Disposition,metabolism and mass balance of delafloxacin in healthy human volunteers following intravenous administration

Abstract

1. The pharmacokinetics and disposition of delafloxacin was investigated following a single intravenous (300?mg, 100?µCi) dose to healthy male subjects.

2. Mean C_max, AUC_0–∞, T_max and t_1/2 values for delafloxacin were 8.98?µg/mL, 21.31?µg?h/mL, 1?h and 2.35?h, respectively, after intravenous dosing.

3. Radioactivity was predominantly excreted via the kidney with 66% of the radioactive dose recovered in the urine. Approximately 29% of the radioactivity was recovered in the faeces, giving an overall mean recovery of 94% administered radioactivity.

4. The predominant circulating components were identified as delafloxacin and a direct glucuronide conjugate of delafloxacin.     

Biotransformation and mass balance of faldaprevir,a hepatitis C NS3/NS4 protease inhibitor in rats

Abstract

1.?The metabolism, pharmacokinetics, excretion and tissue distribution of a hepatitis C NS3/NS4 protease inhibitor, faldaprevir, were studied in rats following a single 2?mg/kg intravenous or 10?mg/kg oral administration of [¹⁴C]-faldaprevir.

2.?Following intravenous dosing, the terminal elimination t_1/2 of plasma radioactivity was 1.75?h (males) and 1.74?h (females). Corresponding AUC_0–∞, CL and V_ss were 1920 and 1900?ngEq?·?h/mL, 18.3 and 17.7?mL/min/kg and 2.32 and 2.12?mL/kg for males and females, respectively.

3.?After oral dosing, t_1/2 and AUC_0–∞ for plasma radioactivity were 1.67 and 1.77?h and 11?300 and 17?900 ngEq?·?h/mL for males and females, respectively.

4.?In intact rats, ≥90.17% dose was recovered in feces and only ≤1.08% dose was recovered in urine for both iv and oral doses. In bile cannulated rats, 54.95, 34.32 and 0.27% dose was recovered in feces, bile and urine, respectively.

5.?Glucuronidation plays a major role in the metabolism of faldaprevir with minimal Phase I metabolism.

6.?Radioactivity was rapidly distributed into tissues after the oral dose with peak concentrations of radioactivity in most tissues at 6?h post-dose. The highest levels of radioactivity were observed in liver, lung, kidney, small intestine and adrenal gland.     

Pharmacokinetics of the angiotensin-convertingenzym e inhibitor,benazepril, and its active metabolite,benazeprilat, in dog

1. The pharmacokinetics of the angiotensin-converting-enzyme (ACE) inhibitor benazepril were evaluated in eight healthy Beagle dogs. Benazepril was administered orally at a dosage of 7·5?mg (about 0·5?mg/kg) both as a single dose and then once daily for 14 consecutive days. The prodrug, benazepril, and its active metabolite, benazeprilat, were measured in plasma using a gas chromatography mass-spectrometry method with massselective detection. 2. Benazepril appeared quickly in the plasma (t_max 0·5?h) and was rapidly eliminated by max metabolism to benazeprilat. Peak benazeprilat concentrations were attained later (t_max 1·25?h) and declined biphasically with a rapid elimination phase (t_½λ₁ 1·1 and 1·7?h after single and the last repeated dose respectively) followed by a terminal elimination phase (t_½λ_Z 11·7 and 19·0?h after single and repeated dose respectively). The mean residence time for benazeprilat was 15·2?h after the single dose and 17·4?h after the 14th dose. 3. Repeated administration of benazepril produced moderate bioaccumulation of benazeprilat; the ratio of AUC_{[0→24 h]}'s after the 14th dose as compared with the single dose was 1·47, equivalent to a half-life for accumulation (t_½acc) of 14·6?h. Steady-state benazeprilat concentrations at peak (C_max) and trough (C_min) were reached within three doses. 4. The pharmacodynamics of benazepril were assessed by measurement of plasma ACE activity. After both single doses and at steady-state, benazepril produced inhibition of ACE activity in all dogs that was maximal at peak effect (E_max = 100%) and long-lasting max (> 85% inhibition was present at 24?h). The long duration of action of benazepril on plasma ACE is due to the presence of the terminal elimination phase of benazeprilat, even though most of the metabolite is rapidly eliminated from the plasma.     

Relative systemic availability of budesonide in patients with asthma after inhalation from two dry powder inhalers

ABSTRACT

Background: To improve dosing consistency and product features, budesonide inhalation powder delivered via a dry powder inhaler (DPI) (DPI?A^* 200?μg) was redesigned to include lactose, a newly shaped mouthpiece, and a new dose indicator (DPI?B^*). Budesonide DPI?B is available in two strengths (90?μg, 180?μg).

Objective: To compare the relative rate and extent of the systemic availability of budesonide inhaled via DPI?A and DPI?B and test for systemic absorption bio­equivalence.

Methods: Adults (n?=37) with asthma as defined by the American Thoracic Society were randomized in an open-label, crossover, single-center, single-dose study to budesonide DPI?A 200?μg × 4 inhalations, budesonide DPI?B 180?μg × 4 inhalations, or budesonide DPI?B 90?μg × 8 inhalations, on 3 days, each separated by a washout period of?≥?5 days. Plasma samples were collected immediately before and up to 12?h after dosing. Primary pharmacokinetic variables were area under the drug plasma concentration–time curve from 0 to infinity (AUC_0–∞) and maximum plasma concentration (C_max); plasma concentration at 12?h (C_12h) and time to maximum plasma concentration (T_max) were secondary variables. Treatments were considered bioequivalent if the 90% confidence intervals (CIs) for their AUC_0–∞ and C_max ratios fell between 80 and 125%. Adverse events were collected.

Results: The 90% CIs for the ratios of AUC_0–∞ and C_max for budesonide DPI?A 200?μg and DPI?B 180?μg and for both budesonide DPI?B strengths fell between 80% and 125% (AUC_0–∞: budesonide DPI?B 180?μg × 4/DPI?A 200?μg × 4: 96.3% [90 % CI: 90.9, 102.1]; budesonide DPI?B 180?μg × 4/DPI?B 90?μg × 8: 92.2% [90 % CI: 87.0, 97.7]; C_max: (budesonide DPI?B 180?μg × 4/DPI?A 200?μg × 4: 100.4% [95 % CI: 92.1, 109.4]; budesonide DPI?B 180?μg × 4/DPI?B 90?μg × 8: 94.4% [90 % CI: 86.6, 102.9]). No differences in C_12h and T_max were found between treatments. All treatments were well tolerated.

Conclusions: Budesonide DPI?A 200?μg and DPI?B 180?μg have systemic absorption bioequivalence, and DPI?B 90?μg and 180?μg are dose-strength equivalent when administered at the same dose. These results may not be generalized to all patients with asthma, as this analysis included only patients with mild-to-moderate asthma aged?≥?19 years.     

Pharmacokinetic study of methylnaltrexone after single and multiple subcutaneous administrations in healthy Chinese subjects

1. Pharmacokinetics of methylnaltrexone (MNTX) were evaluated after subcutaneous administrations (s.c.) in healthy Chinese subjects.

2. In a cross-over single dose study, 12 subjects were given 0.075, 0.15, and 0.3?mg/kg of MNTX bromide injection. In a multiple doses study, another 12 subjects subcutaneously received 0.15?mg/kg of MNTX bromide injection every 48?h, in total five administrations. The concentrations of MNTX in plasma were quantified by LC–MS/MS.

3. After single s.c. administrations of 0.075, 0.15, and 0.3?mg/kg of MNTX bromide, C_max values of MNTX were 93.5?±?28.6, 191?±?37, and 364?±?54?ng/mL, respectively, and AUC_0–∞ were 88.8?±?8.8, 181?±?16, and 357?±?34?ng?h/mL, respectively. The t_1/2 of MNTX was about 7.7?h. After multiple doses administration, the C_max, C_av, AUC_ss, and MRT_0–∞ values were 191?±?50, 3.79?±?0.40?ng/mL, 182?±?19?ng?h/mL, and 3.56?±?1.17?h, respectively.

4. Methylnaltrexone bromide displayed dose-proportional pharmacokinetics in the dose range of 0.075–0.3?mg/kg. After multiple doses administration, t_1/2 was slightly prolonged, with the cumulative factor of 1.02. This study provides a pharmacokinetic reference after a single dose and multiple doses of MNTX bromide in Chinese subjects.     

Disposition of LY333531, a selective protein kinase C β inhibitor,in the Fischer 344 rat and beagle dog

1. Studies were conducted in the Fischer 344 rat and beagle dog to determine the disposition of LY333531 and its equipotent active des-methyl metabolite, LY338522, both potent and selective inhibitors of the β-isozyme of protein kinase C. 2. Male Fischer 344 rats and female beagle dogs received a single 5-mgkg^?1 oral dose of ¹⁴C-LY333531. Urine, faeces, bile and plasma were collected and analysed for ¹⁴C, LY333531 and LY338522. 3. LY333531 was eliminated primarily in the faeces (91% by 120 h in rat, 90% by 96h in dog). Bile contributed the majority of the radioactivity excreted in the faeces in rat (66% in the cannulated bile duct study) and a variable but significant proportion in dog. 4. Pharmacokinetics following a single 5?mg kg^?1 oral dose of ¹⁴C-LY333531 to the male rat produced C_max and AUC_0-∞ for LY333531 of 14.7 ng ml^?1 and 60.8ng h ml^?1, respectively, with a half-life of 2.5 h. LY338522 and total radioactivity showed similar profiles. 5. In the female dog at the same dose, C_max and AUC_0-∞ of LY333531 were higher, producing 245 ± 94 ng ml^?1 and 1419 ± 463ng h ml^?1, respectively, with a half-life of 5.7 h. 6. The data indicate that the disposition of LY333531 is similar in rat and dog.     

Absorption,distribution and excretion of the new thienopyridine agent prasugrel in rats

Prasugrel is converted to the pharmacologically active metabolite after oral dosing in vivo. In this study, ¹⁴C-prasugrel or prasugrel was administered to rats at a dose of 5?mg?kg^–1. After oral and intravenous dosing, the values of AUC_0–∞ of total radioactivity were 36.2 and 47.1?µg?eq.?h?ml^–1, respectively. Oral dosing of unlabeled prasugrel showed the second highest AUC_0–8 of the active metabolite of six metabolites analyzed. Quantitative whole body autoradiography showed high radioactivity concentrations in tissues for absorption and excretion at 1?h after oral administration, and were low at 72?h. The excretion of radioactivity in the urine and feces were 20.2% and 78.7%, respectively, after oral dosing. Most radioactivity after oral dosing was excreted in bile (90.1%), which was reabsorbed moderately (62.4%). The results showed that orally administered prasugrel was rapidly and fully absorbed and efficiently converted to the active metabolite with no marked distribution in a particular tissue.     

Pharmacokinetic and bioequivalence study of endogenous compound tretinoin 10 mg capsules in healthy volunteers by base line correction approach

Tretinoin belongs to the class of retinoids indicated in induction of remission in acute promyelocytic leukemia (APL-FAB classification AML-M3). It is an endogenous metabolite of Vitamin A and is normally present in human plasma. The objective of the present study was to evaluate the bioequivalence between the Tretinoin 10?mg capsules of Ranbaxy Laboratories Limited and VESANOID^® 10?mg capsules of Roche Pharmaceuticals Inc. It was a 2-way cross-over single dose study in 60 adult Indian male volunteers under fasting conditions. Since tretinoin is endogenously present in the human body, for baseline adjustment four pre-dose samples were collected. Plasma samples were analyzed for tretinoin by using validated liquid chromatographic mass spectrometry (LC-MS/MS) method. This method has separated both isomeric metabolites (i.e. isotretinoin and 9-oxo retinoic acid) from tretinoin to accurately measure the tretinoin concentrations in plasma for this study. The Mean ± SD of pharmacokinetic parameters T_max, C_max, and AUC_0?t for tretinoin were 2.55?±?0.84 and 2.40?±?0.86?h, 34.29?±?10.45 and 32.77?±?9.16?ng/ml, 87.28?±?30.99 and 80.81?±?24.68?ng.h/ml, respectively, for test and reference. The ratios of least square means and its 90% confidence interval for C_max, AUC_0?t and AUC_0–∞ on both baseline corrected and uncorrected data were found to be within 80–125%.     

Pharmacokinetics and bioequivalence of two strontium ranelate formulations after single oral administration in healthy Chinese subjects

1. Pharmacokinetics of exogenous strontium (Sr) and bioequivalence of a new oral formulation of strontium ranelate compared with the brand-name drug in healthy Chinese subjects was evaluated.

2. A balanced, randomized, single-dose, two-treatment parallel study was conducted in 36 healthy Chinese subjects. Subjects were randomly allocated into two groups of 18 to receive a single oral dose of test formulation and reference formulation under a fasting state, respectively. Blood samples were collected at 19 designated time points up to 240-h post-dose. Serum concentrations of Sr were quantified by ICP-MS.

3. A total of 36 subjects were enrolled and completed the study. Nine mild adverse events in 6 subjects were reported. The C_max, AUC_0–72?h, AUC_0–t, and AUC_0–∞ of test and reference formulations shown as mean?±?SD were 6.97?±?1.78 and 6.78?±?1.80?µg/mL, 199?±?51 and 187?±?38?µg·h/mL, 303?±?89 and 278?±?54?µg·h/mL, and 337?±?109 and 305?±?60?µg·h/mL, respectively.

4. Two formulations were bioequivalent, and both were generally well tolerated.

     

Effect of age and gender on pharmacokinetics and pharmacodynamics of a single ticagrelor dose in healthy individuals

Purpose

The aim of this study was to assess age and gender effects on ticagrelor pharmacokinetics and pharmacodynamics (PK/PD).

Methods

Forty healthy individuals [18–45?years (young); ≥65?years (elderly); ten men, ten women per age group) received 200?mg ticagrelor.

Results

Ticagrelor was rapidly absorbed [time to maximum concentration (C_max) (t_max) 2.5–3.0?h], and its major active metabolite, AR-C124910XX rapidly formed (t_max 3.0–3.5?h) in all groups. Ticagrelor exposure was higher in elderly vs. the young [area under the curve from time 0 to infinity (AUC_0-∞) 52%; C_max 63% higher] and women vs. men (AUC_0-∞ 37%; C_max 52% higher). Mean terminal elimination half-life was slightly longer in women vs. men but was unaffected by age. Similar results were observed for AR-C124910XX (elderly vs. young, AUC_0-∞ 48%; C_max 61% higher), and in women vs. men (AUC_0-∞ 55%; C_max 56% higher). Across all groups, ticagrelor produced substantial final-extent inhibition of platelet aggregation (IPA): >90% at 4 and 8?h postdose. Individuals with highest ticagrelor exposure (i.e., elderly) had the lowest IPA, indicating an age-related platelet sensitivity effect. In young individuals, platelet sensitivity was greater in men vs. women. Ticagrelor tolerability was not affected by age or gender.

Conclusions

Systemic exposures to ticagrelor and AR-C124910XX were higher in elderly vs. young and in women vs. men. Age- and gender-related changes in IPA were apparent, but substantial IPA was achieved in all groups. No adjustment in ticagrelor dose should be considered necessary based on age and gender.     

Stability and bioavailability of diltiazem/polyethylene oxide matrix tablets

Abstract

The aim of this study was to prepare and evaluate in vitro and in vivo; Diltiazem-Hydrochloride (DTZ) in sustained-release matrix tablets. Stability of DTZ tablets prepared with polyethylene oxide (MWs 900?000, 4?000?000, and 8?000?000) with or without addition of electrolytes was carried-out for 1-month, under short-term storage at 40?°C/75% RH. Stability was evaluated by DTZ content, DSC and drug release using the Flow-Through Cell (USP # IV). The majority of stored tablets were stable for 1-month under short-term storage with respect to DTZ content and drug release. DSC curves of stored samples showed appearance of new exothermic peak after 1-month storage at 40?°C/75% RH, which was not observed after 5?years storage at room temperature. A selected formula was tested in vivo against reference product on eight healthy human volunteers. DTZ-plasma profiles were different between the two formulae. However, no statistically significant differences were detected between C_max, AUC_0–48 and AUC_0–∞. The two products were therapeutically in-equivalent, as 90% confidence intervals “T/R” were 88.82–205.76, 91.40–139.94, and 93.73–134.97 for C_max, AUC_0–48 and AUC_0–∞, respectively. This study highlighted possible differences observed between the two regimes frequently applied for stability testing.     

Effects of fenugreek,garden cress,and black seed on theophylline pharmacokinetics in beagle dogs

Abstract

Context: Herb–drug interactions are a serious problem especially for drugs with a narrow therapeutic index, taking into consideration that herbal medicines are commonly used in various parts of the world.

Objective: The present study investigates the effect of fenugreek, garden cress, and black seed on the pharmacokinetics of theophylline in beagle dogs.

Materials and methods: Beagle dogs received theophylline (200?mg) orally and blood samples were withdrawn at different time intervals (0.33, 0.66, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24, and 30?h). After a suitable washout period, each herb was given orally at doses of 25, 7.5, and 2.5?g, twice daily for 7 d. On the eighth day, theophylline was re-administrated orally and blood samples were collected. Plasma concentrations of theophylline were determined using HPLC and pharmacokinetic parameters were calculated using a non-compartmental analysis.

Results: Treatment with fenugreek (25?g, orally) lead to a decrease in C_max and AUC_0–t of theophylline of about 28% (p?<?0.05) and 22% (p?<?0.05), respectively, with no significant changes in T_1/2λ compared with the baseline values. Garden cress caused a decrease in C_max to a lesser extent and delayed T_max of theophylline (2.10?±?0.24?h versus 3.40?±?0.74?h), while AUC_0–∞ increased by 37.44%. No significant effect was observed for the black seed treatment on theophylline disposition as measured by C_max, T_max, AUC_0–∞, and CL/F.

Discussion and conclusion: The concurrent use of fenugreek or garden cress alters theophylline pharmacokinetic behavior in an animal model. This could represent a modulation in cytochrome P450 activity, which is responsible for theophylline metabolism in beagle dogs. Further confirmation of these results in humans will warrant changes in theophylline dosing before the co-administration of such herbs.     

Comparative in vitro and in vivo bioavailability of naproxen from tablet and caplet formulations

A 500 mg dose of naproxen in a caplet formulation (product A) or a tablet (Naprosyn 500, product B) was administered to 14 fasting healthy subjects on two separate occasions, separated by a 1–2 week washout period in an open, randomized crossover. Blood samples were drawn periodically and plasma naproxen concentrations measured by HPLC. The median time T_max to reach peak concentration for product A was shorter than that for product B (1·025 h versus 1·5 h) but A and B were similar with respect to median peak plasma concentration C_max (77·9 mg 1^?1 versus 71·4 mg 1^?1), and average area AUC_0–∞ under the plasma concentration—time curve (1210·2 mg 1^?1 h versus 1211·0 mg 1^?1 h). In vitro parameters (A versus B) of mean dissolution time MDT (5·03 min versus 15·0 min), and time for 70% dissolution T₇₀ (6·67 min versus 20·2 min), differed significantly.     

Dose proportionality of stavudine in hiv seropositive asymptomatic subjects: Application to bioequivalence assessment of various capsule formulations

The dose proportionality and bioequivalence of the capsule formulations used in clinical trials and the proposed commercial formulations of stavudine were assessed in an openlabel, single-dose, randomized four-way crossover study in 16 asymptomatic HIV-infected males. One capsule of stavudine (5, 10, 20, or 40 mg) was administered orally to each subject in each of the four treatment periods. Serial blood samples were collected for 10 h after each dose and the plasma was assayed for intact stavudine by a validated radioimmunoassay method. The plasma concentration-time data were subjected to noncompartmental pharmacokinetic analysis. For doses ranging from 5 to 40 mg, mean C_max and AUC_0-∞ values were in the range of 110.36–889.34 ng mL^?1 and 246.46–1945.97 h ng mL^?1 respectively. The mean C_max and AUC_0-∞ of stavudine increased in a dose-proportional manner. Irrespective of the dose, mean C_max values were observed at a median t_max of 0.75 h or less. Mean t_1/2 values were 1.97, 1.77, 1.67 and 1.66 h for the 5, 10, 20, and 40 mg capsules, respectively. For bioequivalence assessment, C_max and AUC_0-∞ values were normalized to the 10 mg dose since these parameters were dose proportional. The 10 mg capsule formulation used in phase-3 clinical trials was chosen as the reference. The relative bioavailability estimates and 90% confidence limits for the dose-normalized C_max values with the 10 mg capsule as the reference were 86% (76%, 96%), 99% (88%, 110%), and 90% (80%, 100%) for the 5, 20, and 40 mg capsules, respectively. The differences in the point estimates of the dose-normalized AUC_0-∞ values for the 5, 20, and 40 mg capsules relative to the 10 mg phase-3 capsule were 1% or less, and the 90% confidence limits were all within 95–106%. These results indicate that stavudine exhibits linear pharmacokinetics and that the 5, 10, 20, and 40 mg capsules of stavudine are bioequivalent.     

EEG,MAO-A inhibition,pharmacokinetics and safety of befloxatone in the elderly

Befloxatone is a new reversible and selective MAO-A inhibitor. The present study aimed to assess the pharmacodynamics (EEG profile and MAO-A inhibition using plasma levels of DHPG), pharmacokinetics and safety after a single dose of 10 mg of befloxatone compared to amitriptyline 50 mg in a randomized, double-blind, three-way crossover, placebo-controlled trial involving 12 elderly subjects. Befloxatone did not show any sedative profile on EEG as no significant changes occurred in slow delta and theta waves or in alpha waves. In contrast, befloxatone produced a non-significant decrease in delta relative power and a significant increase in the (12–40 Hz) beta waves compared to placebo and/or amitriptyline depending on the EEG lead. MAO-A inhibition by befloxatone was evidenced by a significant reduction in DHPG plasma levels (peak activity of −85 per cent and AUC_{0–24 h} of −46 per cent compared to placebo). The pharmacokinetics parameters obtained after a single 10-mg oral dose of befloxatone were: t_max, 2 h; C_max, 33·7 ng/ml; t_1/2β, 14·5 h; AUC_0–∞, 255 ng/ml for befloxatone and t_max, 2 h; C_max, 29·4 ng/ml; t_1/2β, 16 h; AUC_0–∞, 596 ng/ml for its main metabolite, O-demethyl befloxatone. These parameters are in the same range as those obtained in healthy young subjects. In conclusion, the present study demonstrated that a single oral dose of 10 mg of befloxatone is safe in the elderly, possesses potent MAO-A inhibition activity and the EEG profile of a non-sedative antidepressant and did not justify dose adjustment compared to young subjects. © 1997 John Wiley & Sons, Ltd.     

Pharmacokinetics of barnidipine hydrochloride,a new dihydropyridine calcium channel blocker,in the rat,dog and human

1. The pharmacokinetics of a new calcium antagonist barnidipine hydrochloride, a stereochemically pure enantiomer, was studied after intravenous and oral dosing to the rat and dog, and oral to man.

2. After intravenous dosing, plasma concentrations of barnidipine hydrochloride declined bi-exponentially with the terminal half-lives of 0·6?h in the rat and 4·1?h in the dog. The blood clearance was 5·21/h/kg in the rat and 3·31/h/kg in the dog, and was comparable with hepatic blood flow in both species.

3. After oral dosing, plasma concentrations of barnidipine hydrochloride peaked rapidly (0·3-0·4?h in the rat and dog, 1·0–1·6?h in man). C_max and AUC rose non-linearly with increasing doses in all three species.

4. The absolute bioavailability was low (11–18% in the rat and 6–9% in the dog), suggesting a marked first-pass metabolism.     

The effect of food on the pharmacokinetic properties and bioequivalence of two formulations of pitavastatin calcium in healthy Chinese male subjects

1.?Pitavastatin is an effective treatment for primary hyperlipidemia and mixed dyslipidemia. The aim of the present study was to investigate the effect of food on the pharmacokinetic properties and bioequivalence of the original, branded, formulation of pitavastatin calcium and a new generic formulation in healthy Chinese male subjects under fasting and fed conditions.

2.?Under fasting and fed conditions, 90% CIs of the geometric mean of generic/branded AUC_0–48?h ratios were 92.2–102.4%, 93.1–104.5%, the ratios of ln(AUC_0–∞) were 92.6–103.7%, 93.2–103.5%, and ln(C_max) ratios were 90.7–110.3%, 84.7–100.8%, respectively. The generic and branded formulations were bioequivalent in terms of rate and extent of absorption under both the conditions. The average values of AUC_0–48?h, AUC_0–∞ and C_max decreased noticeably following a high-fat breakfast. Values for AUC_0–48?h were 87.69% and 83.7%, values for AUC_0–∞ were 87.5% and 84.6%, and values for C_max were 45.0% and 50.4% in subjects given the generic and branded preparations, respectively. The absorption of pitavastatin calcium tablets was delayed following a high-fat meal, with T_max increasing by up to 2.43-fold.

3.?Both formulations were generally well tolerated, with no serious adverse reactions reported. The newly developed generic formulation may provide a reliable alternative to the branded tablets for patients with primary hyperlipidemia or mixed dyslipidemia.     

Pharmacokinetics and metabolism of [14C]-tozadenant (SYN-115), a novel A2a receptor antagonist ligand,in healthy volunteers

1.?This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of ¹⁴C-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease.

2.?Six healthy male subjects received a single oral dose of tozadenant (240?mg containing 81.47?KBq of [¹⁴C]-tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC-MS/MS and HPLC-AMS with fraction collection.

3.?At 4?h, the C_max of tozadenant was 1.74?μg/mL and AUC_(0–t) 35.0?h?μg/mL, t_1/2 15?h, Vz/F 1.82?L/kg and CL/F 1.40?mL/min/kg. For total [¹⁴C] radioactivity, the C_max was 2.29?μg?eq/mL at 5?h post-dose and AUC_(0–t) 43.9?h?μg?eq/mL. Unchanged tozadenant amounted to 93% of the radiocarbon AUC_(0–48h). At 312?h post-dose, cumulative urinary and fecal excretion of radiocarbon reached 30.5% and 55.1% of the dose, respectively. Unchanged tozadenant reached 11% in urine and 12% of the dose in feces. Tozadenant was excreted as metabolites, including di-and mono-hydroxylated metabolites, N/O dealkylated metabolites, hydrated metabolites.

4.?The only identified species circulating in plasma was unchanged tozadenant. Tozadenant was primarily excreted in urine and feces in the form of metabolites.     

Localization and disposition of a non-peptide angiotensin II type 1 receptor antagonist,and its glucuronide metabolite,in rat

1. The disposition of radioactivity of a non-peptide angiotensin II type 1 receptor antagonist (E4177) has been studied in groups of male rats after a single oral 1?mg/kg dose of ¹⁴C-E4177 was administered by gavage. We have also used light-microscopic autoradiography to investigate the localization of radioactivity in the target tissues for this angiotensin II receptor antagonist. 2. The radioactivity was absorbed quickly, and the maximum blood levels (C_max) were reached at 0·38 ± 0·14?h after dosing. The concentrations then declined bi-exponentially with a mean apparent half-life for the first phase (t_½α) of 0·46 ± 0·07?h and a terminal half life (t_½β) of 6·22 ± 1·08?h. By 24 h, the levels had decreased to 2·7 ± 1·5% C_max. The blood beta max levels radioactivity at 48?h after administration were below the limit of quantification. 3. Radioactivity was distributed throughout the body at 15?min after administration. Tissues inwhich radioactivity was present at higher levels thaninplasma were the liver and kidney. Radioactivity was rapidly eliminated from the tissues and was not retained in any individual organ. 4. The major route of excretion was via the bile. Since > 90% of the administered radioactivity was recovered by 24?h after administration, the excretion was relatively rapid. The major metabolite in bile was a glucuronide of E4177 biphenylcarboxylic acid (E4177- Glu). 5. Light-microscopic autoradiographic observations revealed a strong localization of radioactivity throughout the surface cells of the adrenal glomerulosa, the blood vessels in kidney and the surface of the aortic smooth muscle cells, which are all rich in angiotensin II type 1 (AT1) receptors.     

Effect of grapefruit juice and food on the pharmacokinetics of pirfenidone in healthy Chinese volunteers: a diet–drug interaction study

1.?Ingestion of grapefruit juice and food could be factors affecting the pharmacokinetics of pirfenidone, a promising drug for treatment of idiopathic pulmonary fibrosis.

2.?A randomized, open-label, three-period crossover study was carried out in 12 healthy Chinese male volunteers who were randomized to one of the three treatments: pirfenidone tablets (0.4?g) were orally administered to fasted or fed subjects, or with grapefruit juice. The washout period was 7 d.

3.?Significantly reduced maximum plasma concentration (C_max, 5.0 5?±?1.39 versus 10.9 0?±?2.94?mg·L^{? 1}), modestly affected area-under-the-plasma concentration–time curve (AUC) from time zero to 12?h post dosing (AUC_0–12?h, 21.8 9?±?6.47 versus 26.1 6?±?7.32?mg·h·L^{? 1}) and delayed time to reach C_max (T_max) were observed in fed group compared with fasted group. Similar effects on C_max (5.8 2?±?1.23 versus 10.9 0?±?2.94?mg·L^{? 1}) and AUC_0–12?h (modest but not statistically significant, 24.4 4?±?7.40 versus 26.1 6?±?7.32?mg·h·L^{? 1}) were observed for grapefruit juice compared to fasted subjects.

4.?Co-administration of pirfenidone with grapefruit juice resulted in modestly reduced overall oral absorption and significantly reduced peak concentrations compared to fasting, which was similar to effect of food ingestion. No adverse events were observed in the study, but relatively dramatic reduction of peak concentrations should raise concerns for clinical efficacy and safety.