Pharmacokinetics of the Melanocortin Type 1 Receptor Agonist PL8177 After Subcutaneous Administration

Background and ObjectivePL8177 is a selective melanocortin 1 receptor agonist in development for the treatment of various immunologic and inflammatory conditions. Here we describe the pharmacokinetics of PL8177 after subcutaneous (sc) delivery in animals and humans.MethodsMice, rats, and dogs were administered sc PL8177 at single doses of 1.0 and 3.0 mg/kg (mice); 1.0, 5.0, and 25.0 mg/kg/day (rats); or 1.5, 8.0, and 40.0 mg/day (dogs). Blood was collected over 24 h (mice) or 28 days (rats and dogs). Safety and pharmacokinetics of single and multiple sc doses were also examined in human volunteers. Two dose levels were tested in two dosing cohorts of 1.0 and 3.0 mg/day for 7 days. Blood samples were collected through Day 1 and on Days 2 to 6 at peak and trough times based on analysis of the first two single-dose cohorts.ResultsIn mice, 3 mg/kg PL8177 resulted in an area under the plasma concentration–time curve from 0 to infinity (AUC_∞) of 1727 ng·h/mL, a maximum plasma concentration (C_max) of 2440 ng/mL, an elimination half-life (t_½) of 0.5 h, and a time to maximum concentration (t_max) of 0.25 h. Results for the 1-mg/kg dose were generally proportional. In rats, mean t_max values were independent of dose and ranged from 0.25 to 1.0 h for single and multiple dosing. C_max values ranged from 516 to 695 ng/mL (1-mg/kg dose) and from 666 to 1180 ng/mL (25-mg/kg dose). In dogs, mean t_max values ranged from 0.4 to 1.3 h for single and multiple dosing. Values for t_max decreased with increasing dose and mean plasma C_max increased less than dose proportionally (96–129 ng·h/mL [1.5 mg], 275–615 ng·h/mL [8.0 mg], and 633–1280 ng·h/mL [40.0 mg]). In humans, PL8177 was observed in the plasma within 15 min after a single dose and persisted for up to 48 h at higher doses. The t_max was 30–45 min (single dose) and 15–45 min (multiple doses). In multiple-dose studies, maximum steady-state plasma concentration (C_max,ss) and AUC_∞ increased with dose. Geometric mean C_max,ss values were 20.1 ng/mL (1.0 mg) and 57.2 ng/mL (3.0 mg). AUC_∞ values were 54.3 ng·h/mL (1.0 mg) and 199 ng·h/mL (3.0 mg). Unchanged PL8177 excreted in the urine was ≤ 1%, and accumulation was minimal.ConclusionPL8177 administration resulted in a consistent pharmacokinetic profile. The measured exposure levels resulted in pharmacologically active PL8177 concentrations at the targeted MC1R. Rapid absorption was seen in healthy volunteers, and multiple-dose administration over 7 days resulted in pharmacokinetic characteristics similar to those observed after single-dose administration. Results support the continued development of PL8177 to treat immunologic and inflammatory conditions.     

Formulation and Evaluation of Irinotecan Suppository for Rectal Administration

Irinotecan suppository was prepared using the moulding method with a homogeneous blend. A sensitive and specific fluorescence method was developed and validated for the determination of irinotecan in plasma using HPLC. The pharmacokinetics of intravenous administered and rectal administered in rabbits was investigated. Following a single intravenous dose of irinotecan (50 mg/kg), the plasma irinotecan concentration demonstrated a bi-exponential decay, with a rapid decline over 15 min. C_max, t_1/2, AUC_0–30h and AUC_0-∞ were 16.1 ± 2.7 g/ml, 7.6 ± 1.2 h, 71.3 ± 8.8 μg·h/ml and 82.3 ± 9.5 μg·h/ml, respectively. Following rectal administration of 100 mg/kg irinotecan, the plasma irinotecan concentration reached a peak of 5.3 ± 2.5 μg/ml at 4 h. The AUC_0–30h and AUC_0-∞ were 32.2 ± 6.2 μg·h/ml and 41.6 ± 7.2 μg·h/ml, respectively. It representing ∼50.6% of the absolute bioavailability.     

Phase I Clinical Study of Edaravone in Healthy Chinese Volunteers: Safety and Pharmacokinetics of Single or Multiple Intravenous Infusions

Objective

The objective of this study was to investigate the safety and pharmacokinetics of edaravone administered by single or successive intravenous infusions in healthy Chinese volunteers.

Methods

A total of 30 subjects (15 males and 15 females) were recruited and randomly assigned to three groups receiving edaravone doses of 20, 30, and 60 mg. All subjects received a single dose of edaravone during a 30-minute period, and only the 30 mg dose group continued to receive the same dose successively by intravenous infusion twice daily for the next 5 days. Plasma concentrations of edaravone were monitored by high-performance liquid chromatography at the following times: 15, 30, 45, 60, 75, 105, 165, 225, 300, 390, 480, 600, and 720 minutes after edaravone administration.

Results

The area under the plasma concentration-time curve during a dosage interval (AUC_τ) values of the single dose in the 20, 30, and 60 mg dose groups were 3.64±1.37, 5.17 ± 0.93, and 11.25 ± 3.42 mg · h/L, respectively, while in the group receiving repeated dosing of 30 mg, the mean AUC_τ value was 5.06 ± 0.89mg · h/L. The corresponding maximum plasma drug concentration (C_max) values were 1599.0 ± 382.6, 2378.7 ± 316.7, and 4540.1 ± 901.1 ng/mL, respectively, in the single-dose groups, and 2479.1 ± 477.9 ng/mL in the 30 mg repeated-dose group. The mean AUC_τ and C_max ratios between the repeated-dose group and the single-dose groups were 0.98 and 1.04. All laboratory test abnormalities (including increased alanine transaminase and triacylglycerol levels, and decreased white blood cell counts and creatinine levels) were mild and tolerable. All abnormal blood biochemical indices returned to normal levels after 7 days.

Conclusion

Edaravone was safe and well tolerated in the volunteers and displayed linear increases in the C_max and AUC_τ values.     

Pharmacokinetics of levosulpiride after single and multiple intramuscular administrations in healthy Chinese volunteers

The main purpose of this study was to evaluate the pharmacokinetics of levosulpiride in humans after single and multiple intramuscular injections. Six males and six females received single dose of either 25 mg or 50 mg levosulpiride, or multiple doses of 25 mg every 12 h for 5 consecutive days. In the single 25 mg study, the mean peak plasma concentration (C_max) was 441 ng/mL, the mean area under the concentration–time curve from 0 to 36 h (AUC_0–36) was 1724 ng h/mL, and the mean elimination half-life (t_1/2) was 7.0 h. In the single 50 mg study, the mean C_max was 823 ng/mL, the mean AUC_0–36 was 3748 ng·h/mL, and the mean t_1/2 was 6.8 h. After multiple doses of 25 mg levosulpiride, the average plasma concentration (C_av) was 136 ng/mL, the fluctuation index (DF) was 3.60, and the accumulation ratio (R) was 1.2. Levosulpiride injections appeared to be well tolerated by the subjects, and can be used for successive administration.KEY WORDS: Levosulpiride, Pharmacokinetics, Intramuscular administration, Safety and tolerability     

Bioequivalence Study of Two Formulations of Ibandronic Acid 150-mg Film-Coated Tablets in Healthy Volunteers Under Fasting Conditions: A Randomized,Open-Label,Three-Way,Reference-Replicated Crossover Study

Aims

This bioequivalence study aimed to compare rate and extent of absorption of a generic medicinal product of ibandronic acid 150-mg film-coated tablet versus Bonviva^®.

Methods

This was a single-centre, open-label, randomized, three-way, three-sequence, reference-replicated, crossover bioequivalence study, under fasting conditions. A single oral dose of ibandronic acid as one 150-mg film-coated tablet was administered in each study period. Each washout period lasted 14 days. Blood samples were collected according to a predefined sampling schedule and up to 48.0 hours after administraton in each period. Plasma concentrations of ibandronic acid were measured using a liquid chromatograph–mass spectrometry/mass spectrometry method. Bioequivalence between generic and reference medicinal products is acceptable if the 90 % confidence intervals (CI) of ratio of least-squares means between the test and the reference product of ln-transformed area under the serum concentration–time curve from time zero to time of last measurable concentration (AUC_0–t) is within the 80.00–125.00 % interval. Prospectively, a scaled average bioequivalence approach for maximum serum concentration (C_max) was established.

Results

153 healthy volunteers were enrolled and randomized. After the test formulation (T) and first and second Bonviva^® (R) dosing, the C_max was 96.71 ± 90.19 ng/mL, 92.67 ± 91.48 ng/mL and 87.94 ± 60.20 ng/mL and the AUC_0–t was 390.83 ± 287.27 ng·h/mL, 388.54 ± 356.76 ng·h/mL and 383.53 ± 246.72, respectively. Ratios of T/R and 90 % CI were 100.92 % (94.35–107.94) for AUC_0–t, 100.90 % (94.37–107.88) for AUC_0–inf and 102.56 % (95.05–110.67) for C_max.

Conclusions

Test formulation of ibandronic acid is bioequivalent in rate and extent of absorption to Bonviva^® following a 150-mg dose, under fasting conditions.     

The Effect of Pioglitazone on Pharmacokinetics of Carbamazepine in Healthy Rabbits

Introduction

Drug–drug interactions can lead to serious and potentially lethal adverse events. In recent years, several drugs have been withdrawn from the market due to interaction-related adverse events. The objective of this study was to evaluate the pharmacokinetic interaction between pioglitazone (PG) and carbamazepine (CBZ) in healthy male rabbits.

Methods

A randomized, two-crossover design study was conducted in six healthy male rabbits. The study consisted of two periods: period one, when each rabbit received a single dose of 70 mg CBZ-suspension. Period two, when each rabbit received a single dose of 70 mg CBZ-suspension co-administered with a single dose of 1.5 mg PG with a washout period of one week between the two periods. Serial blood samples were collected over a period of 48 h. Chemiluminescent enzyme immunoassay (CLEIA) was used to measure CBZ in serum. Pharmacokinetic (PK) parameters C_max, T_max, t _1/2, AUC_0-t, AUC _0-∞, and k_e were determined for the two periods using non-compartmental analysis.

Results

In the two periods of treatment, C_max, T_max, AUC_0-t, AUC_0-∞, t _½ and k_e for CBZ were administered alone and in combination with PG. C_max, the mean peak plasma concentration was 4.33 ± 2.4 μg/mL versus 4.76 ± 2.1 μg/ml, t_max, time taken to reach, was 2.91 ± 1.11 h versus 3.6 ± 1.83 h, total area under the curve AUC_0-t was 64.90 ± 43.6 μg·h/ml versus 102.90 ± 66.9 μg·h/ml, AUC_0-∞ was 74.0 ± 52.6 μg·h/ml versus 124.3 ± 85 μg·h/mL, t _½ was 14.10 ± 2.5 h versus 16.43 ± 6.43 h and elimination rate constant k_e was 0.050 ± 0.009 h⁻¹ versus 0.057 ± 0.049 h⁻¹, respectively. No statistical differences were found in pharmacokinetic of CBZ in both cases (P > 0.05).

Conclusion

The result of the study demonstrated that PG does not affect pharmacokinetic parameters of CBZ. Therefore, no cautions regarding dose or administration pattern of CBZ with PG should be taken.     

Metabolism and Disposition of Tribendimidine and Its Metabolites in Healthy Chinese Volunteers

Background: Tribendimidine is a new anthelmintic agent synthesized by Chinese scientists. It is a broad spectrum agent with high activity against parasites. However, its disposition and metabolism remain unknown.Objective: To investigate the metabolism, disposition, and metabolites of tribendimidine in healthy human volunteers.Methods: Twelve healthy Chinese volunteers were chosen after clinical assessment of health status and laboratory tests. They received single oral doses of tribendimidine 400mg enteric-coated tablets. Blood and urine samples were collected at scheduled timepoints. Samples were qualitatively and quantitatively analyzed by liquid chromatography-mass spectrometric (LC-MS) and high performance liquid chromatography (HPLC) methods, respectively.Results: Tribendimidine was rapidly and completely broken down to p-(1-dimethylamino ethylimino) aniline (dADT) and terephthalaldehyde (TPAL). Furthermore, dADT was partially transformed to acetylated dADT, and TPAL completely transformed to terephalic acid (TPAC). The main pharmacokinetic parameters (± SD) of dADT were as follows: elimination half life (t_1/2) 4.74 ± 1.80 h; elimination rate constant (K_e) 0.16 ± 0.06 h⁻¹; apparent volume of distribution (Vd/F) 12.23 ± 8.69L • kg⁻¹; apparent total clearance of the drug from plasma (CL/F) 1.63 ± 0.58L • h⁻¹ • kg⁻¹; area under the plasma concentration-time curve (AUC) from time 0 to time 24 hours (AUC₂₄) 4.29 ± 1.88 μg • mL⁻¹ • h; AUC from time zero to infinity (AUC_∞) 4.45 ± 1.81 μg • mL⁻¹ • h; maximum plasma drug concentration (C_max) 0.64 ± 0.27 μg • mL⁻¹; and time to C_max (t_max) 4.20 ± 0.71 h. A total of 35.28% dADT and 28.50% TPAC were excreted through the urine within 24 hours after tribendimidine administration.Conclusion: These results reveal the disposition, metabolism, and main metabolites of tribendimidine in healthy Chinese volunteers.     

Pharmacokinetics of PEGylated recombinant human endostatin (M2ES) in rats

Aim:

M₂ES is PEGylated recombinant human endostatin. In this study we investigated the pharmacokinetics, tissue distribution, and excretion of M₂ES in rats.

Methods:

¹²⁵I-radiolabeled M₂ES was administered to rats by intravenous bolus injection at 3 mg/kg. The pharmacokinetics, tissue distribution and excretion of M₂ES were investigated using the trichloroacetic acid (TCA) precipitation method.

Results:

The serum M₂ES concentration-time curve after a single intravenous dose of 3 mg/kg in rats was fitted with a non-compartment model. The pharmacokinetic parameters were evaluated as follows: C_max=28.3 μg·equ/mL, t_1/2=71.5 h, AUC_(0–∞)=174.6 μg·equ·h/mL, Cl=17.2 mL·h⁻¹·kg⁻¹, MRT=57.6 h, and V_ss=989.8 mL/kg for the total radioactivity; C_max=30.3 μg·equ/mL, t_1/2=60.1 h, AUC_(0–∞)=146.2 μg·equ·h/mL, Cl=20.6 mL·h⁻¹·kg⁻¹, MRT=47.4 h, and V_ss=974.6 mL/kg for the TCA precipitate radioactivity. M₂ES was rapidly and widely distributed in various tissues and showed substantial deposition in kidney, adrenal gland, lung, spleen, bladder and liver. The radioactivity recovered in the urine and feces by 432 h post-dose was 71.3% and 8.3%, respectively. Only 0.98% of radioactivity was excreted in the bile by 24 h post-dose.

Conclusion:

PEG modification substantially prolongs the circulation time of recombinant human endostatin and effectively improves its pharmacokinetic behavior. M₂ES is extensively distributed in most tissues of rats, including kidney, adrenal gland, lung, spleen, bladder and liver. Urinary excretion was the major elimination route for M₂ES.     

Very Short-Term Effects of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin on the Secretion of Insulin,Glucagon, and Incretin Hormones in Japanese Patients with Type?2 Diabetes Mellitus: Analysis of Meal Tolerance Test Data

Background

Sitagliptin inhibits dipeptidyl peptidase-4, which inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. To assess its antidiabetic potency, we used meal tolerance tests (MTTs) to determine the very short-term effects of sitagliptin on plasma concentrations of insulin and glucagon.

Methods

On day 1, patients with newly diagnosed or uncontrolled type 2 diabetes mellitus started a calorie-restricted diet. On day 2, the first MTT was performed, before treatment with sitagliptin 50 mg/day started later the same day. On day 5, a second MTT was performed. Area under the concentration–time curves (AUCs) of relevant laboratory values were calculated [AUC from time zero to 2 h (AUC_0–2h) and from time zero to 4 h (AUC_0–4h)].

Results

Fifteen patients were enrolled. AUCs for postprandial plasma glucose were decreased after 3 days of sitagliptin treatment [AUC_0–2h 457 ± 115 mg/dL·h (25.4 ± 6.4 mmol/L·h) to 369 ± 108 mg/dL·h (20.5 ± 6.0 mmol/L·h); AUC_0–4h 896 ± 248 mg/dL·h (49.7 ± 13.8 mmol/L·h) to 701 ± 246 mg/dL·h (38.9 ± 13.7 mmol/L·h); both p < 0.001]. AUC_0–2h and AUC_0–4h for postprandial plasma glucagon also decreased: 195 ± 57 to 180 ± 57 pg/mL·h (p < 0.05) and 376 ± 105 to 349 ± 105 pg/mL·h (p < 0.01), respectively. The AUC_0–2h [median with quartile values (25 %, 75 %)] for active GLP-1 increased: 10.5 (8.5, 15.2) to 26.4 (16.7, 32.4) pmol/L·h (p = 0.03).

Conclusions

Very short-term (3-day) treatment with sitagliptin decreases postprandial plasma glucose significantly. This early reduction in glucose may result partly from suppression of excessive glucagon secretion, through a direct effect on active GLP-1. Improvement in postprandial plasma glucose, through suppression of glucagon secretion, is believed to be an advantage of sitagliptin for the treatment of patients with type 2 diabetes.     

Lisdexamfetamine Dimesylate Effects on the Pharmacokinetics of Cytochrome P450 Substrates in Healthy Adults in an Open-Label,Randomized, Crossover Study

Introduction

This open-label, randomized, two-period drug interaction study assessed lisdexamfetamine dimesylate (LDX) effects on cytochrome P450 (CYP) enzyme (CYP1A2, CYP2D6, CYP2C19, and CYP3A) activity.

Methods

Thirty healthy volunteers were administered the Cooperstown cocktail (CYP1A2 [caffeine 200 mg], CYP2D6 [dextromethorphan 30 mg], CYP2C19 [omeprazole 40 mg], and CYP3A [midazolam 0.025 mg/kg] substrates) or Cooperstown cocktail + oral LDX 70 mg. Blood samples for pharmacokinetic analysis were collected pre-dose and serially for 72 h post-dose. Treatment differences in the primary endpoints, maximum plasma concentration (C_max) and area under the plasma concentration versus time curve from 0 to infinity (AUC_0–∞), were assessed using geometric mean ratios with 90 % CIs.

Results

Geometric least squares (LS) means (without versus with LDX) for C_max (ng/mL) were 5370 versus 5246 for caffeine, 2.43 versus 2.87 for dextromethorphan, 35.23 versus 35.11 for midazolam, and 677.9 versus 466.9 for omeprazole; and for AUC_0–∞ (ng·h/mL) were 56,207 versus 56,688 for caffeine, 34.85 versus 37.27 for dextromethorphan, 92.07 versus 93.04 for midazolam, and 1428 versus 1499 for omeprazole. Geometric LS mean ratios were within the standard bioequivalence testing range, except for omeprazole and dextromethorphan C_max. Parent/metabolite C_max and AUC_0–∞ ratios were similar between treatments except for dextromethorphan/dextrorphan AUC_0–∞ ratio, which was lower with LDX. No serious or severe treatment-emergent adverse events were reported.

Conclusions

LDX did not alter CYP1A2, CYP2D6, or CYP3A activity. A small C_max reduction for omeprazole and its metabolite was observed, possibly reflecting an effect either on the activity of CYP2C19 or omeprazole absorption.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-015-0090-z) contains supplementary material, which is available to authorized users.     

Pharmacokinetic Effects of Simultaneous Administration of Single-Dose Gabapentin 500?mg and Zolpidem Tartrate 10?mg in Healthy Volunteers: A Randomized,Open-Label,Crossover Trial

Objective

Gabapentin is being investigated as a potential treatment for occasional disturbed sleep. This study assessed the pharmacokinetics and tolerability of gabapentin 500 mg and the commonly prescribed sedative/hypnotic zolpidem tartrate 10 mg, administered separately and in combination.

Methods

Forty healthy participants (19 male, 21 female) were randomized into this three-period crossover study [mean (range) age 34.1 (18–45) years, weight 68.3 (51.4–92.7) kg; 60 % white]. Participants were dosed with gabapentin alone (n = 39), zolpidem tartrate alone (n = 38), and the combination (gabapentin + zolpidem) (n = 38) over three treatment periods, which were separated by ≥7 days. Blood samples were collected pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24 and 36 h post-dose. Plasma concentrations of each drug were assayed using validated methods. Pharmacokinetic parameters were estimated from plasma concentration–time data using standard non-compartmental methods.

Results

For gabapentin + zolpidem combination versus gabapentin alone, mean pharmacokinetic parameters were peak plasma concentration (C_max) 4.61 versus 4.72 µg/mL, time to C_max (t_max) 4.63 versus 3.64 h and the area under plasma concentration–time curve extrapolated to infinity (AUC_0–∞) 53.4 versus 51.0 µg h/mL. For the combination versus zolpidem alone, mean pharmacokinetic parameters were C_max 154 versus 138 ng/mL, t_max 1.45 versus 1.84 h and AUC_0–∞ 912 versus 854 ng h/mL. The 90 % confidence intervals for C_max (rate of absorption) and AUC_0–∞ (extent of absorption) comparing the combination versus single drug administration fell within the 80–125 % range accepted for bioequivalence. All treatments were well tolerated.

Conclusion

The pharmacokinetics of gabapentin 500 mg and zolpidem tartrate 10 mg are unaffected when both drugs are taken simultaneously, compared with each drug taken alone.     

Food Effects on the Pharmacokinetics of Doxylamine Hydrogen Succinate 25 mg Film-Coated Tablets: A Single-Dose,Randomized, Two-Period Crossover Study in Healthy Volunteers

Background

Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. The data available on the pharmacokinetic profile of doxylamine in humans are limited, notwithstanding that this drug has been marketed in European countries for more than 50 years. In fact, no data on the effect of food on the pharmacokinetic parameters of doxylamine are available.

Objective

The objective of this study was to evaluate the pharmacokinetic parameters of doxylamine following a single oral dose of doxylamine hydrogen succinate 25 mg in healthy human subjects under fed and fasting conditions.

Study Design

This was a single-center, randomized, single-dose, laboratory-blinded, two-period, two-sequence, crossover study.

Setting

The study was conducted in a phase I clinical unit.

Subjects and Methods

A single oral dose of doxylamine hydrogen succinate 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under either fed conditions (high-fat, high-calorie food intake) or fasting conditions in each study period. The drug administrations were separated by a wash-out period of seven calendar days. Plasma samples were collected for up to 60 hours postdose, and plasma doxylamine concentrations were determined by a high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using noncompartmental analysis. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography.

Results

In total, 24 healthy subjects (12 male and 12 female) were included in the study. Doxylamine succinate 25 mg tablets exhibited similar oral bioavailability of doxylamine in the fasting state (mean maximum plasma drug concentration [C_max] 118.21 ng/mL, coefficient of variation [CV] 19.2%; mean area under the plasma concentration time curve from time zero to time t [AUC_t] 1746.97 ng · h/mL, CV 31.6%) and in the fed state (mean C_max 120.99 ng/mL, CV 15.0%; mean AUC_t 1712.20 ng · h/mL, CV 26.7%). No statistically significant between-treatment differences were observed for any of the pharmacokinetic parameters under study. The fed: fasting ratios of the geometric least squares means with corresponding 90% confidence intervals for C_max and AUC_t were within the range of 80–125%.

Conclusion

High-fat, high-calorie food intake does not affect the kinetics of doxylamine in healthy subjects. The drug was safe and well tolerated by the subjects in this study.     

Pharmacokinetic Dose Proportionality Between Two Strengths (12.5?mg and 25?mg) of Doxylamine Hydrogen Succinate Film-Coated Tablets in Fasting State: A Single-Dose,Randomized, Two-Period Crossover Study in Healthy Volunteers

Background

Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose proportionality of the pharmacokinetics of doxylamine are available, although this drug has been marketed in European countries for more than 50 years.

Objective

The objective of this study was to evaluate and compare the dose proportionality between two marketed strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate after a single oral dose administration under fasting conditions in healthy human subjects.

Study Design

This was a single-center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study.

Setting

The study was conducted in a phase I clinical unit.

Subjects and Methods

A single oral dose of doxylamine hydrogen succinate of 12.5 mg (equivalent to 8.7 mg of doxylamine base) or 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under fasting conditions in each study period. The drug administrations were separated by a wash-out period of 7 calendar days. Blood samples were collected for up to 60 h post-dose, and plasma doxylamine levels were determined by an ultra high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using non-compartmental analysis. Dose proportionality was assessed based on the parameter area under the concentration–time curve (AUC_{t normalized}). Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs and 12-lead electrocardiogram (ECG).

Results

In total, 12 healthy volunteers (3 male; 9 female) were included in the study. Mean maximum observed plasma concentration (C_max) and area under the concentration–time curve from time zero to time t (AUC_t) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean C_max 61.94 ng/mL, coefficient of variation (CV) 23.2 %; mean AUC_t 817.33 ng·h/mL, CV 27.4 %; and 25 mg: mean C_max 124.91 ng/mL, CV 18.7 %; mean AUC_t 1630.85 ng·h/mL, CV 22.8 %]. Mean AUC_{t normalized} was 815.43 ng·h/mL, CV 22.8 % for 25 mg. The dose-normalized geometric mean ratio (%, 12.5 mg/25 mg) of AUC_t was 98.92 (90 % CI: 92.46, 105.83). The most common adverse event was somnolence.

Conclusions

Exposure to doxylamine was proportional over the therapeutic dose range of 12.5–25 mg in healthy volunteers. Based on the results, a predictable and linear increase in systemic exposure can be expected. Doxylamine hydrogen succinate was safe and well tolerated.     

Comparative pharmacokinetics of cefuroxime lysine after single intravenous,intraperitoneal, and intramuscular administration to rats

Aim:

To compare the pharmacokinetic parameters of cefuroxime lysine, a new second-generation of cephalosporin antibiotics, after intravenous (IV), intraperitoneal (IP), or intramuscular (IM) administration.

Methods:

Twelve male and 12 virgin female Sprague-Dawley rats, weighing from 200 to 250 g, were divided into three groups (n=4 for each gender in each group). The rats were administered a single dose (67.5 mg/kg) of cefuroxime lysine via IV bolus or IP or IM injection. Blood samples were collected and analyzed with a validated UFLC-MS/MS method. The concentration-time data were then calculated by compartmental and non-compartmental pharmacokinetic methods using DAS software.

Results:

After IV, IP or IM administration, the plasma cefuroxime lysine disposition was best described by a tri-compartmental, bi-compartmental or mono-compartmental open model, respectively, with first-order elimination. The plasma concentration profiles were similar through the 3 administration routes. The distribution process was rapid after IV administration [t_1/2(d), 0.10±0.11 h vs 1.36±0.65 and 1.25±1.01 h]. The AUMC_0–∞ is markedly larger, and mean residence time (MRT) is greatly longer after IP administration than that in IV, or IM routes (AUMC_0–∞: 55.33±20.34 vs 16.84±4.85 and 36.17±13.24 mg·h²/L; MRT: 0.93±0.10 h vs 0.37±0.07 h and 0.65±0.05 h). The C_max after IM injection was significantly higher than that in IP injection (73.51±12.46 vs 49.09±7.06 mg/L). The AUC_0–∞ in male rats were significantly higher than that in female rats after IM administration (66.38±16.5 vs 44.23±6.37 mg·h/L). There was no significantly sex-related difference in other pharmacokinetic parameters of cefuroxime lysine between male and female rats.

Conclusion:

Cefuroxime lysine shows quick absorption after IV injection, a long retension after IP injection, and a high C_max after IM injection. After IM administration the AUC_0–∞ in male rats was significantly larger than that in female rats.     

Zanamivir Oral Delivery: Enhanced Plasma and Lung Bioavailability in Rats

The objective of this study was to enhance the oral bioavailability (BA) of zanamivir (ZMR) by increasing its intestinal permeability using permeation enhancers (PE). Four different classes of PEs (Labrasol^®, sodium cholate, sodium caprate, hydroxypropyl β-cyclodextrin) were investigated for their ability to enhance the permeation of ZMR across Caco-2 cell monolayers. The flux and P_app of ZMR in the presence of sodium caprate (SC) was significantly higher than other PEs in comparison to control, and was selected for further investigation. All concentrations of SC (10-200 mM) demonstrated enhanced flux of ZMR in comparison to control. The highest flux (13 folds higher than control) was achieved for the formulation with highest SC concentration (200 mM). The relative BA of ZMR formulation containing SC (PO-SC) in plasma at a dose of 10 mg/kg following oral administration in rats was 317.65% in comparison to control formulation (PO-C). Besides, the AUC_{0-24 h} of ZMR in the lungs following oral administration of PO-SC was 125.22 ± 27.25 ng hr ml^-1 with a C_max of 156.00 ± 24.00 ng/ml reached at 0.50±0.00 h. But, there was no ZMR detected in the lungs following administration of control formulation (PO-C). The findings of this study indicated that the oral formulation PO-SC containing ZMR and SC was able to enhance the BA of ZMR in plasma to an appropriate amount that would make ZMR available in lungs at a concentration higher (>10 ng/ml) than the IC₅₀ concentration of influenza virus (0.64-7.9 ng/ml) to exert its therapeutic effect.     

Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat, a non-purine selective inhibitor of xanthine oxidase

AIM

This study examined the effect of co-administration of febuxostat, an investigational urate lowering therapy, and hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat.

METHODS

Healthy subjects (36 healthy men and women) received single doses of febuxostat 80 mg alone and febuxostat 80 mg + hydrochlorothiazide 50 mg, separated by 7 days in an open-label, randomized, crossover fashion. Plasma concentrations of febuxostat and urinary and serum concentrations of uric acid were assessed.

RESULTS

Mean febuxostat C_max, AUC_(0–t), AUC_(0–∞), t_1/2,z, CL/F and V_ss/F values for regimens co-administration/febuxostat alone were 2.9/2.9 µg ml⁻¹, 9.3/9.1 µg ml⁻¹ h, 9.6/9.3 µg ml⁻¹ h, 6.5/6.1 h, 8.8/9.3 l h⁻¹ and 45/44 l, respectively. Geometric mean ratios (co-administration : febuxostat alone) and their 90% confidence intervals for febuxostat plasma C_max, AUC_(0–t), and AUC_(0–∞) were 1.00 (0.86, 1.17), 1.03 (0.98, 1.09), and 1.04 (0.98, 1.10), respectively; all of the 90% CIs were within the no effect range of 0.8 to 1.25. Serum uric acid C_mean,24h, C_mean,48h and CL_R for both regimens co-administration/febuxostat alone were 216/203 µmol l⁻¹, 218/202 µmol l⁻¹ and 9.1/10.1 ml min⁻¹, respectively. Although serum uric acid C_mean,24h and C_mean,48h values were higher and CL_R values lower after co-administration compared with dosing of febuxostat alone, with the differences being statistically significant (P < 0.003), none of the differences (6.5%–9.5%) was considered clinically significant.

CONCLUSION

Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.     

QiShenYiQi pills,a Chinese patent medicine,increase bioavailability of atorvastatin by inhibiting Mrp2 expression in rats

ContextAtorvastatin (ATV) and QiShenYiQi pills (QSYQ), a Chinese patent medicine, are often co-prescribed to Chinese cardiovascular patients. The effects of QSYQ on the pharmacokinetics of ATV have not been studied.ObjectiveWe investigated the influence of QSYQ on the pharmacokinetics of ATV and its metabolites upon oral or intravenous administration of ATV to rats.Materials and methodsSprague-Dawley rats (n = 5/group) were pre-treated with oral QSYQ (675 mg/kg) or vehicle control for 7 days and then orally administrated ATV (10 mg/kg) or intravenously administrated ATV (2 mg/kg). Serum concentrations of ATV and metabolites were determined by ultra-high performance liquid chromatography tandem mass spectrometry. Expression of metabolic enzymes and transporters in jejunum and ileum were measured by quantitative real-time PCR and Western blot.ResultsQSYQ resulted in an increase of AUC_0-12 h of ATV from 226.67 ± 42.11 to 408.70 ± 161.75 ng/mL/h and of C_max of ATV from 101.46 ± 26.18 to 198.00 ± 51.69 ng/mL and in an increased of para-hydroxy atorvastatin from 9.07 ± 6.20 to 23.10 ± 8.70 ng/mL in rats administered ATV orally. No change was observed in rats treated intravenously. The expression of multidrug resistance-associated protein 2 mRNA and protein decreased in ileum, and the mRNA of P-glycoprotein decreased in jejunum, though no change in protein expression was found.Discussion and conclusionsQSYQ increased bioavailability of ATV administered orally through inhibiting the expression of Mrp2 in ileum. Clinicians should pay close attention to potential drug-drug interactions between ATV and QSYQ.     

Comparative pharmacokinetic analysis of raw and steamed Panax notoginseng roots in rats by UPLC-MS/MS for simultaneously quantifying seven saponins

ContextAfter being steamed, the restorative effects of Panax notoginseng (Burk.) F. H. Chen (Araliaceae) will be strengthened. However, the underlying mechanism remains elusive.ObjectiveTo compare the pharmacokinetics of ginsenosides Rg₁, Rb₁, Rd, Re, Rg₅, Rk₁, notoginsenoside R₁ (GRg₁, GRb₁, GRd, GRe, GRg₅, GRk₁ and NGR₁) in the raw and steam-processed P. notoginseng (RPN and SPN).Materials and methodsThe pharmacokinetics of seven components after oral administration of SPN and RPN extracts (1.0 g/kg) were investigated, respectively, in SD rats (two groups, n = 6) using UPLC-MS/MS.ResultsThe approach elicited good linear regression (r² > 0.991). The accuracy, precision and stability were all within ± 15%. The extraction recoveries and matrix effects were 75.0–100.8% and 85.1–110.3%, respectively. Compared with the RPN group, AUC_0–t of GRg₁ (176.63 ± 42.49 ng/h/mL), GRb₁ (5094.06 ± 1453.14 ng/h/mL), GRd (1396.89 ± 595.14 ng/h/mL), and NGR₁ (135.95 ± 54.32 ng/h/mL), along with C_max of GRg₁ (17.41 ± 5.43 ng/mL), GRb₁ (361.48 ± 165.57 ng/mL), GRd (62.47 ± 33.65 ng/mL) and NGR₁ (23.97 ± 16.77 ng/mL) decreased remarkably with oral administration of the SPN extracts, while GRe showed no significantly difference. Of note, GRg₅ and GRk₁ could not be detected in the plasma.ConclusionsInfluence of the processing reduced the systemic exposure levels to GRg₁, GRb₁, GRd and NGR₁. It is the first report of comparative pharmacokinetic study of multiple saponins analysis after oral administration of RPN and SPN extract, which might be helpful for further studies on its steam-processing mechanism.     

Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A,for the treatment of Alzheimer's disease

Aim:

Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects.

Methods:

This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including C_max, AUC_{0–72 h} and AUC_0–∞ were calculated. Tolerance assessments were conducted throughout the study.

Results:

ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean t_max of huperzine A was 0.76–0.82 h; the AUC_{0–72 h} and C_max of huperzine A showed approximately dose-proportional increase over the dose range of 0.5–1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed.

Conclusion:

ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers.     

Solid lipid nanoparticles for nose to brain delivery of haloperidol: in vitro drug release and pharmacokinetics evaluation

In the present study, haloperidol (HP)-loaded solid lipid nanoparticles (SLNs) were prepared to enhance the uptake of HP to brain via intranasal (i.n.) delivery. SLNs were prepared by a modified emulsification–diffusion technique and evaluated for particle size, zeta potential, drug entrapment efficiency, in vitro drug release, and stability. All parameters were found to be in an acceptable range. In vitro drug release was found to be 94.16±4.78% after 24 h and was fitted to the Higuchi model with a very high correlation coefficient (R²=0.9941). Pharmacokinetics studies were performed on albino Wistar rats and the concentration of HP in brain and blood was measured by high performance liquid chromatography. The brain/blood ratio at 0.5 h for HP-SLNs i.n., HP sol. i.n. and HP sol. i.v. was 1.61, 0.17 and 0.031, respectively, indicating direct nose-to-brain transport, bypassing the blood–brain barrier. The maximum concentration (C_max) in brain achieved from i.n. administration of HP-SLNs (329.17±20.89 ng/mL, T_max 2 h) was significantly higher than that achieved after i.v. (76.95±7.62 ng/mL, T_max 1 h), and i.n. (90.13±6.28 ng/mL, T_max 2 h) administration of HP sol. The highest drug-targeting efficiency (2362.43%) and direct transport percentage (95.77%) was found with HP-SLNs as compared to the other formulations. Higher DTE (%) and DTP (%) suggest that HP-SLNs have better brain targeting efficiency as compared to other formulations.KEY WORDS: Brain targeting, Haloperidol, Intranasal route, Pharmacokinetics, Solid lipid nanoparticles