Significant Differences In Cmax Research Articles

Comparative pharmacokinetics of intravenous and subcutaneous pantoprazole in sheep and goats

Abomasal ulcers are a significant concern in intensive animal farming due to their impact on animal health and productivity. While proton pump inhibitors (PPIs) such as pantoprazole (PTZ) show promise in treating these ulcers, data on PTZ's pharmacokinetics (PK) in adult goats and sheep are limited. This study aims to fill this gap by investigating and comparing PTZ's PK in these species following single intravenous (IV) and subcutaneous (SC) administrations. Five healthy male goats and sheep were included in the study. PTZ concentrations in plasma samples were determined using a validated analytical method. Non-compartmental analysis was conducted, and statistical comparisons were made between IV and SC administrations and between species. Sheep and goats showed similar systemic exposure levels regardless of the administration route. However, sheep had a shorter t1/2 due to a higher Vd compared to goats. Cl values were comparable in both species, with low extraction ratio values. There were no significant differences in Cmax and Tmax between the two species with regards to SC administration, and complete bioavailability was observed. The MAT exceeded the t1/2 in both species, indicating a potential flip-flop phenomenon. Considering the AUC as a predictor for drug efficacy, and observing no significant differences in systemic exposure between sheep and goats for any route of administration, dosage adjustment between the two species may not be necessary. In field settings, SC administration proves more practical, providing not only complete bioavailability but also a longer half-life compared to IV. Further studies are warranted to explore the PK/PD of PTZ in small ruminants with abomasal ulcers, to fully comprehend its therapeutic efficacy in such scenarios.

A crossover study to evaluate the pharmacokinetics and bioequivalence of hydroxychloroquine tablets in healthy Chinese subjects.

Hydroxychloroquine (HCQ) has a high variability and a long half-life in the human body. The purpose of this study was to evaluate the bioequivalence of a generic HCQ tablet (test preparation) versus a brand HCQ tablet (reference preparation) under fasting and fed conditions in a crossover design. This was an open-label, two-period randomized, single-dose, crossover study in 47 healthy Chinese subjects who were sequentially and randomly allocated either to the fed group (high-fat meal; n = 23) or the fasting group (n = 24). Participants in each group were randomized to the two arms to receive either a single 200-mg dose of the test preparation or a 200-mg dose of the reference preparation. The application of the two preparations in each patient was separated by a 28-day washout period, regarded as sufficiently long to avoid significant interference from residual drug in the body. Whole blood samples were collected over 72 hours after drug administration. A total of 23 subjects completed both the fed and the fasting parts of the trial. There were no significant differences in Cmax, AUC0-72h, and T1/2 between the test and reference preparation (p < 0.05). Food had no significant effect on Cmax and T1/2 (p < 0.05), but AUC0-72h values were significantly reduced under fed condition compared to fasting condition (p < 0.05). The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of Cmax and AUC0-72h were 0.84 - 1.05 and 0.89 - 0.98 in the fed study, and 0.97 - 1.07 and 0.97 - 1.05 in the fasting study, respectively. The carryover effect due to non-zero blood concentrations resulted in higher AUC0-72h values in the second period for both test and reference formulations and had no effect on the statistical results. No serious adverse events were reported. The investigation demonstrated that the test and reference preparations are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese subjects.

Pharmacokinetics and safety of injected ornidazole compared to its enantiomer levornidazole in healthy Chinese subjects.

To compare the pharmacokinetics of levornidazole and ornidazole in healthy Chinese subjects after a single intravenous injection, and to determine whether the chiral inversion of levornidazole occurs in vivo. The study was a randomized, open-label, two-period crossover, single-dose design. A total of 12 subjects were enrolled in this study. Subjects received an intravenous injection of either levornidazole sodium chloride injection (200mL: 0.5g) or ornidazole sodium chloride injection (200mL: 0.5g) once per period. The plasma concentrations of levornidazole, ornidazole, and their metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Phenix WinNolin software (version 6.4) was used to calculate the pharmacokinetic parameters of levornidazole, ornidazole, and their metabolites. Dexornidazole was not detected in the plasma or urine. After a single intravenous injection of levornidazole or ornidazole, there was no significant difference in Cmax between the two drugs (p<0.05). The AUC0-∞ and AUC0-t of levornidazole were slightly lower than those of ornidazole. Metabolites M1 and M4 were detected in the plasma of both drugs, and their pharmacokinetic parameters were similar. Metabolites M1, M2, and M4 were present in urine. The average cumulative urinary excretion rates of levornidazole and its metabolites M1 and M4 were: during 0-24 hours (8.14±0.80%, 0.560±0.072%, and 1.42±0.19%) and 0-60 hours (10.5±1.0%, 0.960±0.084%, and 2.52±0.20%), the average cumulative urinary excretion rates of ornidazole and its metabolites M1 and M4 were: 0-24 hours (8.64±0.98%, 0.486±0.074%, and 1.46±0.21%), 0-60 hours (11.8±1.0%, 0.888±0.070%, and 2.76±0.20%). The incidence of adverse reactions was similar between the two drugs. No chiral inversion of levornidazole occurred in vivo after intravenous administration of levornidazole. The pharmacokinetic parameters and cumulative excretion rates of levornidazole and ornidazole were similar. The safety results were basically consistent between the two drugs.

Topical pharmacokinetics of brinzolamide suspensions in rabbits and variability analysis for sample size and design considerations

Identifying critical attributes for complex locally acting ophthalmic formulations and establishing in vitro-in vivo correlations can facilitate selection of appropriate thresholds for formulation changes that reflect lack of impact on in vivo performance. In this study the marketed antiglaucoma product Azopt® (1% brinzolamide suspension) and five other brinzolamide formulations varying in particle size distributions and apparent viscosities were topically administered in rabbits, and their ocular pharmacokinetics was determined in multiple ocular tissues. Statistical evaluation with ANOVA showed no significant differences between the formulations in the peak drug concentration (Cmax) in the aqueous humor and iris-ciliary body. As a post-hoc analysis, the within animal and total variability was determined for Cmax in the aqueous humor and iris-ciliary body. Based on the observed variability, we investigated the sample size needed for two types of study designs to observe statistically significant differences in Cmax. For the sample size calculations, assuming both 25% and 50% true differences in Cmax between two formulations, two study designs were compared: paired-eye dosing design (one formulation in one eye and another formulation in the other eye of the same animal at the same time) versus parallel-group design. The number of rabbits needed in the paired-eye dosing design are much lower than in the parallel-group design. For example, when the true difference in aqueous humor Cmax is 25%, nine rabbits are required in the paired-eye design versus seventy rabbits (35 per treatment) in the parallel-group design to observe a statistically significant difference with a power of 80%. Therefore, the proposed paired-eye dosing design is a viable option for the design of pharmacokinetic studies comparing ophthalmic products to determine the impact of formulation differences.

Selection of Odronextamab Pediatric Dosing Regimens for Aggressive Non-Hodgkin Lymphoma Via a Modeling and Simulation Approach

Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity, independent of T-cell receptor-mediated recognition. Clinical studies of odronextamab in adult patients with relapsed/refractory CD20+ B-cell malignancies are ongoing. Encouraging efficacy has been reported in patients participating in the Phase I study ELM-1 (NCT02290951; Bannerji R, et al. Lancet Haematol. 2022;9:e327-39). In the US, approximately 800 new cases of pediatric non-Hodgkin lymphoma (NHL) are diagnosed each year. Improved treatment options are needed for pediatric patients, particularly those with relapsed/refractory disease following chemoimmunotherapy, who have poor outcomes. A study of odronextamab in relapsed/refractory pediatric patients with B-cell NHL (B-NHL) is being planned. The objective of this analysis was to determine intravenous (IV) regimens for testing in pediatric patients that can achieve similar exposures to those achieved in adults. Methods The analysis was conducted in 6 steps: 1) A population pharmacokinetic (PK) model was developed with data from adults receiving IV odronextamab and assessed effects of body weight (WT) on drug clearance (CL) and volume of distribution (V); 2) A virtual pediatric population was created with demographics derived from the 2017-2018 National Health and Nutrition Examination Survey database; 3) Pediatric model parameters were extrapolated from those of adults by applying effects of WT and age on CL and V as appropriate; 4) Odronextamab PK profiles were simulated in virtual pediatric patients aged 6 months to 18 years in 4 weight bands (≥40 kg, 20-39 kg, 10-19 kg, 6-9 kg) using the extrapolated pediatric population model parameters; 5) Odronextamab drug amounts were adjusted in each weight band for each weekly (QW) dosing period, and every 2 weeks (Q2W) dosing period with the aim of matching adult patient exposures; and 6) Pediatric regimens were selected for testing based on 2 criteria. Firstly, for safety, median maximal concentration (Cmax) during Cycle 1 step-up dosing within 80-125% of the adult value. Secondly, for efficacy, median minimal concentration (Cmin) at steady state during Cycle 2 onwards not less than the adult value. Results Step-up dosing is used in Weeks 1-3 of treatment of adult patients with odronextamab to mitigate the risk of cytokine release syndrome, a common adverse event with T-cell engaging therapies. Applying a simulation approach, dosing regimens tiered by WT bands were proposed for pediatric patients (Table). Children with WT ≥40 kg could receive the adult's regimen; those weighing <40 kg could receive reduced doses according to their WT bands. The regimens and model assumptions will be tested in a pediatric study with patients weighing ≥20 kg enrolled first. The proposed regimens were predicted to achieve odronextamab exposures similar to those with the adult regimen. No significant difference in Cmax was predicted with the step-up doses; the ratios of median Cmax for the pediatric WT groups relative to adults fell within 0.831-1.24. The median Cmin values at steady state were not below those observed in adults. Additional exploratory simulations were performed to assess uniform weight-based dosing (mg/kg) for the overall pediatric population. This approach was inferior to the regimens tiered by WT bands due to above-target concentrations among individuals weighing ≥20 kg and below-target concentrations in those weighing 6-9 kg. Conclusion The modeling and simulation approach allowed the identification of dosing regimens that might be suitable for investigational use in children with B-NHL. Based on predicted PK profiles, pediatric dosing regimens tiered by WT bands may preserve the efficacy of odronextamab observed in adults, without increasing the risk of acute toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Study and exploration of the pharmacokinetics of traditional Tibetan medicine Ruyi Zhenbao tablets after single and long-term administration

Tibetan medicine is one of the oldest traditional medicine systems in the world. Taking the Ruyi Zhenbao tablet (RYZB) as an example, which is a widely used classic oral Tibetan medicine, this article discusses the pharmacokinetics of single administration and long-term treatment and analyzed its metabolic properties and tissue distribution in vivo. After single administration, blood samples were collected before administration and at different time points after administration in different groups of rats. In the study of long-term treatment effects, blood samples were collected from the animals in each group on days 1, 15, and 30 and on day 15 after withdrawal. The results showed that after a single administration, the dose change had no significant effect on the T1/2 and Tmax of agarotetrol, isoliquiritigenin, and piperine (p > 0.05). There was a certain correlation between the increase in AUC0-t and the Cmax of agarotetrol, isoliquiritigenin, piperine, and the increase in dosage, with a dose range of 0.225–0.900 g/kg. There were no significant differences in Cmax and AUC0-t of ferulic acid at different doses (p > 0.05). Meanwhile, there was no significant sex-based difference in the pharmacokinetic parameters of these four components in rats. After long-term administration, the distribution agarotetrol in various tissues of rats was kidney > liver > heart > brain; the tissue distribution in low- and medium-dose groups of isoliquiritigenin was liver > kidney > heart > brain, and in the high-dose group, kidney > liver > heart > brain. The tissue distribution of piperine in each dose group was liver > kidney > heart > brain, and that of ferulic acid in each dose group was kidney > liver > heart > brain. Through the establishment of the previously developed methodology, the pharmacokinetic properties of RYZB were analyzed after a single administration and long-term administration. Our findings confirmed this approach for the exploration and establishment of a pharmacokinetic evaluation of Tibetan medicine, to support its guiding role in clinical application, but also to accelerate research into Tibetan medicine theory and medicine and to provide a solid foundation for the translation of Tibetan medicine throughout the world.

Safety and Tolerability of Carboplatin and Paclitaxel in Cancer Patients with HIV (AMC-078), an AIDS Malignancy Consortium (AMC) Study

BackgroundPersons living with human immunodeficiency virus are an underserved population for evidence-based cancer treatment. Paclitaxel and carboplatin (PCb) is an active regimen against a variety of solid tumors, including several seen in excess in patients with HIV infection. We performed a pilot trial to evaluate the safety of full-dose PCb in people living with human immunodeficiency virus and cancer.MethodsEligible patients, stratified by concurrent antiretroviral therapy (ART) that included CYP3A4 inhibitors or not, received paclitaxel (175 mg/m2) in combination with carboplatin (target AUC 6) intravenously every 3 weeks for up to 6 cycles.ResultsSixteen evaluable patients received 64 cycles of PCb, including 6 patients treated with CYP3A4 inhibiting ART (ritonavir). The adverse event profile was consistent with the known toxicity profile of PCb, with no differences between the 2 strata. There were 4 partial responses (25%, 95% CI: 7%-52%), and overall, CD4+ lymphocyte count was similar after completion of therapy (median: 310/μL) compared with baseline values (median: 389/μL). Pharmacokinetic studies in 6 patients revealed no significant differences in Cmax or AUCinf for paclitaxel between the 2 cohorts.ConclusionFull doses of PCb chemotherapy are tolerable when given concurrently with ART in people living with human immunodeficiency virus with cancer, including patients receiving CYP3A4 inhibitors.ClinicalTrials.gov IdentifierNCT01249443.

Effect of erythromycin on abomasal emptying in suckling lambs with experimental endotoxemia

Abomasal hypomotility and consequently a decrease in abomasal emptying rate is one of the most important factors in ruminant abomasal disorders. Endotoxemia is clinically recognized by abnormalities in cardiovascular function, renal failure, decreased gastrointestinal motility and shock. This can lead to bloating and sudden death in lambs that have not received enough colostrum. The aim of the study was to investigate the effect of erythromycin treatment on abomasal emptying rate in endotoxemic lambs. Fifteen suckling lambs arranged in 3 groups (n = 5) were studied in this study. Endotoxemia was induced in two groups (Positive control and Erythromycin) at 0.1 μg/kg body weight LPS in 10 mL normal saline over 5 min IV and erythromycin was injected to erythromycin group at 8.8 mg/kg BW IM. Negative control received 2 mL normal saline IM. Abomasal emptying rate was assessed by acetaminophen absorption test, which was fed with milk at 50 mg/kg BW, 30 min after each treatment. Samples were collected at 15 min intervals up to 240 min and abomasal emptying rate was assessed for each group. Results showed there were significant differences in Cmax, Tmax and AUC among groups (endotoxemia groups and control group) (P < 0.05), confirming a decrease in abomasal emptying rate in lambs with endotoxemia. The results also indicated that compared to affected lambs not treated with erythromycin, abomasal emptying rate was significantly higher in lambs treated with erythromycin that means erythromycin increased abomasal emptying rate (P < 0.05).

Impact of jet pulverization and wet milling techniques on properties of aripiprazole long-acting injection and absorption mechanism research in vivo

This study aims to explore the influence of wet milling and jet pulverization on the aripiprazole microcrystalline long-acting injection. Crystal form and particle size distribution were taken as inspection indicators in vitro, and process parameters were optimized. The formulation prepared by wet milling (AMLAI-WM) was shown to undergo a slight conversion of crystal form by DSC, PXRD, TG, FT-IR and have a wider particle size distribution with D50 and Span values of 2.967 μm and 3.457 compared to the formulation fabricated by jet pulverization (AMLAI-JP) with 2.887 μm and 2.258 respectively. In addition, the in vitro release of AMLAI-WM was faster, whereby the pharmacokinetic data indicated that AMLAI-WM was absorbed more quickly within five days with AUC0-5d of 5243.7 μg·L-1·h and 4818.28 μg·L-1·h, respectively. Furthermore, no statistically significant differences in Cmax, tmax and AUC between AMLAI-JP and the commercial formulation (Abilify Maintena™) were found. The absorption mechanism was studied and showed a 1.4-fold later Tmax after depletion of macrophages and significantly lower Cmax and AUC after inhibiting angiogenesis, indicating inflammatory granuloma could facilitate drug plasma exposure. Overall, we demonstrated that jet pulverization was a good strategy for long-acting microcrystalline injection, and that the absorption behavior was affected by both particle size distribution and inflammatory granuloma.

Pharmacokinetic and pharmacodynamic evaluation of the new prolonged-release leuprorelin acetate microspheres for injection compared with Enantone® in healthy Chinese male volunteers

ABSTRACT Purpose To compare the pharmacokinetics, pharmacodynamics and safety of the new prolonged-release leuprorelin acetate microspheres for injection (3.75 mg) with the reference product Enantone® (3.75 mg). Method 48 healthy male volunteers were enrolled and randomly received a single 3.75 mg dose of the test drug or Enantone®. Results There were no significant differences in Cmax, AUC0-t and AUC0-48 between the test group and reference group (P > 0.05). The 90% confidence intervals of the two groups were 87.49%~112.74%, 97.15%~154.25%, and 80.85%~109.01%, respectively. Twenty-eight days after administration, both groups reached 100.0% castration level; there was no difference in the time from administration to reaching castration level between the two groups (P > 0.05); However, the difference between the two groups in the duration of castration level was statistically significant (P < 0.05). There were no major or serious adverse events, and the severity was mild to moderate. Conclusion The pharmacokinetic characteristics of leuprorelin in two groups were consistent. The two groups exhibited similar inhibitory effects on testosterone and more subjects in the test group maintained a longer castration time than those in the reference group.

Pharmacokinetic Characterization of a Prototype Mini Nicotine Lozenge.

Cigarette smoking remains a substantial public health problem. Nicotine replacement therapy (NRT) is an effective treatment that increases the success of a quit attempt. There are different NRT formats with no difference in efficacy, but their pharmaceutical form or route of administration may translate into individual preferences. A novel prototype mini lozenge was developed to offer smokers a new NRT option to aid in their quit attempt. Two studies were conducted to characterize the pharmacokinetic parameters and to evaluate its bioequivalence to a commercially available nicotine mini lozenge. Two randomized, open-label, crossover studies were conducted to evaluate either the 2 or 4mg dose level. Heavy smokers in otherwise good health were randomly assigned to one of two treatment sequences: the prototype mini lozenge followed by a commercially available mini lozenge, or the converse. After a 5 to 7day washout period, subjects crossed over to receive the other study treatment. Blood sampling occurred pre- and post-dose nicotine and was assessed using a validated solid-phase extraction with ultra-high-performance liquid chromatography and tandem mass spectrometry. The primary endpoint was bioequivalence as determined by maximal plasma nicotine concentration (Cmax) and the extent of nicotine absorption (AUC0-t and AUC0-∞). The secondary endpoints included the time to Cmax (Tmax), half-life, the elimination constant (Kel), and safety. The prototype mini lozenge was bioequivalent to the commercially available mini lozenge, with no significant difference in Cmax, AUC0-t, or AUC0-∞ or any of the secondary outcomes. The most common treatment-emergent adverse event was throat irritation, of which all cases were mild in severity. There were no serious adverse events. The prototype mini lozenge is bioequivalent to a commercially available mini lozenge and may provide smokers with a new oral NRT option to aid in smoking cessation and of tobacco dependence through the relief of nicotine withdrawal symptoms, including cravings.

Pharmacokinetics and bioavailability of tildipirosin following intravenous and subcutaneous administration in horses.

This study was designed to investigate the safety and pharmacokinetic (PK) profile of tildipirosin in horses after intravenous (i.v.) and subcutaneous (s.c.) injection of a single dose at 4mg/kg of body weight (b.w.). A total of 12 healthy mixed breed horses were used in the study. Horses were monitored for systemic and local adverse effects, and whole blood samples were collected for hematology and plasma biochemistry analysis at time (0) and at 6, 24, and 72h after drug administration. For PK analysis, blood samples were collected at pre-determined times before and after tildipirosin administration. Plasma concentrations of tildipirosin were determined using ultra-high-performance liquid chromatography-ultraviolet detection method (UHPLC-UV). All horses tolerated the i.v. injection of tildipirosin without showing any systemic adverse effects. However, a non-painful, soft swelling appeared at the s.c. injection site in 5 horses (41.7%). On average, tildipirosin reached a maximum plasma concentration (Cmax ) of 1257ng/ml (geometric mean) between 0.5 and 1.5h after s.c. administration (Tmax ). The geometric mean values for total body clearance (Cl), the apparent volume of distribution based on the terminal phase (Vz ), and the apparent volume of distribution at steady-state (Vss ) were 0.52 L/kg·h, 22 L/kg, and 10.0 L/kg, respectively. Data collected in this study suggests that tildipirosin can be used safely in horses with caution.

Effects of paroxetine on the pharmacokinetics of atomoxetine and its metabolites in different CYP2D6 genotypes.

The aim of this study was to investigate the effects of paroxetine, a potent inhibitor of CYP2D6, on the pharmacokinetics of atomoxetine and its two metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine, in different CYP2D6 genotypes. Twenty-six healthy subjects were recruited and divided into CYP2D6*wt/*wt (*wt=*1 or *2, n = 10), CYP2D6*wt/*10 (n = 9), and CYP2D6*10/*10 groups (n = 7). In atomoxetine phase, all subjects received a single oral dose of atomoxetine (20mg). In paroxetine phase, after administration of a single oral dose of paroxetine (20mg) for six consecutive days, all subjects received a single oral dose of atomoxetine with paroxetine. Plasma concentrations of atomoxetine and its metabolites were determined up to 24 h after dosing. During atomoxetine phase, there were significant differences in Cmax and AUC0-24 of atomoxetine and N-desmethylatomoxetine among three genotype groups, whereas significant differences were not found in relation to CYP2D6*10 allele after administration of paroxetine. AUC ratios of 4-hydroxyatomoxetine and N-desmethylatomoxetine to atomoxetine were significantly different among three genotype groups during atomoxetine phase (all, P < 0.001), but after paroxetine treatment significant differences were not found. After paroxetine treatment, AUC0-24 of atomoxetine was increased by 2.3-, 1.7-, and 1.3-fold, in CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 groups in comparison to atomoxetine phase, respectively. AUC ratio of 4-hydroxyatomoxetine to atomoxetine in each group was significantly decreased, whereas AUC ratio of N-desmethylatomoxetine to atomoxetine significantly increased after administration of paroxetine. In conclusion, paroxetine coadministration significantly affected pharmacokinetic parameters of atomoxetine and its two metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine. When atomoxetine was administered alone, Cmax, AUC0-24 and CL/F of atomoxetine were significantly different among the three CYP2D6 genotype groups. However, after paroxetine coadministration, no significant differences in these pharmacokinetic parameters were observed among the CYP2D6 genotype groups.

Pharmacokinetics and bioavailability of tildipirosin following intravenous and subcutaneous administration in sheep.

Tildipirosin is a semi-synthetic macrolide antibiotic commonly used in cattle and swine to treat bacterial pneumonia. The objective of this study was to investigate the pharmacokinetic profile of tildipirosin after a single intravenous (i.v.) and subcutaneous (s.c.) administration in healthy lambs. Eighteen lambs were randomly divided into three groups (n=6 each). Lambs received a single s.c. dose of tildipirosin at 4 and 6mg/kg b.w. in group 1 and 2, respectively. Lambs in group 3 received a single i.v. dose of tildipirosin at 4mg/kg b.w. Blood samples were collected at 0, 0.5, 0.75, 1.5, 2, 3, 4, 6, 8, 10, 24, 36, 48hr, and every 24hr to day 21, and thereafter at day 28 posttildipirosin administration. The plasma concentrations of tildipirosin were determined using high-performance liquid chromatography with tandem mass spectrometry detection (LC⁄MS⁄MS). All lambs appeared to tolerate both the intravenous and subcutaneous injection of tildipirosin. Following i.v. administration, the elimination half-life (T1/2 ), mean residence time (MRT), volume of distribution (Vd/F), and total body clearance (Cl/F) were 119.6±9.0hr, 281.9±25.7hr, 521.1±107.2 L, and 2.9±0.5L/hr, respectively. No significant differences in Cmax (657.0±142.8 and 754.6±227.1ng/ml), Tmax (1.21±0.38 and 1.35±0.44hr), T1/2 (144±17.5, 156.5±33.4hr), and MRT (262.0±30.2 and 250.6±54.5hr) were found in tildipirosin after s.c. dosing at 4 and 6mg/kg b.w., respectively. The absolute bioavailability (F) of tildipirosin was 71.5% and 75.3% after s.c. administration of 4 and 6mg/kg b.w., respectively. In conclusion, tildipirosin was rapidly absorbed and slowly eliminated after a single s.c. administration in healthy lambs. Tildipirosin could be used for the treatment and prevention of respiratory bacterial infections in sheep. However, further in vitro and in vivo studies to determine the efficacy and safety are warranted. To our knowledge, this is the first study to determine the tildipirosin pharmacokinetic parameters in sheep plasma.

Intranasal epinephrine effects on epinephrine pharmacokinetics and heart rate in a nasal congestion canine model

BackgroundHistamine release and vasodilation during an allergic reaction can alter the pharmacokinetics of drugs administered via the intranasal (IN) route. The current study evaluated the effects of histamine-induced nasal congestion on epinephrine pharmacokinetics and heart rate changes after IN epinephrine.MethodsDogs received 5% histamine or saline IN followed by 4 mg epinephrine IN. Nasal restriction pressure, epinephrine concentration, and heart rate were assessed. Maximum concentration (Cmax), area under plasma concentration-time curve from 1 to 90 min (AUC1–90), and time to reach Cmax (Tmax) were measured. Clinical observations were documented.ResultsIn the 12 dogs in this study, nasal congestion occurred at 5–10 min after IN histamine administration versus no nasal congestion after IN saline. After administration of IN epinephrine, IN histamine-mediated nasal congestion was significantly reduced to baseline levels at 60, 80, and 100 min. There were no significant differences in Cmax and AUC1–90 between histamine and saline groups after IN epinephrine delivery (3.5 vs 1.7 ng/mL, p = 0.06, and 117 vs 59 ng/mL*minutes, p = 0.09, respectively). After receiving IN epinephrine, the histamine group had a significantly lower Tmax versus the saline group (6 vs 70 min, respectively; p = 0.02). Following IN epinephrine administration, the histamine group showed rapidly increased heart rate at 5 min, while there was a delayed increase in heart rate (occurring 30–60 min after administration) in the saline group. Clinical observations included salivation and emesis.ConclusionIN histamine led to more rapid epinephrine absorption and immediately increased heart rate compared with IN saline. IN epinephrine decreased histamine-induced nasal congestion.

Intranasal epinephrine in dogs: Pharmacokinetic and heart rate effects.

Epinephrine is the standard of care for the treatment of severe allergy and anaphylaxis. Epinephrine is most often administered through the intramuscular (IM) route via autoinjector. The current study aimed to evaluate an alternative method of epinephrine treatment through intranasal (IN) delivery in dogs. The pharmacokinetic (PK) parameters of maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), and area under the plasma concentration‐time curve from 0 to 90 minutes (AUC0–90) were observed after IN epinephrine (2, 3, 4, 5, 10, and 20 mg) and IM epinephrine via autoinjector (0.15 and 0.3 mg) for 90 minutes. Heart rate effects were measured after IN (2 and 5 mg) and IM (0.15 and 0.3 mg) epinephrine administration. IN epinephrine (5 mg) demonstrated significantly greater plasma epinephrine concentration at 1 minute as compared with IM epinephrine (0.3 mg) (1.68 ± 0.65 ng/mL vs 0.21 ± 0.08 ng/mL, P = .03). There were no significant differences in Cmax, Tmax, and AUC0–90 between 2‐mg IN and 0.15‐mg IM epinephrine or between 5‐mg IN and 0.3‐mg IM epinephrine. IN epinephrine reduced heart rate increases, as compared to IM epinephrine. IN and IM epinephrine were both well‐tolerated. Overall, IN epinephrine demonstrated advantages over IM epinephrine, including the rapid increase in plasma epinephrine and lack of increased heart rate over time.

Comparative pharmacokinetics of osmotic-controlled and immediate-release Eperisone tablet formulation in healthy human subjects using a sensitive plasma LC-ESI-MS/MS method

To evaluate and compare the pharmacokinetic (PK) characteristics of a newly developed oral osmotically controlled drug delivery system of Eperisone 150 mg tablets with Eperisone immediate release (IR) marketed tablet brand as a reference formulation. It was a single dose, two treatment, two sequence, randomized, crossover study, involving 12 healthy human subjects. A modified, sensitive LC-ESI-MS/MS method was developed and validated as per FDA guidelines for estimation of Eperisone in plasma using a simple extraction and quick protein precipitation method. Non-compartmental pharmacokinetic model was used for PK analysis. Results were statistically compared using logarithmically transformed data, where p > 0.05 was considered as non-significant with 90% CI limit of 0.8–1.25. The bio-analytical method used for estimating drug plasma concentration was found to be simple, selective, linear, accurate and precise with 0.01 ng/ml as limit of detection. The comparative PK analysis revealed an insignificant difference in AUC0-∞, AUC0-t, Vz/F, Cl/F and t1/2λz, whereas a significant difference in Cmax, Tmax and MTTs were found. The relative bioavailability of Eperisone osmotic tablet was 109.7%. The osmotic controlled release drug formulation was found to release Eperisone for an extended period with less inter individual fluctuation in pharmacokinetic variables.

Riluzole Oral Suspension: Bioavailability Following Percutaneous Gastrostomy Tube-modeled Administration Versus Direct Oral Administration

PurposeDuring amyotrophic lateral sclerosis progression, up to 85% of patients develop dysphagia. Riluzole oral suspension 50 mg/10 mL is bioequivalent to riluzole 50-mg film-coated tablets administered orally under fasting conditions. Here, we compare the bioavailability of a single 50-mg dose of riluzole oral suspension via intragastric tube, a proxy for percutaneous endoscopic gastrostomy administration, with that of oral administration in healthy volunteers under fasting conditions. Secondary objectives included the plasma pharmacokinetic and safety profiles of each administration route. MethodsThis was a single-center, single-dose, open-label, randomized, 2-period, 2-sequence, crossover bioequivalence/bioavailability study. Healthy volunteers were randomized to riluzole oral suspension 50 mg/10 mL either via nasogastric tube or orally, with a 5-day washout before crossover. FindingsA total of 32 subjects were randomized (safety population); 30 were eligible for pharmacokinetic analysis. The ratios (nasogastric tube/oral) of the geometric least squares means and the geometric 90% CIs of AUC0–t, AUC0–inf, and Cmax were calculated to be 90.60% (85.66%–95.82%), 90.43% (85.47%–95.67%), and 96.99% (89.40%–105.23%), respectively, indicating bioequivalence. No significant differences in Cmax, Tmax, Kel, and t1/2el between treatments were found. Overall, riluzole oral suspension was well tolerated. No deaths or other serious adverse events were reported. ImplicationsIn this study, riluzole oral suspension was bioequivalent when administered intragastrically and orally in healthy subjects under fasting conditions. Both administration methods were well tolerated. These results show that intragastric administration of riluzole oral suspension may provide an important formulation option in people with amyotrophic lateral sclerosis who have a percutaneous endoscopic gastrostomy tube.

Effects of CYP2C19 Genetic Polymorphisms on the Pharmacokinetic and Pharmacodynamic Properties of Clopidogrel and Its Active Metabolite in Healthy Chinese Subjects

PurposeSome studies in the white population have shown that carriers of at least 1 loss-of-function allele in the gene that encodes the cytochrome P-450 2C19 isozyme (CYP2C19) have lower levels of the clopidogrel active metabolite (CAM) and a reduced antiplatelet effect of clopidogrel. However, data are limited regarding the association between CYP2C19 genetic variants and exposure to CAM and on the pharmacodynamic properties of CAM in the Chinese population. Data from the white population cannot be extrapolated to the Chinese population because of the marked interethnic differences in CYP2C19 variants. This study was aimed to investigate the influence of CYP2C19 genetic polymorphisms on the pharmacokinetic properties of CAM and the antiplatelet effect of clopidogrel in healthy Chinese volunteers, and to provide evidence for the role of a CYP2C19 genotyping test in predicting the antiplatelet effect of clopidogrel in the Chinese population. MethodsTwenty healthy subjects received a single 300-mg dose of clopidogrel and were assigned to 1 of 3 groups according to CYP2C19 genotype: CYP2C19 *1/*1 (normal metabolizers [NM]; n = 8), CYP2C19 *1/*2 or *3 (intermediate metabolizers [IM]; n = 10) and CYP2C19 *2/*2 or *3 and *3/*3 (poor metabolizers [PM]; n = 2). Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration. The plasma concentrations of clopidogrel and CAM were analyzed by LC-MS/MS, and adenosine diphosphate–induced platelet aggregation was measured by light-transmittance aggregometry. FindingsThere were no significant differences in Cmax and AUC0–t of clopidogrel prodrug in the NM group compared with the IM and PM groups. The mean CAM Cmax value was significantly higher in the NM group than in IM and PM groups (45.39 [12.57] vs 29.15 [7.92] ng/mL [P = 0.003] and 19.55 [2.19] ng/mL [P = 0.004], respectively). The mean CAM AUC0–t value was significantly higher in the NM group than in the IM and PM groups (61.05 [21.63] vs 37.67 [11.01] ng · h/mL [P = 0.007] and 27.08 [2.72] ng · h/mL [P = 0.016]). The NM group exhibited a significantly higher percentage of inhibition of platelet aggregation than did the IM or PM group (P = 0.001). The correlations between the pharmacokinetic properties (Cmax, AUC0–t) of CAM and the pharmacodynamic data (maximal and inhibition of platelet aggregation) were significant (both, Pearson r > 0.5 and P < 0.01). ImplicationIn these healthy Chinese subjects, carriers of CYP2C19 loss-of-function allele(s) had significantly reduced exposure of CAM and decreased levels of inhibition of platelet aggregation with clopidogrel; these genotypes therefore might be a determinant for the formation of CAM and its antiplatelet effects. Study identifier: ChiCTR-OCH-14004382.

Development of a selective and sensitive high-performance liquid chromatography-tandem mass spectrometry assay to support pharmacokinetic studies of LY-487,379 in rat and marmoset

Drugs modulating the metabotropic glutamate type 2 receptor (mGluR2) activity may have therapeutic benefits in treating a large spectrum of neuro-psychiatric disorders, from schizophrenia to Parkinson's disease, both as a symptomatic therapy and potential disease-modifying paradigm. LY-487,379 is a highly selective mGluR2 positive allosteric modulator that is widely used to study mGluR2 function using experimental animal models. The common marmoset is a small primate that has long been used in neuroscience. However, given its small size and small circulating blood volume, conducting studies to determine the PK profile of LY-487,379 is challenging. We developed and validated a sensitive and selective analytical method that enables quantification of LY-487,379 using a limited volume of plasma (10 μL). The analytical method consists of protein precipitation followed by high-performance liquid chromatography with heat assisted electrospray ionization mass spectrometry (HPLC-HESI-MS/MS). The chromatographic separation was achieved using gradient elution with a mobile phase consisting of acetonitrile and 0.01% formic acid in water on a Thermo Scientific Aquasil C18 analytical column (100 × 2.1 mm I.D., 5 μm) operating at 40 °C and at a flow rate of 300 μL/min. The method displays a linear relationship ranging from 0.2 to 100 ng/mL. Intra- and inter-day relative standard deviations are <1.4% and 7.9%, respectively and the relative error ranged from −6.9 to 9.7%. The method was used to quantify LY-487,379 in both rat and marmoset plasma, and PK parameters were determined after a single subcutaneous dose of 1.0 mg kg−1 in both species and significant differences in Cmax, AUC and T1/2 were observed.