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.     

Switching α-Glucosidase Inhibitors to Miglitol Reduced Glucose Fluctuations and Circulating Cardiovascular Disease Risk Factors in Type 2 Diabetic Japanese Patients

Background and Objectives

In this study we examined the effects of switching α-glucosidase inhibitors (α-GI) from acarbose or voglibose to miglitol on glucose fluctuations and circulating concentrations of cardiovascular disease risk factors, such as soluble adhesion molecules (sE-selectin, sICAM-1 and sVCAM-1), a chemokine monocyte chemoattractant protein (MCP)-1, plasminogen activator inhibitor-1, and fatty acid-binding protein 4, in type 2 diabetic patients for 3 months.

Methods

We enrolled 47 Japanese patients with type 2 diabetes, with HbA_1c levels with 7.26 ± 0.5 % (mean ± standard deviation), and who were treated with the highest approved dose of acarbose (100 mg/meal) or voglibose (0.3 mg/meal) in combination with insulin or sulfonylurea. Patients’ prior α-GIs were switched to a medium dose of miglitol (50 mg/meal), and the new treatments were maintained for 3 months. Thirty-five patients who completed the 3-month study and provided serum samples were analyzed.

Results

The switch to miglitol for 3 months did not affect HbA_1c, fasting glucose, triglycerides, total-cholesterol or C-reactive protein levels, or result in any adverse events. Glucose fluctuations were significantly improved by the change in treatment (M-value: 10.54 ± 4.32 to 8.36 ± 2.54), while serum protein concentrations of MCP-1 (525.04 ± 288.06–428.11 ± 163.78 pg/mL) and sE-selectin (18.65 ± 9.77–14.50 ± 6.26 ng/mL) were suppressed.

Conclusion

Our results suggest that switching from acarbose or voglibose to miglitol for 3 months suppressed glucose fluctuations and serum protein levels of MCP-1 and sE-selectin in type 2 diabetic Japanese patients, with fewer adverse effects.     

Population pharmacokinetics and Bayesian estimator of mycophenolic acid in children with idiopathic nephrotic syndrome

AIMS

To develop a population pharmacokinetic model for mycophenolic acid (MPA) in children with idiopathic nephrotic syndrome (INS) treated with mycophenolate mofetil (MMF), identify covariates that explain variability and determine the Bayesian estimator of the area under the concentration–time curve over 12 h (AUC_0–12).

METHODS

The pharmacokinetic model of MMF was described from 23 patients aged 7.4 ± 3.9 years (range 2.9–14.9) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag–time and first-order absorption and elimination was developed. The final model was validated using visual predictive check. Bayesian estimator was validated using circular permutation method.

RESULTS

The population pharmacokinetic parameters were apparent oral clearance 9.7 l h⁻¹, apparent central volume of distribution 22.3 l, apparent peripheral volume of distribution 250 l, inter-compartment clearance 18.8 l h⁻¹, absorption rate constant 5.16 h⁻¹, lag time 0.215 h. The covariate analysis identified body weight and serum albumin as individual factors influencing the apparent oral clearance. Accurate Bayesian estimation of AUC_0–12 was obtained using the combination of three MPA concentrations measured just before (T₀), 1 and 4 h (T₁ and T₄) after drug intake with a small error of 0.298 µg h⁻¹ ml⁻¹ between estimated and reference AUC_0–12.

CONCLUSIONS

The population pharmacokinetic model of MPA was developed in children with INS. A three-point (T₀, T₁ and T₄h) Bayesian estimator of AUC_0–12 was developed and might be used to investigate the relation between MPA pharmacokinetic and pharmacodynamics in children with INS and determine if there is any indication to monitor MPA exposure in order to improve patient outcome based on individual AUC-controlled MMF dosing.     

Teneligliptin,a Dipeptidyl Peptidase-4 Inhibitor,Improves Early-Phase Insulin Secretion in Drug-Na?ve Patients with Type 2 Diabetes

Introduction

It remains unknown whether dipeptidyl peptidase-4 (DPP-4) inhibitors improve early-phase insulin secretion in Japanese patients with type 2 diabetes (T2D), a disease characterized by impaired insulin secretion. We investigated the changes in insulin secretion before and after treatment with the DPP-4 inhibitor teneligliptin in patients with T2D with a low insulinogenic index (IGI) determined by the oral glucose tolerance test (OGTT).

Methods

An open-label, prospective clinical study was conducted. Thirteen drug-naïve patients (mean age 55.5 ± 3.9 years) with T2D underwent OGTT before and after teneligliptin 20 mg/day monotherapy. Plasma levels of glucose (PG), insulin, and C-peptide were measured at 0, 30, 60, 90, and 120 min after glucose loading in the OGTT. Homeostasis model assessment (HOMA)-β, IGI, and the total or incremental area under the curve (AUC) for PG and insulin were measured. AUC_120min for the secretory units of islets in transplantation (SUIT) index was also measured.

Results

HbA1c significantly decreased from 8.3 ± 0.4 % at baseline to 6.3 ± 0.2 % after 12 weeks of teneligliptin treatment (p < 0.05). Incremental AUC_120min PG also significantly decreased, and β-cell function assessed by IGI_30min, AUC_120min insulin, and the AUC_120min SUIT index significantly increased (0.16 ± 0.05 vs. 0.28 ± 0.06, 2692 ± 333 µU·2h/mL vs. 3537 ± 361 µU·2h/mL, and 4261 ± 442 vs. 8290 ± 1147, respectively; all p < 0.05). HOMA-β was unchanged. The reduction in incremental AUC_120min PG was significantly associated with the augmentation of IGI_30min and the AUC_120min SUIT index. No severe adverse events were observed.

Conclusions

Twelve weeks of teneligliptin treatment improved IGI_30min, AUC_120min, and the SUIT index in drug-naïve Japanese patients with T2D.     

Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients

AIMS

Pharmacokinetic (PK) and pharmacodynamic (PD) monitoring strategies and clinical outcome were evaluated in enteric-coated mycophenolate sodium (EC-MPS)-treated renal allograft recipients.

METHODS

PK [mycophenolic acid (MPA)] and PD [inosine monophosphate dehydrogenase (IMPDH) activity] data were analysed in 66 EC-MPS and ciclosporin A (CsA)-treated renal allograft recipients. Adverse events were considered in a follow-up period of 12 weeks.

RESULTS

Analyses confirmed a limited sampling strategy (LSS) consisting of PK and PD data at predose, 1, 2, 3 and 4 h after oral intake as an appropriate sampling method (MPA r²= 0.812; IMPDH r²= 0.833). MPA AUC_0–12 of patients with early biopsy-proven acute rejection was significantly lower compared with patients without a rejection (median MPA AUC_0–12 28 µg*h ml⁻¹ (7–45) vs. 40 µg*h ml⁻¹ (16–130), P < 0.01), MPA AUC_0–12 of patients with recurrent infections was significantly higher compared with patients without infections (median MPA AUC_0–12 65 µg*h ml⁻¹ (range 37–130) vs. 37 µg*h ml⁻¹ (range 7–120), P < 0.005). Low 12-h IMPDH enzyme activity curve (AEC_0–12) was associated with an increased frequency of gastrointestinal side-effects (median IMPDH AEC_0–12 43 nmol*h mg⁻¹ protein h⁻¹[range 12–67) vs. 75 nmol*h mg⁻¹ protein h⁻¹ (range 15–371), P < 0.01].

CONCLUSIONS

Despite highly variable absorption data, an appropriate LSS might be estimated by MPA AUC_0–4 and IMPDH AEC_0–4 in renal transplant patients treated with EC-MPS and CsA. Regarding adverse events, the suggested MPA-target AUC_0–12 from 30 to 60 µg*h ml⁻¹ seems to be appropriate in renal allograft recipients.     

Verapamil decreases the glucose-lowering effect of metformin in healthy volunteers

Aim

The organic cation transporter 1 (OCT1) plays a key role in the cellular transport of metformin and its subsequent glucose-lowering effect. A recent non-clinical study reported that metformin uptake into hepatocytes is regulated via OCT1, and that uptake was strongly inhibited by verapamil. Therefore, we investigated the effects of verapamil co-administration on the pharmacokinetics and pharmacodynamics of metformin in humans.

Methods

We evaluated the pharmacokinetics and the anti-hyperglycaemic effects of metformin using an oral glucose tolerance test (OGTT) in 12 healthy participants, before (day 1) and after metformin treatment (day 2), and again on days 15 and 16 after co-administration with verapamil.

Results

Verapamil inhibited the ability of metformin to reduce maximum blood glucose concentrations (ΔG_max) by 62.5% (P = 0.008) and decreased the area under the glucose concentration–time curve (ΔAUC_gluc) by 238% (P = 0.015). However, verapamil did not significantly alter the C_max and the AUC of metformin, nor its renal clearance.

Conclusions

Our results suggest that verapamil remarkably decreases the glucose-lowering effect of metformin, possibly by acting as a competitive inhibitor of OCT1.     

The Effects of Moxifloxacin on QTc Interval in Healthy Korean Male Subjects

Background and objective

Moxifloxacin 400 mg is a widely used positive control in thorough QT (TQT) studies, but its QT-prolonging effects in Korean subjects have not been studied. The present study was conducted to collect pilot data in Korean subjects after moxifloxacin administration to evaluate the adequacy of moxifloxacin as a positive control.

Methods

Thirty-eight, healthy, Korean, male subjects were recruited for pharmacokinetic (PK) blood sampling and electrocardiography (ECG) recordings at three different study sites. On day 1, a baseline 12-lead ECG was recorded, and on day 2, ECG recordings were conducted after placebo, or moxifloxacin 400- or 800-mg administration. Baseline-corrected, placebo-adjusted, corrected QT (ΔΔQTc) values were calculated. Blood samples were collected after moxifloxacin administration and PK parameters were assessed.

Results

A total of 33 subjects completed the study. The largest time-matched ΔΔQTc occurred approximately 4 h after dosing, with ΔΔQTcI (QT interval corrected by individual QT-RR regression model) values of 11.66 ms (moxifloxacin 400 mg) and 20.96 ms (800 mg). The mean and 90 % confidence intervals of ΔΔQTcI did not include zero at any of the measurement time points. There was a positive correlation between plasma moxifloxacin concentration and ΔΔQTcI (r = 0.422). Dose-proportional PK profiles were observed.

Conclusion

Moxifloxacin 400 mg is an adequate positive control in Korean TQT studies. Our results indicate that moxifloxacin 400 mg can be used to evaluate the cardiac safety of a drug in Korean subjects.     

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.     

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.     

Single-Dose,Randomized, Open-Label,Two-Way,Crossover Bioequivalence Study of Two Formulations of Pregabalin 300?mg Hard Capsules in Healthy Volunteers Under Fasting Conditions

Aims

This bioequivalence study was conducted to assess the bioequivalence of two formulations, test and reference, of pregabalin 300 mg hard capsules, under fasting conditions.

Methods

This was a single-center, randomized, single-dose, open-label, laboratory-blinded, two-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected prior to and up to 36 h after dosing. Pregabalin plasma concentrations were determined, using a validated method, by reversed phase high performance liquid chromatography coupled to a tandem mass spectrometry detector (LC–MS–MS). Pharmacokinetic metrics used for bioequivalence assessment were the AUC_(0–t) (area under the plasma concentration–time curve from time zero to time of last observed non-zero plasma concentration) and the C_max (maximum observed plasma concentration). These parameters were determined from the pregabalin plasma concentration data using noncompartmental analysis.

Results

Forty healthy subjects, age ranging from 18 to 43 years old, were enrolled and randomized, of whom 39 completed the study. The ratio of geometric least square means for C_max was 99.29 % (90 % confidence interval [CI] 93.29–105.67). The ratio of geometric least square means for AUC_(0–t) was 101.54 % (90 % CI 100.13–102.98). The 90 % CIs were within the predefined range (80.00–125.00).

Conclusions

Bioequivalence between test and reference formulations, under fasting conditions, was concluded both in terms of rate and extent of absorption.     

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.     

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.     

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.     

Absence of Pharmacokinetic and Pharmacodynamic Interactions between Almorexant and Warfarin in Healthy Subjects

Background and Objective

Almorexant is the first representative of the new class of orexin receptor antagonists, which could become a new treatment option for insomnia. The present study investigated the potential interaction between almorexant and warfarin.

Methods

In this open-label, two-way crossover, drug–drug interaction study, healthy male subjects received, in a randomized fashion, almorexant 200 mg once daily for 10 days and a single dose of 25 mg warfarin co-administered on day 5 (treatment A) and a single dose of 25 mg warfarin on day 1 (treatment B). Serial blood samples for warfarin pharmacokinetics and pharmacodynamics were drawn during both treatments.

Results

Of the 14 enrolled subjects, one withdrew due to an adverse event and 13 completed the study. Almorexant had no effect on the pharmacokinetics of warfarin. The geometric mean ratios (90 % confidence interval) for the area under the plasma concentration–time curve to infinity (AUC_0–∞) of S- and R-warfarin were 0.99 (0.89, 1.09) and 1.05 (0.95, 1.16), respectively, and for the maximum plasma concentration (C_max) were 0.99 (0.86, 1.14) and 1.00 (0.88, 1.13), respectively. The main pharmacodynamic variable was the AUC for the international normalized ratio (AUC_INR). Almorexant had no effect on this variable as demonstrated by a geometric mean ratio of 0.99 (0.82, 1.19). Secondary pharmacodynamic variables including maximum effect (E_max), the time to the maximum INR, and factor VII plasma concentrations were also not affected by almorexant.

Conclusion

No dose adjustment of warfarin is necessary when concomitantly administered with almorexant.     

Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations

Aims

The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB.

Methods

A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6–8 months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB.

Results

After administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC_0–24 h) was shown, although a tendency towards an increased oral exposure could be observed as the AUC_0–24 h was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity.

Conclusions

The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation.     

Pharmacokinetics of Coadministration of Guanfacine Extended Release and Methylphenidate Extended Release

Background

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

Objective

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

Study Design

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

Setting

The study was conducted at a single clinical research center.

Participants

Thirty-eight healthy adults were randomized in this study.

Interventions

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

Main Outcome Measures

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

Results

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

Conclusions

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

Ibuprofen Sodium Is Absorbed Faster than Standard Ibuprofen Tablets: Results of Two Open-Label,Randomized, Crossover Pharmacokinetic Studies

Background

A novel ibuprofen (IBU) formulation, Advil^® Film-Coated Tablets (IBU_Na), was developed.

Objective

Pharmacokinetic comparison of IBU_Na versus other IBU formulations.

Study Design

Two randomized, single-dose, open-label, five-way crossover pharmacokinetic studies.

Setting

Inpatient research clinic.

Subjects

Seventy-one healthy adult volunteers.

Intervention

Study 1: In three periods, fasted subjects received 400-mg IBU dose equivalents as IBU_Na 2 × 256 mg, Advil^® Liqui-Gels^® (IBU_LG) 2 × 200 mg, and Motrin^® IB (IBU_Mot) 2 × 200 mg tablets. In two periods following a high-fat breakfast, subjects received 400-mg IBU dose equivalents as IBU_Na 2 × 256 mg and IBU_LG 2 × 200 mg. Study 2: In five study periods, fasted subjects received 400-mg IBU dose equivalents as IBU_Na 2 × 256 mg, Advil^® FastGel^® (IBU_FG) 2 × 200 mg, Nurofen^® (IBU_Nur) 2 × 200 mg, Advil^® (IBU_Adv) 2 × 200 mg, and Nurofen^® Express containing IBU lysinate (IBU_Lys) 2 × 342 mg.

Main Outcome Measure

Log-transformed area under the plasma concentration versus time curve to last observable concentration (AUC_L) and maximum plasma concentration (C_max) were the primary pharmacokinetic parameters; time to maximum measured plasma concentration (T_max) was analyzed post hoc.

Results

IBU_Na was bioequivalent to IBU_LG (fasted and fed) and IBU_FG and IBU_Lys (fasted) for rate (C_max) and extent (AUC_L) of IBU absorption. After fasting, AUC_L was bioequivalent for IBU_Na and IBU_Mot, IBU_Adv, and IBU_Nur, but C_max occurred significantly earlier with IBU_Na. After fasting, median IBU_NaT_max was comparable to that for IBU_LG, IBU_FG, and IBU_Lys, but was much shorter than that for IBU_Mot, IBU_Nur, and IBU_Adv. Food slowed absorption of IBU_Na and IBU_LG similarly. All treatments were tolerated similarly.

Conclusion

IBU_Na is absorbed faster but to a similar extent as standard IBU formulations.     

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

Background

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

Objectives

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

Methods

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

Results

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

Conclusion

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

Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate

Background and purpose:

Changes in tissue P-glycoprotein (P-gp) activity during pregnancy could affect the pharmacokinetics and thus the efficacy and toxicity of many drugs. Therefore, using positron emission tomography (PET) imaging, we tested whether gestational age affects tissue P-gp activity in the pregnant non-human primate, Macaca nemestrina.

Experimental approach:

Mid-gestational (day 75 ± 13, n= 7) and late-gestational (day 150 ± 10, n= 5) age macaques were imaged after administration of a prototypic P-gp substrate, ¹¹C-verapamil (13.7–75.4 MBq·kg⁻¹), before and during intravenous infusion of a P-gp inhibitor, cyclosporin A (CsA) (12 or 24 mg·kg⁻¹·h⁻¹). Accumulation of radioactivity in the fetal liver served as a reporter of placental P-gp activity. P-gp activity was expressed as CsA-induced percent change in the ratio of the area (0–9 min) under the ¹¹C-radioactivity concentration–time curve in the tissue (AUC_tissue) to that in the maternal plasma (AUC_plasma).

Key results:

The CsA-induced change in AUC_{fetal liver}/AUC_{maternalplasma} of ¹¹C-radioactivity significantly increased from mid- (35 ± 25%) to late gestation (125 ± 66%). Likewise, the CsA-induced change in AUC_{maternal brain}/AUC_plasma increased from mid- (172 ± 80%) to late gestation (337 ± 148%). The AUC ratio for the other maternal tissues was not significantly affected. Neither the CsA blood concentrations nor the level of circulating ¹¹C-verapamil metabolites were significantly affected by gestational age.

Conclusions and implications:

P-gp activity at the blood–brain barrier and the placental barrier in the macaque increased with gestational age. If replicated in humans, the exposure of the fetus and maternal brain to P-gp substrate drugs, and therefore their efficacy and toxicity, will change during pregnancy.