Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients

What is already known about this subject

• In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability.
• Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients.

What this study adds

• Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus.
• Clearance was modelled and days postoperation and corticosteroids dose were significant covariates.

Aims

The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics.

Methods

The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring.

Results

A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 ± 0.2 l h⁻¹. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 ± 0.5 days, with a maximal value of 5.6 l h⁻¹. Moreover clearance increased by approximately 1.6 fold (range 0.5–1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 ± 13 l kg⁻¹) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F.

Conclusions

The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.     

Formulation and in vitro characterization of cefpodoxime proxetil gastroretentive microballoons

Background and the purpose of the study

The objective of the present work was to improve bioavailability of cepodoxime proxetil through gastroretentive microballoon formulation.

Methods

Microballoons of cefpodoxime proxetil were formulated by solvent evaporation and diffusion method employing hydroxypropylmethyl cellulose (HPMC) and ethyl cellulose (EC) polymers and characterized for particle size, surface morphology, incorporation efficiency, floating behavior, in vitro drug release study and differential scanning calorimetry (DSC).

Results

The average particle size of formulated microballoons was in the range of 54.23±2.78–95.66±2.19µm. Incorporation efficiencies of over 83.77±0.85% were achieved for the optimized formulations. Most of formulations remained buoyant (having buoyancy percentage maximum of 81.36±1.96%) for more than 12 hrs indicating good floating behavior of microballoons. Higher values of correlation coefficients were obtained with Higuchi''s square root of time kinetic treatment heralding diffusion as predominant mechanism of drug release.

Conclusion

Inferences drawn from in vitro studies suggest that microballoons may be potential delivery system for cefpodoxime proxetil with improvement in bioavailability in comparison to conventional dosage forms.     

Pharmacokinetics of two formulations of omeprazole administered through a gastrostomy tube in patients with severe neurodevelopmental problems

AIMS

Omeprazole is often administered through a gastrostomy tube as either (i) a Multiple Unit Pellet System (MUPS®) tablet disintegrated in water (MUPS® formulation), or (ii) a suspension in 8.4% sodium bicarbonate (suspension formulation). This bioavailability study evaluates this practice in tube-fed patients with severe neurodevelopmental problems.

METHODS

Nonblinded, two-phase cross-over trial.

RESULTS

In seven of 10 patients, bioavailability was higher for the suspension formulation than for the MUPS® formulation. Median (90% confidence interval) area under the plasma concentration–time curve ratio (MUPS® over suspension) was 0.5 (0.06–2.37).

CONCLUSIONS

In this population, omeprazole MUPS® formulation has no apparent advantage over the more easily administered suspension formulation.     

Sustained-release effervescent floating matrix tablets of baclofen: development, optimization and in vitro-in vivo evaluation in healthy human volunteers

Background and the purpose of the study

Baclofen, a centrally acting skeletal muscle relaxant, is indicated in the long-term treatment of spasticity. It is difficult to formulate baclofen sustained release dosage forms because its absorption on arrival to colon (or even before) is low or nonexistent. In the present investigation efforts were made to improve the bioavailability of baclofen by increasing the residence time of the drug through sustained-release matrix tablet formulation via gastroretentive mechanism.

Methods

Tablets were prepared by wet granulation technique. The influence of gas generating and gel forming agents, amount of baclofen and total weight of tablet on physical properties, in vitro buoyancy, floating lag time, drug release, DSC, X-ray studies were investigated. The release mechanisms were explored and explained by applying zero order, first order, Higuchi and Korsmeyer equations. The selected formulations were subjected to stability study for the period of three months.

Results

For all formulations, kinetics of drug release from tablet followed Higuchi''s square root of time kinetic treatment heralding diffusion as predominant mechanism of drug release. Formulations containing 20 mg and 40 mg (F-1 and F-7) showed similar release profiles. There was no significant change in the selected formulations, when subjected to accelerated stability conditions over a period of three months. X-ray imaging in six healthy human volunteers revealed a mean gastric retention period of 5.50±0.7 hrs for the selected formulation.

Conclusion

Stable, sustained release effervescent floating matrix tablets of baclofen could be prepared by wet granulation technique.     

Dosing equation for tacrolimus using genetic variants and clinical factors

AIM

To develop a dosing equation for tacrolimus, using genetic and clinical factors from a large cohort of kidney transplant recipients. Clinical factors and six genetic variants were screened for importance towards tacrolimus clearance (CL/F).

METHODS

Clinical data, tacrolimus troughs and corresponding doses were collected from 681 kidney transplant recipients in a multicentre observational study in the USA and Canada for the first 6 months post transplant. The patients were genotyped for 2 724 single nucleotide polymorphisms using a customized Affymetrix SNP chip. Clinical factors and the most important SNPs (rs776746, rs12114000, rs3734354, rs4926, rs3135506 and rs2608555) were analysed for their influence on tacrolimus CL/F.

RESULTS

The CYP3A5*1 genotype, days post transplant, age, transplant at a steroid sparing centre and calcium channel blocker (CCB) use significantly influenced tacrolimus CL/F. The final model describing CL/F (l h⁻¹) was: 38.4 ×[(0.86, if days 6–10) or (0.71, if days 11–180)]×[(1.69, if CYP3A5*1/*3 genotype) or (2.00, if CYP3A5*1/*1 genotype)]× (0.70, if receiving a transplant at a steroid sparing centre) × ([age in years/50]^−0.4) × (0.94, if CCB is present). The dose to achieve the desired trough is then prospectively determined using the individuals CL/F estimate.

CONCLUSIONS

The CYP3A5*1 genotype and four clinical factors were important for tacrolimus CL/F. An individualized dose is easily determined from the predicted CL/F. This study is important towards individualization of dosing in the clinical setting and may increase the number of patients achieving the target concentration. This equation requires validation in an independent cohort of kidney transplant recipients.     

Preparation, characterization and in vivo evaluation of bergenin-phospholipid complex

Aim:

To prepare a bergenin-phospholipid complex (BPC) to increase oral bioavailability of the drug.

Methods:

In order to obtain the acceptable BPC, a spherical symmetric design-response surface methodology was used for process optimization. The influence of reaction medium, temperature, drug concentration and drug-to-phospholipid ratio on the combination percentage and content of bergenin in BPC were evaluated. BPC was then characterized by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), ultra-violet (UV) spectroscopy, fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and X-ray powder diffraction. The physicochemical properties such as microscopic shape, particle size, zeta-potential, solubility, crystalline form, and hygroscopicity were tested. The pharmacokinetic characteristics and bioavailability of BPC were investigated after oral administration in rats in comparison to bergenin and the physical mixture (bergenin and phospholipids).

Results:

BPC was successfully prepared under the optimum conditions [temperature=60 °C, drug concentration=80 g/L and drug-to-phospholipids ratio=0.9 (w/w)]. The combination percentage was 100.00%±0.20%, and the content of bergenin in the complex was 45.98%±1.12%. Scanning electron microscopy and transmission electron microscopy of BPC showed spherical particles. The average particle size was 169.2±20.11 nm and the zeta-potential was -21.6±2.4 mV. The solubility of BPC in water and in n-octanol was effectively enhanced. The C_max and AUC_0→∞ of BPC were increased, and the relative bioavailability was significantly increased to 439% of bergenin.

Conclusion:

The BPC is a valuable delivery system to enhance the oral absorption of bergenin.     

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.     

Absolute bioavailability of imidafenacin after oral administration to healthy subjects

Aims

To investigate the absolute bioavailability of imidafenacin, a new muscarinic receptor antagonist, a single oral dose of 0.1 mg imidafenacin was compared with an intravenous (i.v.) infusion dose of 0.028 mg of the drug in healthy subjects.

Methods

Fourteen healthy male subjects, aged 21–45 years, received a single oral dose of 0.1 mg imidafenacin or an i.v. infusion dose of 0.028 mg imidafenacin over 15 min at two treatment sessions separated by a 1-week wash-out period. Plasma concentrations of imidafenacin and the major metabolites M-2 and imidafenacin-N-glucuronide (N-Glu) were determined. The urinary excretion of imidafenacin was also evaluated. Analytes in biological samples were measured by liquid chromatography tandem mass spectrometry.

Results

The absolute oral bioavailability of imidafenacin was 57.8% (95% confidence interval 54.1, 61.4) with a total clearance of 29.5 ± 6.3 l h⁻¹. The steady-state volume of distribution was 122 ± 28 l, suggesting that imidafenacin distributes to tissues. Renal clearance after i.v. infusion was 3.44 ± 1.08 l h⁻¹, demonstrating that renal clearance plays only a minor role in the elimination of imidafenacin. The ratio of AUC_t of both M-2 and N-Glu to that of imidafenacin was reduced after i.v. infusion from that seen after oral administration, suggesting that M-2 and N-Glu in plasma after oral administration were generated primarily due to first-pass metabolism. No serious adverse events were reported during the study.

Conclusions

The absolute mean oral bioavailability of imidafenacin was determined to be 57.8%. Imidafenacin was well tolerated following both oral administration and i.v. infusion.

What is already known about this subject

• The absolute bioavailability of imidafenacin in rats and dogs is 5.6% and 36.1%, respectively.
• The pharmacokinetic profiles of imidafenacin after oral administration have been revealed.
• Imidafenacin is primarily metabolized to metabolites by CYP3A4 and UGT1A4.

What this study adds

• The absolute bioavailability of imidafenacin in human is 57.8%.
• The pharmacokinetic profiles of imidafenacin after intravenous administration are revealed.
• The formation of metabolites in the plasma is caused mainly by first-pass effects.

     

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.     

Enhancement of oral bioavailability of the poorly water-soluble drug silybin by sodium cholate/ phospholipid-mixed micelles

Aim:

To evaluate a mixed micellar drug delivery system composed of sodium cholate and phospholipid for oral administration of silybin, a promising hepatoprotectants.

Methods:

The optimum formulation of sodium cholate/phospholipid-mixed micelles containing silybin was obtained based on the study of pseudo-ternary phase diagram. The dissolution of silybin-mixed micelles was investigated. The pharmacokinetic characteristics and bioavailability after oral administration of silybin-mixed micelles and silybin-N-methylglucamine were compared in dogs.

Results:

The mean particle size of prepared mixed micelles was 75.9±4.2 nm. The largest solubility of silybin was found to be 10.0±1.1 mg/mL in the optimum formulation of mixed micelles. The silybin-sodium cholate/phospholipid-mixed micelles showed a very slow release of silybin 17.5% (w/w) within 72 h in phosphate buffer (pH 7.4) and 15.6% (w/w) in HCl solution (pH 1.2). After oral administration to dogs, the relative bioavailability of mixed micelles versus silybin-N-methylglucamine in dogs was 252.0%.

Conclusion:

Sodium cholate/phospholipid-mixed micelles are promising carriers in orally delivery of silybin, considering their capability of enhancing bioavailability and large-scale production.     

Sublingual administration of furosemide: new application of an old drug

What is already known about this subject

• Furosemide is an effective diuretic, but its absorption may be too slow to allow oral treatment in certain patients.

What this study adds

• In healthy volunteers, sublingual administration is associated with a higher C_max, a higher bioavailability and a more accentuated initial natriuretic response than oral furosemide. Sublingual administration may offer advantages over oral administration of furosemide in certain clinical situations.

Background

In patients with decompensated heart failure, absorption of orally administered furosemide may be delayed, possibly leading to impaired pharmacodynamic effects. Sublingual administration may represent an alternative in such situations.

Methods

In a crossover study including 11 healthy men, 20 mg furosemide was administered intravenously, orally and sublingually on three different days. Pharmacokinetics and pharmacodynamics were assessed from repeated blood and urine samples.

Results

Compared with oral administration, sublingual administration was associated with 43% higher C_max[difference 215 ng ml⁻¹, 95% confidence interval (CI) 37, 392], a higher urinary recovery (8.9 vs. 7.3 mg, difference 1.6 mg, 95% CI 0.3, 2.9), an 28% higher AUC (difference 328 ng h⁻¹ ml⁻¹, 95% CI 24, 632) and a higher bioavailability of furosemide (59 vs. 47%, difference 12.0%, 95% CI −1.2, 25.2). Sodium excretion was higher after sublingual compared with oral administration (peak excretion rate 1.8 vs. 1.4 mmol min⁻¹, P < 0.05), whereas urine volume did not differ significantly between the two application modes. In comparison, intravenous administration showed the expected more rapid and intense response.

Conclusion

Sublingually administered furosemide tablets differ in certain kinetic and dynamic properties from identical tablets given orally. Sublingual administration of furosemide may offer therapeutic advantages in certain groups of patients.     

An open-label, single-dose bioavailability study of the pharmacokinetics of CAT-354 after subcutaneous and intravenous administration in healthy males

AIM

To assess the bioavailability and pharmacokinetics of CAT-354, an anti-IL-13 human monoclonal IgG4 antibody, following subcutaneous (s.c.) and intravenous (i.v.) administration.

METHODS

This was a single-dose, randomized, open-label, parallel-group bioavailability study. Healthy male subjects aged 20–54 years were randomly assigned to one of three dose groups (n= 10/group) to receive CAT-354: 150 mg i.v.; 150 mg s.c. or 300 mg s.c. (two 150 mg injections). Serum pharmacokinetics, adverse events (AEs), vital signs, electrocardiograms and laboratory parameters were assessed.

RESULTS

CAT-354 showed bioavailability of 62% and 60% after 150 mg and 300 mg s.c. doses, respectively, and linear pharmacokinetics over the dose range tested. Peak serum concentrations in the s.c. groups occurred after 3–9 (median 5) days, with a mean elimination half-life of 19.2 ± 3.1 days (150 mg) and 19.4 ± 3.59 days (300 mg) after s.c. and 21.4 ± 2.46 days after i.v. administration. Volume of distribution at steady state (V_ss) was 4960 ± 1440 ml kg⁻¹ after i.v. (slightly greater than plasma volume). Average apparent clearances (CL/F) were 292 ± 82.3 and 307 ± 109 ml day⁻¹ after 150 and 300 mg s.c., respectively; systemic CL of 188 ± 84.0 ml day⁻¹ after i.v. dosing was consistent with endogenous IgG and reticuloendothelial elimination. No severe or serious AEs occurred. Among 40 reported AEs, 25 were headache, sinus disorders/respiratory symptoms and changes in body temperature perception.

CONCLUSIONS

CAT-354 exhibited bioavailability of approximately 60% when given s.c. to healthy male subjects.     

Relative bioavailability of terbutaline to the lung following inhalation, using urinary excretion

AIMS

The aim of the study was to determine the relative lung and systemic bioavailability of terbutaline.

METHODS

On separate days healthy volunteers received 500 µg terbutaline study doses either inhaled from a metered dose inhaler or swallowed as a solution with and without oral charcoal. Urine samples were provided at timed intervals post dosing.

RESULTS

Mean (SD) urinary terbutaline 0.5 h post inhalation, in 12 volunteers, with (IC) and without (I) oral charcoal and oral (O) dosing was 7.4 (2.2), 6.5 (2.1) and 0.2 (0.2) µg. I and IC were similar and both significantly greater than O (P < 0.001). Urinary 24 h terbutaline post I was similar to IC + O. The method was linear and reproducible, similar to that of the urinary salbutamol method.

CONCLUSIONS

The urinary salbutamol pharmacokinetic method post inhalation applies to terbutaline. Terbutaline study doses can replace routine salbutamol during these studies when patients are studied.     

Calcineurin inhibitors acutely improve insulin sensitivity without affecting insulin secretion in healthy human volunteers

AIM

The introduction of calcineurin inhibitors (CNIs) ciclosporin (CsA) and tacrolimus (Tac) has improved the outcome of organ transplants, but complications such as new onset diabetes mellitus after transplantation (NODAT) cause impairment of survival rates. The relative contribution of each CNI to the pathogenesis and development of NODAT remains unclear. We sought to compare the impact of CsA and Tac on glucose metabolism in human subjects.

METHODS

Ten healthy men underwent 5 h infusions of CsA, Tac and saline in a randomized, double-blind, crossover study. During infusion glucose metabolism was investigated using following methods: a hyperinsulinaemic-euglycemic clamp, an intravenous glucose tolerance test (i.v.GTT), glucose-stimulated insulin concentration–time series and indirect calorimetry.

RESULTS

Clamp derived insulin sensitivity was increased by 25% during CsA (P < 0.0001) and 13% during Tac administration (P = 0.047), whereas first phase and pulsatile insulin secretion were unaffected. Coinciding with the CNI induced improved insulin sensitivity, glucose oxidation rates increased, while insulin clearance rates decreased, only non-significantly. Tac singularly lowered hsCRP concentrations, otherwise no changes were observed in circulating glucagon, FFA or adiponectin concentrations. Mean blood concentrations of CNIs were 486.9 ± 23.5 µg l⁻¹ for CsA and 12.8 ± 0.5 µg l⁻¹ for Tac.

CONCLUSIONS

Acute effects of i.v. CsA, and to a lesser degree Tac infusions, in healthy volunteers include increased insulin sensitivity, without any effect on first phase or pulsatile insulin secretion.     

Safety, tolerability and pharmacokinetics of an intravenous bolus of sildenafil in patients with pulmonary arterial hypertension

AIMS

To assess pharmacokinetics and pharmacodynamics of a 10 mg intravenous sildenafil bolus in pulmonary arterial hypertension (PAH) patients stabilized on 20 mg sildenafil orally three times daily.

METHODS

Pharmacokinetic parameters were calculated using noncompartmental analysis.

RESULTS

After an acute increase, plasma concentrations stabilized within the range reported previously for a 20 mg oral tablet. At 0.5 h, mean ± SD changes from baseline were −8.4 ± 11.7 mmHg (systolic pressure), −2.6 ± 7.3 mmHg (diastolic pressure) and −3.5 ± 10.4 beats min⁻¹ (heart rate). There was no symptomatic hypotension.

CONCLUSIONS

Although further research is warranted, a 10 mg sildenafil intravenous bolus appears to provide similar exposure, tolerability and safety to the 20 mg tablet.     

3-Iodothyronamine: a modulator of the hypothalamus-pancreas-thyroid axes in mice

BACKGROUND AND PURPOSE

Preclinical pharmacology of 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, indicates that it is a rapid modulator of rodent metabolism and behaviour. Since T1AM undergoes rapid enzymatic degradation, particularly by MAO, we hypothesized that the effects of T1AM might be altered by inhibition of MAO.

EXPERIMENTAL APPROACH

We investigated the effects of injecting T1AM (i.c.v.) on (i) feeding behaviour, hyperglycaemia and plasma levels of thyroid hormones and (ii) T1AM systemic bioavailability, in overnight fasted mice, under control conditions and after pretreatment with the MAO inhibitor clorgyline. T1AM (1.3, 6.6, 13, 20 and 26 µg·kg⁻¹) or vehicle were injected i.c.v. in fasted male mice not pretreated or pretreated i.p. with clorgyline (2.5 mg·kg⁻¹). Glycaemia was measured by a glucorefractometer, plasma triiodothyronine (fT3) by a chemiluminescent immunometric assay, c-fos activation immunohistochemically and plasma T1AM by HPLC coupled to tandem-MS.

KEY RESULTS

T1AM, 1.3 µg·kg⁻¹, produced a hypophagic effect (−24% vs. control) and reduced c-fos activation. This dose showed systemic bioavailability (0.12% of injected dose), raised plasma glucose levels and reduced peripheral insulin sensitivity (−33% vs. control) and plasma fT3 levels. These effects were not linearly related to the dose injected. Clorgyline pretreatment strongly increased the systemic bioavailability of T1AM and prevented the hyperglycaemia and reduction in fT3 induced by T1AM.

CONCLUSIONS AND IMPLICATIONS

T1AM induces central and peripheral effects including hyperglycaemia and a reduction in plasma fT3 levels in fasted mice. These effects critically depend on the concentration of T1AM or its metabolites in target organs.     

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.     

Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients

Aim:

To evaluate the pharmacokinetics of tacrolimus in Chinese stable liver transplant recipients converted from immediate release (IR) tacrolimus-based immunosuppression to modified release (MR) tacrolimus-based immunosuppression.

Methods:

Open-label, multi-center study with a one-way conversion design was conducted. Eighty-three stable liver recipients (6–24 months post-transplant) with normal renal and stable hepatic function were converted from IR tacrolimus twice-daily treatment to MR tacrolimus once-daily treatment on a 1:1 (mg: mg) total daily dose basis. Twenty-four hour pharmacokinetic studies were carried out on d 0 (pre-conversion), d 1, and d 84 (post-conversion).

Results:

The area under the blood concentration–time curve of MR tacrolimus from 0 to 24 h (AUC_0–24) on d 1 was comparable to that of IR tacrolimus on d 0, with a 90% confidence interval (CI) for MR/IR tacrolimus of 92%–97%. The AUC_0–24 value for MR tacrolimus on d 84 with the daily dose increased by 14% was approximately 17% lower than that for IR tacrolimus. The 90% CI was 77%–90%, outside the bioequivalence range of 80%–125%. There was a good correlation between AUC_0–24 and concentration at 24 h (C₂₄) for IR tacrolimus (d 0, r=0.930) and MR tacrolimus (d 1, r=0.936; d 84, r=0.903).

Conclusion:

The exposure to tacrolimus when administered MR tacrolimus once daily is not equivalent to that for IR tacrolimus twice daily after an 84-day conversion in Chinese stable liver transplant recipients. The dose should be adjusted on the basis of trough levels. The therapeutic drug monitoring for patients treated with IR tacrolimus is considered to be applicable to MR tacrolimus.     

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.