microscale epithelial absorption of drug delivered with a nasal spray pump. Ranges of suspended particle sizes, drug solubilities, and partition coefficients were evaluated.

Results

Considering mometasone furoate as an example, suspended drug particle sizes in the range of 1-5 μm did not affect the total nasal epithelial uptake. However, the microscale absorption of suspended drug particles with low solubilities was affected by particle size and this controlled the extent to which the drug penetrated into the distal nasal regions.

Conclusions

The nasal-DAC model was demonstrated to be a useful tool in determining the nasal exposure of spray formulations with different drug particle sizes and solubilities. Furthermore, the model illustrated a new strategy for topical nasal drug delivery in which drug particle size is selected to increase the region of epithelial surface exposure using mucociliary clearance while minimizing the drug dose exiting the nasopharynx.

     

Speed of onset, efficacy and tolerability of zolmitriptan nasal spray in the acute treatment of migraine: a randomised, double-blind, placebo-controlled study

INTRODUCTION: Migraine is a common, disabling condition that has a significant impact on patients and relatives, and is a considerable economic burden on society. Migraine patients want fast-acting treatments with high efficacy. Previous studies have demonstrated that orally administered formulations of zolmitriptan are rapidly and highly effective in the acute treatment of migraine. The objective of this study was to assess the efficacy, speed of onset and tolerability of the nasal spray formulation of zolmitriptan in migraine treatment. METHODS: This multicentre, randomised, double-blind study recruited 2122 patients (aged 18-65 years) who had an established diagnosis of migraine (according to International Headache Society criteria), with or without aura. Patients were randomised to receive zolmitriptan 5mg nasal spray or placebo to treat up to two migraine attacks within 15 minutes of headache pain becoming moderate or severe. The primary endpoint was headache response (reduction in migraine pain from severe/moderate to mild/none) at 2 hours, 1 hour, 30 minutes and 15 minutes post-dose (analysed using a step-down approach). Secondary endpoints included headache response at 4 hours, pain-free rates at 30 minutes and 1, 2 and 4 hours, and sustained headache response and pain-free status at 24 hours post-dose. RESULTS: The headache response rate at 2 hours post-dose was 66.2% for the zolmitriptan group, compared with 35.0% for the placebo group (p < 0.001). Zolmitriptan nasal spray also produced significantly higher headache response rates than placebo at all earlier timepoints assessed, starting as early as 15 minutes post-dose (p < 0.001). Similar results were obtained for the analysis of the first attack. Significantly higher pain-free rates were obtained with zolmitriptan nasal spray, compared with placebo, from 15 minutes post-dose onward (p < 0.005). Zolmitriptan nasal spray was also significantly superior to placebo for headache response at 4 hours, sustained headache response at 24 hours and sustained pain-free rate at 24 hours.Zolmitriptan nasal spray was well tolerated, with most adverse events being of short duration and mild or moderate intensity. CONCLUSIONS: Zolmitriptan nasal spray is highly effective in the acute treatment of migraine and has a very fast onset of action, producing significant headache response and pain-free rates as early as 15 minutes post-dose (the earliest assessment in this study). In addition to the very fast onset of action, zolmitriptan nasal spray produced significantly higher sustained headache response and pain-free rates at 24 hours post-dose compared with placebo. These desirable efficacy outcomes were combined with good tolerability.     

High Resolution Visualization and Analysis of Nasal Spray Drug Delivery

Purpose

Effective nasal drug delivery of new-generation systemic drugs requires efficient devices that can achieve targeted drug delivery. It has been established that droplet size, spray plume, and droplet velocity are major contributors to drug deposition. Continual effort is needed to better understand and characterise the physical mechanisms underpinning droplet formation from nasal spray devices.

Methods

High speed laser photography combined with an in-house designed automated actuation system, and a highly precise traversing unit, measurements and images magnified in small field-of-view regions within the spray was performed.

Results

The qualitative results showed a swirling liquid sheet at the near-nozzle region as the liquid is discharged before ligaments of fluid are separated off the liquid sheet. Droplets are formed and continue to deform as they travel downstream at velocities of up to 20 m/s. Increase in actuation pressure produces more rapid atomization and discharge time where finer droplets are produced.

Conclusions

The results suggest that device designs should consider reducing droplet inertia to penetrate the nasal valve region, but find a way to deposit in the main nasal passage and not escape through to the lungs.     

Uptake and metabolism of ciclesonide and retention of desisobutyryl-ciclesonide for up to 24 hours in rabbit nasal mucosa

Background

The nasal tissue uptake and metabolism of ciclesonide, a new-generation corticosteroid under investigation for treatment of allergic rhinitis, to its active metabolite, desisobutyryl-ciclesonide (des-CIC), was evaluated when administered to rabbits in a hypotonic versus an isotonic ciclesonide suspension. Nasal mucosa extracts from normal Japanese white rabbits were evaluated by high-performance liquid chromatography with tandem mass spectrometry detection after a single 143-μg dose of ciclesonide. Retention and formation of fatty acid conjugates of des-CIC were also measured in nasal mucosa extracts postadministration of a hypotonic ciclesonide suspension (143-μg single dose).

Results

Versus an isotonic suspension, the hypotonic suspension achieved higher concentrations of des-CIC (5.6-fold, 11.4-fold, and 13.4-fold; p < 0.05 for all) and ciclesonide (25.3-fold, 34.2-fold [p = not significant], and 16-fold [p < 0.05]) at 30, 120, and 240 min postadministration. Additionally, when administered via a hypotonic suspension, des-CIC was retained up to 24 h postadministration (45.46 pmol/g tissue). Highest concentration of major fatty acid ester conjugate, des-CIC-oleate, was detected in nasal mucosa at 8 h postadministration.

Conclusion

These data suggest that a hypotonic ciclesonide suspension provides higher intracellular concentrations of des-CIC up to 24 h, thereby providing a rationale for investigation of ciclesonide as a convenient once-daily nasal spray for treatment of allergic rhinitis.     

<Emphasis Type="Italic">In Vitro</Emphasis> Assessment of Spray Deposition Patterns in a Pediatric (12 Year-Old) Nasal Cavity Model

Purpose

Nasal sprays available for the treatment of cold and allergy symptoms currently use identical formulations and devices for adults as well as for children. Due to the obvious differences between the nasal airway dimensions of a child and those of an adult, the performance of nasal sprays in children was evaluated.

Methods

Deposition patterns of nasal sprays administered to children were tested using a nasal cast based on MRI images obtained from a 12 year old child’s nasal cavity. Test formulations emitting a range of spray patterns were investigated by actuating the device into the pediatric nasal cast under controlled conditions.

Results

The results showed that the nasal sprays impacted in the anterior region of the 12 year old child’s nasal cavity, and only limited spray entered the turbinate region – the effect site for most topical drugs and the primary absorptive region for systemically absorbed drugs.

Conclusion

Differences in deposition patterns following the administration of nasal sprays to adults and children may lead to differences in efficacy between these populations. Greater anterior deposition in children may result in decreased effectiveness, greater anterior dosage form loss, and the increased potential for patient non-compliance.

     

Does a Hot Drink Provide Faster Absorption of Paracetamol Than a Tablet? A Pharmacoscintigraphic Study in Healthy Male Volunteers

Purpose

To investigate the hypothesis that paracetamol is absorbed faster from a hot drink than from a standard tablet using simultaneous scintigraphic imaging and pharmacokinetic sampling.

Methods

Twenty-five healthy male volunteers received both paracetamol formulations in a randomised manner. The formulation administered in the first treatment arm was radiolabelled to allow scintigraphic monitoring. In both treatment arms, blood samples were taken for assessing paracetamol absorption.

Results

Following the hot drink, paracetamol absorption was both significantly faster and greater over the first 60 min post-dose compared with the tablet, as evidenced by the median time to reach t_0.25?μg/mL of 4.6 and 23.1 min, respectively, and AUC_0-60 of 4668.00 and 1331.17 h*ng/mL, respectively. In addition, t_max was significantly shorter for the hot drink (median time = 1.50 h) compared with the tablet (1.99 h). However, C_max was significantly greater following the tablet (9,077 ng/mL) compared with the hot drink (8,062 ng/mL). Onset of gastric emptying after the hot drink was significantly faster than after the standard tablet (7.9 versus 54.2 min), as confirmed scintigraphically.

Conclusions

Compared with a standard tablet, a hot drink provides faster absorption of paracetamol potentially due to more rapid gastric emptying.     

Influence of the Nanocomposite MgAl-HTlc on Gastric Absorption of Drugs: In Vitro and Ex Vivo Studies

Purpose

Furosemide (FURO) is a BCS class IV drug preferentially absorbed in the gastric environment. A previous study demonstrated that its intercalation into the lamellar inorganic matrix MgAl-HTlc, giving rise to MgAl-HTlc-FURO, improves its dissolution in acidic medium. As the gastric absorption of drugs can be hindered from the biological barriers mucus and gastric mucosa, the purpose of this work was to evaluate the effect of MgAl-HTlc on gastric pH, the possible modifications induced on mucus rheology and the influence on both artificial and biological membranes.

Methods

Firstly the effect of growing MgAl-HTlc concentrations on gastric pH was evaluated. Both drug flux across the mucus layer and permeability across an artificial and biological membrane (gastric mucosa) have been studied as well.

Results

The results highlighted that drug flux across gastric mucus is improved in presence of MgAl-HTlc-FURO and that MgAl-HTlc is able to modify mucus structure in a reversible manner. From permeability studies emerged that the use of a biological membrane is the most suitable for such studies and that MgAl-HTlc-FURO enhances FURO Papp.

Conclusions

Data obtained suggest that MgAl-HTlc is a suitable material able to improve the biopharmaceutical properties of class IV BCS drugs.     

<Emphasis Type="BoldItalic">In Silico</Emphasis> Absorption Analysis of Valacyclovir in Wildtype and <Emphasis Type="BoldItalic">Pept1</Emphasis> Knockout Mice Following Oral Dose Escalation

Purpose

We developed simulation and modeling methods to predict the in vivo pharmacokinetic profiles of acyclovir, following escalating oral doses of valacyclovir, in wildtype and Pept1 knockout mice. We also quantitated the contribution of specific intestinal segments in the absorption of valacyclovir in these mice.

Methods

Simulations were conducted using a mechanistic advanced compartmental absorption and transit (ACAT) model implemented in GastroPlus?. Simulations were performed for 3 h post-dose in wildtype and Pept1 knockout mice following single oral doses of 10, 25, 50 and 100 nmol/g valacyclovir, and compared to experimentally observed plasma concentration-time profiles of acyclovir.

Results

Good fits were obtained in wildtype and Pept1 knockout mice. Valacyclovir was primarily absorbed from duodenum (42%) and jejunum (24%) of wildtype mice, with reduced uptake from ileum (3%) and caecum/colon (1%), for a total of 70% absorption. In contrast, the absorption of valacyclovir in Pept1 knockout mice was slow and sustained throughout the entire intestinal tract in which duodenum (4%), jejunum (14%), ileum (10%) and caecum/colon (12%) accounted for a total of 40% absorption.

Conclusion

The ACAT model bridged the gap between in situ and in vivo experimental findings, and facilitated our understanding of the complicated intestinal absorption processes of valacyclovir.

     

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Fimasartan Following Single and Repeated Oral Administration in the Fasted and Fed States in Healthy Subjects

Background and Objectives

Fimasartan (BR-A-657) is a novel, non-peptide angiotensin II receptor antagonist with a selective type I receptor blockade effect. Two first-in-human studies investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of fimasartan.

Methods

Fasted single oral tablet doses of fimasartan 20–480mg or placebo were administered to 40 healthy male subjects (aged 19–54 years) in a double-blind, randomized, sequential-group design. Subjects receiving fimasartan 240mg also received the same treatment in the fed state after an interval of 7 days. In another study, oral tablet doses of fimasartan 120 and 360mg or placebo were given once daily for 7 days to groups of eight fasted healthy male subjects (aged 20–55 years) in a double-blind, randomized, sequential-group design. Safety and tolerability were assessed. The PK and PD of fimasartan were also evaluated and compared for the different doses.

Results

Fimasartan was safe and well tolerated, but with an increased incidence of low BP and postural dizziness for the 360mg dose after repeated administration. Fimasartan produced increases in plasma renin activity, angiotensin I and II, which were not dose dependent. Maximal increases occurred between 6 and 8 hours post-dose, lasting up to 48 hours. Fimasartan was absorbed rapidly after all doses and had a multiphasic distribution. Two peaks in the plasma concentration-time profile were observed in most subjects. Steady state was achieved after three doses, and accumulation was minimal after repeated doses for 7 days (24–30%). The effective half-life ranged from 9.84 to 13.2 hours. The systemic exposure of fimasartan was dose proportional, and no marked food effect was noted after administration of 240mg in the fed state. Urinary excretion of fimasartan was very low (1.74–2.51%), suggesting non-renal elimination.

Conclusion

Fimasartan had a good safety profile and was well tolerated after fasted single oral doses of 20–480mg, a fed single oral dose of 240mg, and fasted repeated oral doses of 120 and 360mg in healthy subjects. In addition, the PK and PD of fimasartan in this population were well characterized. Further studies are needed to evaluate the safety, efficacy, and dose-response relationship of fimasartan in patients with hypertension.     

Visualization and Quantification of Nasal and Olfactory Deposition in a Sectional Adult Nasal Airway Cast

Purpose

To compare drug deposition in the nose and olfactory region with different nasal devices and administration techniques. A Sar-Gel based colorimetry method will be developed to quantify local deposition rates.

Methods

A sectional nasal airway cast was developed based on an MRI-based nasal airway model to visualize deposition patterns and measure regional dosages. Four nasal spray pumps and four nebulizers were tested with both standard and point-release administration techniques. Delivered dosages were measured using a high-precision scale. The colorimetry correlation for deposited mass was developed via image processing in Matlab and its performance was evaluated through comparison to experimental measurements.

Results

Results show that the majority of nasal spray droplets deposited in the anterior nose while only a small fraction (less than 4.6%) reached the olfactory region. For all nebulizers considered, more droplets went beyond the nasal valve, leading to distinct deposition patterns as a function of both the nebulizer type (droplet size and initial speed) and inhalation flow rate. With the point-release administration, up to 9.0% (±1.9%) of administered drugs were delivered to the olfactory region and 15.7 (±2.4%) to the upper nose using Pari Sinus.

Conclusions

Standard nasal devices are inadequate to deliver clinically significant olfactory dosages without excess drug losses in other nasal epitheliums. The Sar-Gel based colorimetry method appears to provide a simple and practical approach to visualize and quantify regional deposition.

     

Observation unit experience for pediatric poison exposures

Background

Short-Stay Emergency Department Observation Units (OU) are an alternative to hospitalization, but data on OU care of pediatric poisoning exposures is limited. We report the experience of a pediatric OU with this population.

Methods

We retrospectively reviewed the charts of children with poison exposure admitted to a pediatric OU during a 30-month period. Data was collected pertaining to demographics, type of exposure, clinical presentation, and rate of hospitalization, and was compared to nonpoisoned OU patients.

Results

Of the 91 pediatric patients with poison exposure, 86 complete charts were available for review (94.5%). Of these patients, 49.5% were female, and 82.4% were < 6 years of age (range 1.5 months to 16.6 years). There were a total of 98 toxicants implicated, the most common of which were psychoactive drugs (25%) and cardiovascular agents (19%). At OU admission, 33 of 88 patients (38%) had altered mental status or abnormal vital signs. Only 2 of the 53 remaining patients developed abnormal vital signs within the OU. Two patients were hospitalized unexpectedly with respiratory distress due to hydrocarbon and charcoal aspiration pneumonitis, respectively; the unexpected hospitalization rate was 2.2%. Three more planned hospitalizations for endoscopy or psychiatric evaluation led to a total hospitalization rate of 5.4%. This hospitalization rate is significantly lower (RR = 0.26, 95% CI = 0.11–0.62) than the hospitalization rate from the OU for nonpoisoned patients (20.3%) during that time. Mean OU length of stay for nonadmitted poisoned patients was 14.35 hours. There were no adverse events noted as a result of OU placement.

Conclusion

Select poisoned pediatric patients appear suitable for OU management and had less frequent unexpected hospitalization from the OU than other diagnoses.     

Phosgene Exposure: A Case of Accidental Industrial Exposure

Introduction

Phosgene is a rare exposure with strong clinical implications. We report a phosgene exposure that resulted in the patient's death.

Case Report

A 58 year-old man arrived to the emergency department 1 hour after exposure to phosgene with complaints of a sore throat. Initial vital signs were blood pressure 175/118 mmHg, heart rate 98/min, respirations 12/min, and oxygen saturation of 93% on room air. Physical exam revealed few scattered rhonchi, without signs of distress. Initial arterial blood gases (ABG's) revealed pH 7.42, pCO2 43 mmHg, pO2 68 mmHg, HCO3 27 meq/L, and oxygen saturation of 93% on room air. Initial chest x-ray 2 hours after the exposure demonstrated clear lung fields. Approximately 2.5 hours after the exposure, he began complaining of dyspnea, restlessness and his oxygen saturation dropped below 90%. He received nebulized albuterol, 1 gram intravenous methylprednisolone, and 100 % oxygen via face mask. Minimal improvement was noted and he was intubated. The post intubation chest x-ray, 3.5 hours after the exposure, revealed diffuse alveolar infiltrates. Acetylcysteine, terbutaline, and IV steroids were administered without improvement. The patient died 30 hours after exposure.

Discussion

There are many misunderstandings concerning phosgene due to its rare presentation. Traditional treatment modalities are often unproven in human trials and were unsuccessful in this case.

Conclusion

This case highlights the significant toxicity that results from phosgene exposure and the challenges of the limited treatment modalities. There is concern for the use of this agent in chemical terrorism.     

Engineering of an Inhalable DDA/TDB Liposomal Adjuvant: A Quality-by-Design Approach Towards Optimization of the Spray Drying Process

Purpose

The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6′-dibehenate (TDB).

Methods

A quality by design (QbD) approach was applied to identify and link critical process parameters (CPPs) of the spray drying process to critical quality attributes (CQAs) using risk assessment and design of experiments (DoE), followed by identification of an optimal operating space (OOS). A central composite face-centered design was carried out followed by multiple linear regression analysis.

Results

Four CQAs were identified; the mass median aerodynamic diameter (MMAD), the liposome stability (size) during processing, the moisture content and the yield. Five CPPs (drying airflow, feed flow rate, feedstock concentration, atomizing airflow and outlet temperature) were identified and tested in a systematic way. The MMAD and the yield were successfully modeled. For the liposome size stability, the ratio between the size after and before spray drying was modeled successfully. The model for the residual moisture content was poor, although, the moisture content was below 3% in the entire design space. Finally, the OOS was drafted from the constructed models for the spray drying of trehalose stabilized DDA/TDB liposomes.

Conclusions

The QbD approach for the spray drying process should include a careful consideration of the quality target product profile. This approach implementing risk assessment and DoE was successfully applied to optimize the spray drying of an inhalable DDA/TDB liposomal adjuvant designed for pulmonary vaccination.

The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample

Rationale

To improve outcomes for patients undergoing extinction-based therapies (e.g., exposure therapy) for anxiety disorders such as post-traumatic stress disorder (PTSD), there has been interest in identifying pharmaceutical compounds that might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known, however, about the effects of OT treatment on conditioned fear responding and extinction in humans.

Objectives

The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction.

Methods

A double-blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal (IN) spray. Forty-five minutes after treatment, participants underwent extinction training. Twenty-four hours later, subjects were tested for extinction recall.

Results

Relative to placebo, the OT group showed increased fear-potentiated startle responding during the earliest stage of extinction training relative to placebo; however, all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later, the OT group showed significantly higher recall of extinction relative to placebo.

Conclusions

The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders.     

Preliminary studies of the pharmacokinetics and tolerability of zolmitriptan nasal spray in healthy volunteers

Two preliminary studies of the pharmacokinetics and tolerability of zolmitriptan nasal spray were conducted, each involving 12 healthy volunteers. In study 1, an initial double-blind, dose escalation phase (placebo or 2.5, 5.0, or 10 mg zolmitriptan intranasally) was followed by an open crossover phase in which all subjects received 10 mg zolmitriptan as a nasal spray, tablet, and oral solution. In study 2, subjects received, on three separate occasions, zolmitriptan 2.5 mg as an intranasal solution at pH 7.4, at pH 5.0, and as an oral tablet. In study 1, plasma concentrations of zolmitriptan and its active metabolite, 183C91, were broadly dose proportional. Plasma concentrations of zolmitriptan were detected earlier following nasal spray administration than after either tablet or oral solution. Similarly, in study 2, zolmitriptan was absorbed more rapidly following nasal spray administration with detectable plasma concentrations 5 minutes after dosing. Plasma levels were maintained at a plateau between 1 and 6 hours postdose, then decreased with a half-life of approximately 3 hours. There was no statistically significant difference for AUG or C(max) values between the two nasal spray solutions or between nasal spray and oral formulations. Other pharmacokinetic parameters for zolmitriptan were similar between the formulations. Plasma concentrations of 183C91 were higher for the first 2 hours after oral than after nasal spray administration. All formulations of zolmitriptan were well tolerated.     

Measurement of Drug Concentration in the Stomach After Intragastric Administration of Drug Solution to Healthy Volunteers: Analysis of Intragastric Fluid Dynamics and Drug Absorption

Purpose

To evaluate the time-profile of intragastric fluid volume in humans after intragastric administration of drug solution.

Methods

Eight healthy volunteers were intragastrically administered 150 mL of drug solution containing atenolol (non-absorbable marker) and salicylic acid, then, aliquots of gastric fluid (ca. 2 mL) were sampled for 2 h through the catheter. Rate constants for secretion and emptying of the fluid were obtained by fitting the time-course of atenolol concentration to the simple gastric fluid transit model. Absorption of salicylic acid from the stomach was estimated by comparing its gastric concentration with that of atenolol.

Results

Kinetic analysis of atenolol concentration in the stomach indicated a rapid emptying of the fluid with an average half-life of 4.2 min. Steady-state intragastric fluid volume in 8 volunteers was estimated as 4–133 mL with an average of 42 mL. Intragastric concentration (normalized by dose) of salicylic acid was always lower than that of atenolol, showing approximately 40% of salicylic acid was absorbed from the stomach before emptying to the intestine.

Conclusions

This study provided valuable information on intragastric fluid dynamics and gastric drug absorption in humans to establish a better in vitro-in vivo correlation in oral drug absorption.     

Evaluation of Mucosal Damage and Recovery in the Gastrointestinal Tract of Rats by a Penetration Enhancer

Purpose

To evaluate absorption barrier recovery in the gastrointestinal tract after treatment with a penetration enhancer by using a poorly absorbed marker and correlate results with morphological recovery.

Methods

Oral gavage of sodium dodecyl sulfate (SDS) was given to Wistar rats. Phenol red (PR) was given at different time points following administration of SDS. Blood samples were obtained from the jugular vein. Pharmacokinetic analysis was performed on the in vivo data using WinNonlin and MATLAB®5 software. The pharmacokinetic parameters of PR were compared to the negative control to measure functional recovery. The intestinal tissues were observed using light and transmission electron microscopy.

Results

Absorption was highest when PR was co-administered with SDS. C _max, AUC and K _a decreased and T _max and MAT increased as the recovery period (time between administration of SDS and PR) increased. The pharmacokinetic parameters approached the negative control profile in one hour after treatment with 1% SDS. Microscopy results showed recovery of paracellular and transcellular barrier at this time.

Conclusions

Absorption barrier recovery could be measured using a poorly absorbed marker. Functional recovery showed a good correlation with morphological recovery. The local effects of SDS were found to be temporary and reversible.     

Pharmacokinetic Comparison Between the Long-Term Anesthetized,Short-Term Anesthetized and Conscious Rat Models in Nasal Drug Delivery

Purpose

To investigate the pharmacokinetic differences between the common nasal delivery models.

Methods

In three different rat models [long-term anesthetized (with nasal surgery), short-term anesthetized (without nasal surgery) and conscious models], tacrine and loxapine were administered via nasal, intravenous and oral routes, and the plasma pharmacokinetics were compared among different models.

Results

Systemic exposures of both drugs and their metabolites were consistently higher in long-term anesthetized model after all routes of administration in comparison to that of conscious model. Nasal bioavailabilities in long-term anesthetized model (tacrine 83%, loxapine 97%) were much higher than that in conscious model (tacrine 10%, loxapine 46%). Further studies on tacrine and its metabolites demonstrated no significant difference in t_1/2 between short-term anesthetized and conscious models after all routes of administration; however, long-term anesthetized model showed significantly longer t_1/2. Regarding the pharmacokinetic parameters (C_max, T_max, AUC, bioavailability) of tacrine and its metabolites, short-term anesthetized model resembled closer to conscious model than long-term anesthetized model.

Conclusions

Plasma clearances of tacrine, loxapine, and their metabolites were much slower in the long-term anesthetized model of nasal delivery probably due to suppressed hepatic and renal clearances, while the short-term anesthetized model imposed less impact on tacrine pharmacokinetics and metabolism.     

The Importance of Villous Physiology and Morphology in Mechanistic Physiologically-Based Pharmacokinetic Models

Purpose

Existing PBPK models incorporating intestinal first-pass metabolism account for effect of drug permeability on accessible absorption surface area by use of “effective” permeability, P _eff , without adjusting number of enterocytes involved in absorption or proportion of intestinal CYP3A involved in metabolism. The current model expands on existing models by accounting for these factors.

Methods

The PBPK model was developed using SAAM II. Midazolam clinical data was generated at GlaxoSmithKline.

Results

The model simultaneously captures human midazolam blood concentration profile and previously reported intestinal availability, using values for CYP3A CLu _int , permeability and accessible surface area comparable to literature data. Simulations show: (1) failure to distinguish absorbing from non-absorbing enterocytes results in overestimation of intestinal metabolism of highly permeable drugs absorbed across the top portion of the villous surface only; (2) first-pass extraction of poorly permeable drugs occurs primarily in enterocytes, drugs with higher permeability are extracted by enterocytes and hepatocytes; (3) CYP3A distribution along crypt-villous axes does not significantly impact intestinal metabolism; (4) differences in permeability of perpetrator and victim drugs results in their spatial separation along the villous axis and intestinal length, diminishing drug-drug interaction magnitude.

Conclusions

The model provides a useful tool to interrogate intestinal absorption/metabolism of candidate drugs.