Population pharmacokinetic model and Bayesian estimator for two tacrolimus formulations--twice daily Prograf and once daily Advagraf

AIM

To investigate the differences in the pharmacokinetics of Prograf® and the prolonged release formulation Advagraf® and to develop a Bayesian estimator to estimate tacrolimus inter-dose area under the curve (AUC) in renal transplant patients receiving either Prograf® or Advagraf®.

METHODS

Tacrolimus concentration–time profiles were collected, in adult renal transplant recipients, at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation from 32 Prograf® treated patients, and one profile was collected from 41 Advagraf® patients more than 12 months post-transplantation. Population pharmacokinetic (popPK) parameters were estimated using nonmem®. In a second step, the popPK model was used to develop a single Bayesian estimator for the two tacrolimus formulations.

RESULTS

A two-compartment model with Erlang absorption (n= 3) and first-order elimination best described the data. In Advagraf® patients, a bimodal distribution was observed for the absorption rate constant (K_tr): one group with a K_tr similar to that of Prograf® treated patients and the other group with a slower absorption. A mixture model for K_tr was tested to describe this bimodal distribution. However, the data were best described by the nonmixture model including covariates (cytochrome P450 3A5, haematocrit and drug formulation). Using this model and tacrolimus concentrations measured at 0, 1 and 3 h post-dose, the Bayesian estimator could estimate tacrolimus AUC accurately (bias = 0.1%) and with good precision (8.6%).

CONCLUSIONS

The single Bayesian estimator developed yields good predictive performance for estimation of individual tacrolimus inter-dose AUC in Prograf® and Advagraf® treated patients and is suitable for clinical practice.     

Inhaler Competence and Patient Satisfaction with Easyhaler?: Results of Two Real-Life Multicentre Studies in Asthma and COPD

Objective

The aim of this study was to investigate patients’ inhaler competence and satisfaction with the Easyhaler^® dry powder inhaler.

Design

Two open, uncontrolled, non-randomised studies.

Setting

Real life based on patients attending 56 respiratory clinics in Hungary.

Participants

Patients with asthma or chronic obstructive pulmonary disease (COPD) (n = 1016).

Intervention

In a 3-month study, adult patients (age range 18–88 years; n = 797) received twice-daily inhalations of formoterol via Easyhaler^®, and in a consequential study (from one visit to another, with 3–12 months in-between) children and adolescents (age range 4–17 years; n = 219) received salbutamol via Easyhaler^® as needed.

Main Outcome Measures

Control of six Easyhaler^® handling steps and patients’ satisfaction with Easyhaler^® based on questionnaires.

Results

Correct performances (minimum and maximum of the six steps) were noticed after one demonstration in 92–98 % of the adults, 87–99 % of the elderly, 81–96 % of the children and 83–99 % of the adolescents. These figures had markedly increased at the last visit. Repeat instructions were necessary in 26 % of the cases. Investigators found Easyhaler^® easy to teach in 87 % of the patients and difficult in only 0.5 %. Patients found Easyhaler^® easy to learn and use, and the patients’ (and parents’) satisfaction with the inhaler was very high. Lung function values [forced expiratory volume in 1 s (FEV₁), forced vital capacity (FVC), peak expiratory flow (PEF)] improved statistically significantly during the studies, indicating good inhaler competence and treatment adherence.

Conclusion

Investigators found Easyhaler^® easy to teach and patients found it easy to use, and their satisfaction with the device was high.     

Bioequivalence of Eslicarbazepine Acetate from Two Different Sources of its Active Product Ingredient in Healthy Subjects

Purpose

To compare the bioavailability (BA) and pharmacokinetic (PK) properties and to demonstrate the bioequivalence (BE) between two active product ingredient (API) sources of eslicarbazepine acetate (ESL) in healthy volunteers.

Design, subjects and methods

Forty healthy male and female subjects aged 18–40 years were randomized to treatment with 400 or 800 mg ESL marketed (MF) formulation [current active pharmaceutical ingredient (API) source] and 400 or 800 mg ESL to-be-marketed (TBM) formulation (new API source) under a gender-balanced, two-period, two-sequence crossover open-label study design. Subjects were assigned to receive either 400 or 800 mg ESL dose strengths, and each was randomly administered on two occasions—either a single oral tablet of MF or a single oral tablet of TBM—separated by a washout period of at least 7 days. Formulations were to be considered bioequivalent if, for both 400 or 800 mg ESL dosage strengths, the test (TBM)/reference (MF) geometric mean ratios (GMR) and 90 % confidence intervals (90 % CI) of the area under the plasma concentration-time curve (AUC) and peak plasma concentration (C_max) were within the predetermined range of 80–125 %.

Results

Test/reference GMR (90 % CI) for the C_max and AUC was respectively 100 % (94–109 %) and 96 % (94–98 %) following 400 mg ESL and 100 % (95–105 %) and 100 % (97–103 %) following 800 mg ESL.

Conclusion

Oral tablet formulations of either 400 or 800 mg ESL from the new API source were found to be bioequivalent to the corresponding marketed Zebinix^® formulation according to the regulatory definition of bioequivalence.     

Evaluation of clinical activity and safety of Daflon 500 mg in type 2 diabetic female patients

Background

The incidence of cardiovascular disease in patients with type 2 diabetes mellitus is approximately twice as high as in the non-diabetic population.

Aim

To investigate the hypoglycemic and hypocholesterolemic effects of Daflon^® 500 mg (DF) administration together with its tolerability and efficacy in reducing the cardiovascular metabolic risk factors in female patients with type 2 diabetes.

Methods

In a well-adequate controlled single-blinded randomized parallel design the tolerability and the efficacy of Daflon^® (500 mg) either alone or with oral hypoglycemic, twice daily for 45 days, was studied in 36 female patients with type 2 diabetes.

Results

None of the patients in the studied groups were reported to have any adverse events throughout the treatment period (45 days), liver and kidney function tests were within normal limits and there was no significant difference between the pre-treatment (day 0) and post-treatment (day 45) values. Female patients receiving Daflon^® either alone or with oral hypoglycemic showed significant decrease in serum glucose; fructosamine; total cholesterol; LDL–cholesterol; triglycerides; malondialdehydes (as index of lipid peroxidation) and C-reactive protein (CRB) levels along with increase in the levels of nitric oxide and blood glutathione.

Conclusion

This study has shown that Daflon^® (500 mg, twice daily for 45 days) is helpful in reducing glucose level and the risk of cardiovascular disease in type 2 diabetic patients.

Recommendation

Further clinical trials are essential for strengthening the evidence base on the role of this drug in the cardiovascular risk in diabetic patients.     

Pharmacokinetics of Coadministration of Guanfacine Extended Release and Methylphenidate Extended Release

Background

α₂-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not sufficiently reduce symptoms. However, data on the pharmacokinetic profiles and safety of combination treatments in ADHD are needed.

Objective

The primary objective of this study was to evaluate the pharmacokinetic profiles of guanfacine extended release (GXR) and methylphenidate hydrochloride (MPH) extended release, alone and in combination.

Study Design

This was an open-label, randomized, three-period crossover, drug–drug interaction study.

Setting

The study was conducted at a single clinical research center.

Participants

Thirty-eight healthy adults were randomized in this study.

Interventions

Subjects were administered single oral doses of GXR (Intuniv^®; Shire Development LLC, Wayne, PA, USA) 4 mg, MPH (Concerta^®; McNeil Pediatrics, Titusville, NJ, USA) 36 mg, or GXR and MPH combined.

Main Outcome Measures

Guanfacine, dexmethylphenidate (d-MPH), and l-methylphenidate (l-MPH) levels were measured with blood samples collected predose and up to 72 h postdose. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms (ECGs).

Results

Thirty-five subjects completed the study. Analyses of the 90 % confidence intervals (CIs) for the geometric mean ratios of the maximum plasma concentration (C_max) and area under the concentration–time curve extrapolated to infinity (AUC_∞) values for guanfacine and d-MPH following administration of GXR or MPH alone or combined met strict bioequivalence criteria (90 % CIs within the interval of 0.80–1.25). Overall, combining GXR and MPH did not alter the pharmacokinetic parameters of either medication. Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache and dizziness following GXR, MPH, and GXR and MPH combined. Two subjects had clinically significant abnormalities in ECG results following coadministration: both events were mild and resolved the same day.

Conclusions

In this short-term, open-label study of healthy adults, coadministration of GXR and MPH did not result in significant pharmacokinetic drug–drug interactions. No unique TEAEs were observed with coadministration of GXR and MPH compared with either treatment alone.     

Novel Δ(9) -tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects

AIMS

Among the main disadvantages of currently available Δ⁹-tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®.

METHODS

This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed.

RESULTS

Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t_1/2 was 72–80 min, t_max was 39–56 min and C_max 2.92–4.69 ng ml⁻¹. THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (−2.7 mm, 95% CI −4.5, −0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min^–1, 95% CI 2.7, 6.5). Namisol® was well tolerated.

CONCLUSIONS

Oral Namisol® showed promising PK and PD characteristics. Variability and t_max of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.     

Acute passive cigarette smoke exposure and inhaled human insulin (Exubera) pharmacokinetics

AIMS

Relative to nonsmokers, the bioavailability of inhaled human insulin (Exubera®; EXU) is markedly increased in chronic smokers. The pharmacokinetics of EXU following passive cigarette smoke exposure is unknown.

METHODS

In an open-label, crossover study, healthy nonsmoking volunteers received two treatments in randomized sequence separated by a 2-week wash-out: (i) EXU 3 mg with no passive smoke exposure and (ii) EXU 3 mg after passive smoke exposure (atmospheric nicotine levels 75–125 μg m⁻³) for 2 h. Blood samples were obtained at prespecified times up to 6 h after EXU administration.

RESULTS

Twenty-seven subjects completed both study periods. Mean plasma insulin AUC₀₋₃₆₀ decreased by 17% [ratio 83%, 95% confidence interval (CI) 68.8, 99.5] and mean C_max by 29% (ratio 71%, 95% CI 59.8, 83.1) after passive cigarette smoke exposure. The median (range) t_max was 60 min (20–120 min) and 75 min (20–360 min) in the EXU with no exposure and EXU passive exposure groups, respectively. EXU was well tolerated.

CONCLUSIONS

Unlike active chronic smoking, acute passive cigarette smoke exposure modestly decreases EXU bioavailability and thus should not increase hypoglycaemia risk. These results are consistent with those from published literature involving technetium-labelled diethylenetriamine penta-acetic acid and suggest that passive cigarette smoke exposure causes an acute decrease in lung permeability vs. active smoking, which causes an increase in permeability.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Active cigarette smoking is associated with increased permeability of the pulmonary alveolar epithelium, resulting in faster absorption of inhaled drugs such as Exubera® (EXU). Absorption of EXU is increased approximately twice to four times as much in chronic smokers compared with nonsmokers.
• The rate of clearance of radioaerosols such as technetium-labelled diethylenetriamine penta-acetic acid is decreased in response to passive smoke exposure.

WHAT THIS STUDY ADDS

• Passive smoke exposure causes a decrease in lung permeability, an effect opposite to that of active smoking.
• Acute passive smoke exposure results in a decrease in EXU bioavailability and does not create a risk of hypoglycaemia.
• These results are consistent with previous studies of radioaerosol lung clearance.

     

An In Vitro Analysis of Disintegration Times of Different Formulations of Olanzapine Orodispersible Tablet: A Preliminary Report

Background

Orodispersible tablets (ODTs) are tablet or wafer forms of medication that disintegrate in the mouth, aided only by saliva. ODTs rely on different fast dissolve/disintegration manufacturing technologies.

Objectives

Disintegration time differences for several olanzapine ODT forms were investigated. Risperdal M-Tab^® was included as a non-olanzapine ODT comparator.

Research Design and Methods

Eleven olanzapine ODT examples and orodispersible risperidone strengths were evaluated in vitro for formulation composition, manufacturing method, disintegration and dissolution characteristics, and formulation differences in comparison with freeze dried Zydis^® ODT. Automated dissolution test equipment captured ODT dissolution rates by measuring real-time release of active ingredient. A high-speed video camera was used to capture tablet disintegration times in warm simulated saliva.

Main Outcome Measure

The main outcome measure was the disintegration and dissolution characteristics of the ODT formulations.

Results

The ODT manufacturing method was associated with time to disintegrate; the fastest were freeze dried tablets, followed by soft compressed tablets and then hard/dense tablets. Olanzapine Zydis^® was the only ODT that completely disintegrated in less than 4 s for all strengths (5, 10, 15, and 20 mg), followed by 5-mg Prolanz FAST^® (12 s) and then risperidone ODT 4 mg (40 s). Reasons for slow dissolution of the olanzapine generics may include low product potency, excipient binding, excipient solubility, active ingredient particle size and incomplete disintegration.

Conclusions

Differences in the formulation and manufacturing process of olanzapine ODTs appear to have a strong influence on the disintegration time of the active compound; differences that may potentially impact their use in clinical practice.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-013-0030-8) contains supplementary material, which is available to authorized users.     

A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects

AIMS

To evaluate the relative plasma and tissue availability of diclofenac after repeated topical administration of a novel diclofenac acid-based delivery system under development (DCF100C).

METHODS

This was a single-centre, open-label, three-period, crossover clinical trial of five discrete diclofenac formulations. Test preparations comprised two concentrations (1.0% and 2.5%) of DCF100C, with and without menthol and eucalyptus oil (total daily doses of 5 mg and 12.5 mg). Voltaren® Emulgel® gel (1.0%) was the commercially available comparator (total daily dose of 40 mg). Topical application was performed onto the thigh of 20 male healthy subjects for 3 days. Applying a Youden square design, each drug was evaluated in 12 subjects, with each subject receiving three test preparations. Blood sampling and in vivo microdialysis in subcutaneous adipose and skeletal muscle tissues were performed for 10 h after additional final doses on the morning of day 4.

RESULTS

All four DCF100C formulations demonstrated a three- to fivefold, dose-dependent increase in systemic diclofenac availability compared with Voltaren® Emulgel® and were approximately 30–40 times more effective at facilitating diclofenac penetration through the skin, taking different dose levels into account. Tissue concentrations were low and highly variable. The 2.5% DCF100C formulation without sensory excipients reached the highest tissue concentrations. AUC(0,10 h) was 2.71 times greater than for Voltaren® Emulgel® (90% CI 99.27, 737.46%). Mild erythema at the application site was the most frequent adverse event associated with DCF100C. There were no local symptoms after treatment with the reference formulation.

CONCLUSION

DCF100C formulations were safe and facilitated greater diclofenac penetration through the skin compared with the commercial comparator. DCF100C represents a promising alternative to oral and topical diclofenac treatments that warrants further development.     

Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies

Aim

This study evaluated the influence of rivaroxaban 20 mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin.

Methods

We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus® and Innovin® reagents. To simulate the combined effects of rivaroxaban and warfarin on INR during switching, warfarin initiation was simulated by adjusting the magnitude of the warfarin effect to reach the desired target INRs over the course of 21 days. The warfarin effect values (obtained every 6 h) and the desired rivaroxaban plasma concentrations were used. Nomograms were generated from rivaroxaban induced increases in INR.

Results

The simulation had good prediction quality. Rivaroxaban induced increases in the total INR from the warfarin attributed INR were seen, which increased with rivaroxaban plasma concentration. When the warfarin only INR was 2.0–3.0, the INR contribution of rivaroxaban with Neoplastin Plus® was 0.5–1.2, decreasing to 0.3–0.6 with Innovin® at median trough rivaroxaban plasma concentrations (38 μg l⁻¹).

Conclusions

The data indicate that measuring warfarin induced changes in INR are best performed at trough rivaroxaban concentrations (24 h after rivaroxaban dosing) during the co-administration period when switching from rivaroxaban to warfarin. Furthermore, Innovin® is preferable to Neoplastin Plus® because of its substantially lower sensitivity to rivaroxaban, thereby reducing the influence of rivaroxaban on the measured INR.     

Bioavailability and disposition of azelastine and fluticasone propionate when delivered by MP29-02, a novel aqueous nasal spray

AIM(S)

To determine azelastine hydrochloride (AZE) and fluticasone propionate (FP) bioavailabilities of the novel nasal spray combination product MP 29-02, compared with MP29-02-based products containing only AZE (MP29-02-AZE-mono), FP (MP29-02-FP-mono), marketed AZE and FP single entity products (Astelin® and FP Boehringer-Ingelheim; FP-BI).

METHODS

Two randomized, three period, six sequence, three treatment crossover studies were conducted in healthy subjects. Study 1 administered 200 µg FP as MP29-02, MP29-02-FP-mono or FP-BI. Study 2 administered 548 µg AZE as MP29-02, MP29-02-AZE-mono or Astelin®. Each dose consisted of two sprays/nostril. Serum FP and plasma AZE were followed over 24 (FP) and 120 h (AZE) and quantified by LC-MS/MS. Peak (C_max) and total exposures AUC(0,t_last) were compared between the treatments by anova.

RESULTS

Study 1: Average FP C_max was very low with all products (≤10 pg ml⁻¹). FP AUC(0,t_last) point estimates (90% CIs) for MP29-02 : MP29-02-FP-mono and MP29-02 : FP-BI ratios (%) were 93.6 (83.6, 104.7) and 161.1 (137.1, 189.3). Corresponding ratios for C_max were 91.0 (82.5, 100.4) and 157.4 (132.5, 187.1). Study 2: AZE AUC(0,t_last) point estimates (90% CIs) for MP29-02 : MP29-02-AZE-mono and MP29-02 : Astelin® ratios (%) were 98.8 (91.0, 107.4) and 105.5 (95.6, 116.4). Corresponding outcomes for C_max were 102.7 (92.1, 114.4) and 107.3 (92.6, 124.3).

CONCLUSIONS

No interactions of AZE and FP were found with the MP29-02 formulation. Azelastine bioavailability was similar for MP29-02 and Astelin®. Maximum and total FP exposure was higher for MP29-02-based products compared with FP-BI. FP concentrations were generally very low with all investigational products and did not suggest clinically meaningful differences concerning systemic safety.     

Influence of food intake on the bioavailability and efficacy of oral calcitonin

AIMS

To investigate the influence of food intake on the bioavailability and pharmacodynamic effects of salmon calcitonin (sCT).

METHODS

A single-blind, randomized, partly placebo-controlled study was conducted in 36 healthy postmenopausal female volunteers aged 62–74 years. The influence of food intake on oral dosing with 0.8 mg of sCT at 22.00 h was evaluated for a (i) predose meal at 18.00 h, (ii) predose meal at 20.00 h, (iii) predose meal at 21.00 h, (iv) postdose meal at 22.10 h, (v) no meal, and (vi) meal at 20.00 h and placebo at 22.00 h. Study biomarkers were plasma sCT levels and changes in the bone resorption marker CTX-I (C-terminal telopeptide of collagen type I).

RESULTS

The predose meal at 18.00 and 21.00 h significantly decreased relative oral bioavailability of sCT to 26% [95% confidence interval (CI) 0.09, 0.73 and 0.09, 0.75, P= 0.009 and P= 0.01]. The meal consumed 10 min after dosing decreased the oral bioavailability of sCT to 59% (95% CI 0.21, 1.68), although nonsignificant (P= 0.48). This decreased bioavailability led to lower relative suppression of serum CTX-I, with an AUC of the 4-h efficacy response of −91%–×–hours for those receiving a meal at 18.00 h, compared with −238%–×–hours for fasting subjects. The Dunnett-adjusted difference between these two treatment sequences was 147%–×–hours (95% CI 68, 225) (P= 0.0003). The AUC was comparable among fasting subjects and those consuming a meal 10 min after dosing.

CONCLUSIONS

Postprandial dosing may limit the bioavailability of orally administered sCT. Maximal benefit can be achieved by dosing at least 10 min prior to meal time.     

Pharmacokinetics of Coadministered Guanfacine Extended Release and Lisdexamfetamine Dimesylate

Background

In clinical practice, α₂-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv^®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug–drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse^®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated.

Objective

The primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination.

Study Design

This was an open-label, randomized, three-period crossover, DDI study.

Setting

The study was conducted in a single clinical research center.

Participants

Forty-two healthy adults were randomized in this study.

Interventions

Subjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination.

Main Outcome Measures

Blood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90 % confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration–time curve extrapolated to infinity (AUC_0–∞) and maximum plasma concentration (C_max) falling within the bioequivalence reference interval (0.80–1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs).

Results

Forty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC_0–∞ and C_max of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90 % CI of the geometric mean ratio of AUC_∞ for the two treatments was within the bioequivalence criteria, but for C_max the upper bound of the 90 % CI exceeded the standard range for bioequivalence by 7 %. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9 % of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3 %) and headache (7.5, 4.9, and 7.3 %) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX.

Conclusions

In healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.     

Biocomparison of Three Formulations of the S1P1 Receptor Modulator Ponesimod in Healthy Subjects

Background

Ponesimod is a potent selective sphingosine-1-phosphate receptor 1 (S1P₁) modulator, which leads to a reduction in circulating lymphocytes, reflecting their sequestration within lymphoid organs. Modulation of the S1P₁ receptor has been previously described to be an effective treatment of autoimmune diseases (e.g., multiple sclerosis).

Objectives

The aim of this study was to compare the relative bioavailability of two polymorphic forms of ponesimod in capsules (Form A versus Form C; Study 1) and the relative bioavailability of a capsule formulation and a tablet formulation (both polymorphic Form C; Study 2).

Methods

Two open-label, randomized, two-way crossover studies in healthy subjects were performed. In Study 1, 12 male subjects received a single dose of 20 mg of polymorphic Form A or Form C of ponesimod in a capsule. In Study 2, 14 male and female subjects (ratio 1:1) received a single dose of 40 mg of polymorphic Form C of ponesimod in either a capsule or a tablet formulation. Pharmacokinetic and safety variables (clinical laboratory test results, vital signs, and an electrocardiogram) were assessed.

Results

Comparison of the exposure to ponesimod following administration of the formulations in Study 1 showed that the 90 % confidence intervals of the geometric mean ratios for the area under the curve from time zero to infinity (AUC_0–inf), the area under the curve from time zero to the time of the last measurable concentration (AUC_0–t), the terminal half-life (t_½), and the maximum plasma concentration (C_max) were all within the 0.80–1.25 bioequivalence interval. In Study 2, more rapid absorption of ponesimod was observed from the tablet formulation than from the capsule formulation. There were no relevant differences in the safety and tolerability profiles between the different formulations.

Conclusion

The two polymorphic forms of ponesimod and tablet versus capsule formulations were similar in terms of pharmacokinetics, safety, and tolerability.     

The Safety of Besifloxacin Ophthalmic Suspension 0.6?% Used Three Times Daily for 7?Days in the Treatment of Bacterial Conjunctivitis

Background

Besifloxacin ophthalmic suspension 0.6 % (Besivance^®; Bausch & Lomb, Rochester, NY, USA) was approved by the FDA in 2009 for the treatment of bacterial conjunctivitis, with a recommended 7-day dosing regimen.

Objective

The objective of this study was to compare the safety of besifloxacin ophthalmic suspension 0.6 %, administered three times a day for 7 days, with that of its vehicle.

Methods

This randomized, multicenter, double-masked, vehicle-controlled, parallel-group study involved 518 patients ≥1 year of age with a clinical diagnosis of bacterial conjunctivitis. Patients were randomized 2:1 to treatment with besifloxacin 0.6 % ophthalmic suspension or vehicle, one drop in the infected eye(s) TID for 7 days. Main outcomes included the incidence and types of adverse events reported by the subject or observed by the investigator at each study visit.

Results

Thirty-one ocular treatment-emergent adverse events (TEAEs) were reported by 28 subjects in the study eye; 19 occurred in 17/344 (4.9 %) besifloxacin patients, and 12 occurred in 11/170 (6.5 %) vehicle patients (p = 0.5362). Only two ocular events (mild instillation site reaction, one case in each group) were considered “definitely related” to study treatment. One event of self-limited dysgeusia in the besifloxacin group was considered definitely related to treatment; there were no other nonocular TEAEs considered related to treatment. There were no serious adverse events, and other safety outcomes (visual acuity, biomicroscopy, ophthalmoscopy) were unremarkable.

Conclusion

These findings indicate that besifloxacin ophthalmic suspension 0.6 % is safe in patients aged 1 year and older when used TID for 7 days.     

Optimizing pharmacokinetic bridging studies in paediatric oncology using physiologically-based pharmacokinetic modelling: application to docetaxel

Aim

Applying physiologically-based pharmacokinetic (PBPK) modelling in paediatric cancer drug development is still challenging. We aimed to demonstrate how PBPK modelling can be applied to optimize dose and sampling times for a paediatric pharmacokinetic (PK) bridging study in oncology and to compare with the allometric scaling population PK (AS-popPK) approach, using docetaxel as an example.

Methods

A PBPK model for docetaxel was first developed for adult cancer patients using Simcyp® and subsequently used to predict its PK profiles in children by accounting for age-dependent physiological differences. Dose (mg m^–2) requirements for children aged 0–18 years were calculated to achieve targeted exposure in adults. Simulated data were then analyzed using population PK modelling with MONOLIX® in order to perform design optimization with the population Fisher information matrix (PFIM). In parallel, the AS-popPK approach was performed for the comparison.

Results

The PBPK model developed for docetaxel adequately predicted its PK profiles in both adult and paediatric cancer patients (predicted clearance and volume of distribution within 1.5 fold of observed data). The revised dose of docetaxel for a child over 1.5 years old was higher than the adult dose. Considering clinical constraints, the optimal design contained two groups of 15 patients, having three or four sampling times and had good predicted relative standard errors (RSE<30%) for almost all parameters. The AS-popPK approach performed reasonably well but could not predict for very young children.

Conclusion

This research shows the clinical utility of PBPK modelling in combination with population PK modelling and optimal design to support paediatric oncology development.     

Urinary pharmacokinetic methodology to determine the relative lung bioavailability of inhaled beclometasone dipropionate

AIM

Urinary pharmacokinetic methods have been identified to determine the relative lung and systemic bioavailability after an inhalation. We have extended this methodology to inhaled beclometasone dipropionate (BDP).

METHOD

Ethics Committee approval was obtained and all subjects gave consent. Twelve healthy volunteers received randomized doses, separated by >7 days, of 2000 µg BDP solution with (OralC) and without (Oral) 5 g oral charcoal, 10 100 µg inhalations from a Qvar® Easibreathe metered dose inhaler (pMDI) with (QvarC) and without (Qvar) oral charcoal and eight 250 µg inhalations from a Clenil® pMDI (Clenil). Subjects provided urine samples at 0, 0.5, 1, 2, 3, 5, 8, 12 and 24 h post study dose. Urinary concentrations of BDP and its metabolites, beclometasone-17-monopropionate (17-BMP) and beclometasone (BOH) were measured.

RESULTS

No BDP, 17-BMP or BOH were detected in any samples post OralC dosing. Post oral dosing no BDP was detected in all urine samples and no 17-BMP or BOH was excreted in the first 30 min. Significantly more (P < 0.001) BDP, 17-BMP and BOH were excreted in the first 30 min and the cumulative 24 h urinary excretions post Qvar and Clenil compared with Oral. The mean ratio (90% confidence interval) of the 30 min urinary excretions for Qvar compared with Clenil was 231.4 (209.6, 255.7) %.

CONCLUSION

The urinary pharmacokinetic methodology to determine the relative lung and systemic bioavailability post inhalation, using 30 min and cumulative 24 h post inhalation samples, applies to BDP. The ratio between Qvar and Clenil is consistent with related clinical and lung deposition studies.     

Proliposomes for oral delivery of dehydrosilymarin: preparation and evaluation in vitro and in vivo

Aim:

To formulate proliposomes with a polyphase dispersed system composed of soybean phospholipids, cholesterol, isopropyl myristate and sodium cholate to improve the oral bioavailability of dehydrosilymarin, an oxidized form of herbal drug silymarin.

Methods:

Dehydrosilymarin was synthesized from air oxidation of silymarin in the presence of pyridine, and proliposomes were prepared by a film dispersion-freeze drying method. Morphological characterization of proliposomes was observed using a transmission electron microscope. Particle size and encapsulation efficiency of proliposomes were measured. The in vitro release of dehydrosilymarin from suspension and proliposomes was evaluated. The oral bioavailability of dehydrosilymarin suspension and proliposomes was investigated in rabbits.

Results:

The proliposomes prepared under the optimum conditions were spherical and smooth with a mean particle size in the range of 7 to 50 nm. Encapsulation efficiency was 81.59%±0.24%. The in vitro accumulative release percent of dehydrosilymarinloaded proliposomes was stable, which was slow in pH 1.2, and increased continuously in pH 6.8, and finally reached 86.41% at 12 h. After oral administration in rabbits, the relative bioavailability of proliposomes versus suspension in rabbits was 228.85%.

Conclusion:

Proliposomes may be a useful vehicle for oral delivery of dehydrosilymarin, a drug poorly soluble in water.     

Opposite malaria and pregnancy effect on oral bioavailability of artesunate – a population pharmacokinetic evaluation

Aim

The aim was to compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7.

Methods

Non-linear mixed-effects modelling was used to compare plasma concentration–time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied 3 months after delivery when fully recovered. Non-compartmental results of the same study have been published previously.

Results

Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied 3 months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin after intravenous artesunate administration. However, malaria and pregnancy had opposite effects on the absorption of orally administered artesunate. Malaria increased the absolute oral bioavailability of artesunate by 87%, presumably by inhibiting first pass effect, whereas pregnancy decreased oral bioavailability by 23%.

Conclusions

The population pharmacokinetic analysis demonstrated opposite effects of malaria and pregnancy on the bioavailability of orally administered artesunate. Lower drug exposures during the second and third trimesters of pregnancy may contribute to lower cure rates and thus the development of drug resistance. Dose optimization studies are required for artesunate containing artemisinin-based combination therapies (ACTs) in later pregnancy.