Atogepant and sumatriptan: no clinically relevant drug–drug interactions in a randomized, open-label, crossover trial

Aim: To evaluate pharmacokinetic interactions of atogepant with sumatriptan, an open-label, randomized, crossover study was conducted. Patients & methods: Thirty healthy adults received atogepant 60 mg, sumatriptan 100 mg, or coadministered drugs. Primary end point was geometric mean ratios (GMRs) and 90% CIs of interventions for area under the plasma concentration–time curve from time 0 to t (AUC0-t) or infinity (AUC0-∞) and peak plasma concentration (Cmax). Results: Atogepant GMRs for AUC0-t and AUC0-∞ versus with sumatriptan were within 90% CI 0.80–1.25, indicating no interaction; atogepant Cmax was reduced by 22% (GMR: 0.78; 90% CI: 0.69–0.89) with sumatriptan. Sumatriptan GMRs for AUC0-t, AUC0-∞ and Cmax versus with atogepant were within 90% CI 0.80–1.25. Conclusion: Atogepant with sumatriptan had no clinically relevant pharmacokinetic interactions.

Design and Evaluation of Efavirenz Loaded Solid Lipid Nanoparticle for Boosting Oral Bioavailability

Present work illustrates that efavirenz-loaded solid lipid nanoparticles were prepared with the objective of increasing bioavailability and protection of drugs due to biocompatible lipidic content. Efavirenz is generally used for the treatment of HIV. Selection of the suitable lipid phase, surfactant, and cosurfactant was done by individual screening method with the construction of pseudo-ternary phase study. The formulations were prepared by the microemulsion method followed by the lyophilization technique. EFV-SLN has shown a mean particle size of 55.73 ± 3.9 nm having a PDI of 0.153 ± 0.451. Zeta potential was found to be -9.98mV and the formulation was found stable. In vivo pharmaco-kinetic studies exhibited 5.41-fold enhancement in peak plasma concentration (

Influence of Bisphosphonates or Recombinant Human Parathyroid Hormone on in Vitro Chemotherapy Sensitivity in Acute Lymphoblastic Leukemia Cells

BACKGROUND Osteonecrosis and low bone mineral density (BMD) are serious osteogenic side effects of acute lymphoblastic leukemia (ALL) treatment. Bisphosphonates and recombinant human parathyroid hormone (rPTH) tend to be used to ameliorate osteonecrosis-related symptoms as well as to enhance bone mineral density in children with ALL and severe bone fragility. Only one preclinical study on the safety of bisphosphonates during ALL treatment is available, which raises concerns about their impact on leukemic drug sensitivity. Here, we assessed the influence of various bone-modifying agents (zoledronate, pamidronate and rPTH) on in vitro cytotoxicity of chemotherapeutic agents (vincristine (VCR), daunorubicin (DNR), dexamethasone (DEXA), 6-mercaptopurine (6-MP), PEG-asparaginase (PEG-ASP)) and prednisone (PRED) that are commonly used in ALL treatment. METHODS Potential cytotoxic effects of the bone-modifying agents on leukemia cell viability and on in vitro cytotoxic responses of chemotherapeutic agents were tested in various T-cell and B-cell leukemia cell lines using methyl-thiazol-tetrazolium (MTT) assays. Bone-modifying agents were added at concentrations up to a five-fold of their physiological peak plasma concentration. For each assay, 50th percentile of maximal inhibitory concentration was determined. To quantify the combined effects of the bone-modifying agents on chemotherapeutic agent-induced cytotoxicity, median (interquartile range) combination indexes (CI) were calculated. We considered a median CI of < 0.8 as synergism and > 1.2 as antagonism (based on the method of Chou). RESULTS Zoledronate, pamidronate or rPTH in combination with DNR, 6-MP and PEG-ASP showed median CI values between 0.8 and 1.2. Variable inconclusive results were obtained in combination with VCR. Only the combination of a five-fold peak plasma concentration of zoledronate or pamidronate with DEXA resulted in median CI values of 1.15 (range, 1.08-1.48), and 1.34 (range, 1.07-1.62), respectively. Additional experiments using DEXA as well as PRED in combination with one-, three- or five-fold physiological peak plasma concentrations of zoledronate or pamidronate revealed that median CI values stay within 0.8 and 1.2, except for DEXA exposed leukemia cells in combination with a five-fold physiological peak plasma concentration of pamidronate which repeatedly showed a median CI value above 1.2 (1.34, range 1.04-1.86). CONCLUSIONS Zoledronate, pamidronate or rPTH do not seem to influence drug sensitivity of DNR, 6-MP or PEG-ASP, even at a five-fold physiological peak plasma concentration. Nevertheless, our findings suggest a minimal effect of pamidronate on DEXA-induced leukemia cell death. This suggests that even though zoledronate or pamidronate do not seem to negatively influence DEXA- or PRED- induced toxicity in expected physiological concentrations (one- to three-fold physiological peak plasma concentrations), these bone-modifying agents may only be considered with caution in individual cases, and preferably in clinical trial settings before being applied on a large scale in children with ALL. Disclosures No relevant conflicts of interest to declare.

Liposomal Resiquimod for Enhanced Immunotherapy of Peritoneal Metastases of Colorectal Cancer

Colorectal cancer with peritoneal metastases is currently treated by cytoreductive surgery and locoregional chemotherapeutics. This standard treatment is associated with high morbidity, mortality, and recurrence rate. To augment the existing therapy, we developed a liposome-based delivery system containing 1,2-stearoyl-3-trimethylammonium-propane chloride (DSTAP), a cationic lipid, to localize a toll-like receptor agonist, resiquimod (R848), in the peritoneal cavity (PerC) for enhancing the immune response against cancer that had spread to the PerC. The liposomes delivered by intraperitoneal injection increased peritoneal retention of R848 by 14-fold while retarding its systemic absorption, leading to a 5-fold decreased peak plasma concentration compared to free R848 in mice. Within the PerC, the DSTAP-liposomes were found in ~40% of the dendritic cells by flow cytometry. DSTAP-R848 significantly upregulated interferon α (IFN-α) in the peritoneal fluid by 2-fold compared to free R848, without increasing the systemic level. Combined with oxaliplatin, a cytotoxic agent inducing immunogenic cell death, DSTAP-R848 effectively inhibited the progression of CT26 murine colorectal tumor in the PerC, while the combination with free R848 only showed a mild effect. Moreover, the combination of oxaliplatin and DSTAP-R848 significantly increased infiltration of CD8+ T cells in the PerC compared to oxaliplatin combined with free R848, indicating enhanced immune response against the tumor. The results suggest that DSTAP-R848 exhibits potential in augmenting existing therapies for treating colorectal cancer with peritoneal metastases via immune activation.

TO STUDY THE PHARMACOKINETIC HERB-DRUG INTERACTION OF MOMORDICA CHARANTIA FRUIT EXTRACT AND PURE CHARANTIN WITH NATEGLINIDE IN RATS

Objective: Momordica charantia fruit extract and antidiabetic drug Nateglinide might be used simultaneously in the treatment of diabetes, so the objective of this study was to investigate pharmacokinetic herb-drug interactions of Momordica charantia fruit extract and pure charantin with nateglinide in rats. Methods: After oral co-administration of Momordica charantia fruit extract (250 mg/kg) and Charantin (10 mg/kg) with nateglinide in rats, drug concentration parameters peak plasma concentration (Cmax), time to reach peak plasma concentration (tmax), elimination half-life (t1/2), apparent volume of distribution (Vd), plasma clearance (Cl), and area under the curve (AUC) were calculated by using the non-compartment model. Results: NAT was absorbed into the circulatory system and reached its peak concentration approximately 2 h after being administered individually. tmax of groups co-administered NAT+MCE has been changed to 4h. A significant decrease in Cmax of NAT from 16.28 µg/ml to 11.37 µg/ml and 10.37 µg/ml with NAT with charantin and NAT with MCE groups, respectively. AUC of NAT decreased from 84.53 h/µg/ml to 53.63 h/µg/ml and 47.17 h/µg/ml by co-administration with Charantin and MCE respectively. Co-administration of nateglinide with Charantin and Momordica charantia fruit extract decreased systemic exposure level of nateglinide in vivo with decreasing Cmax and AUC and an increase in t1/2, Cl and Vd. Conclusion: From this study, it can be concluded that nateglinide, Momordica charantia fruit extract, and pure Charantin existed pharmacokinetic herb-drug interactions in the rat which has to be correlated with the anti-diabetic study. Further studies should be done to understand the effect of other herbal ingredients of Momordica charantia fruit extract on nateglinide as well as to predict the herb-drug interaction in humans.

Pharmacokinetics and Bioavailability of Carprofen in Rainbow Trout (Oncorhynchus mykiss) Broodstock

The aim of this study was to determine the pharmacokinetics of carprofen following intravenous (IV), intramuscular (IM) and oral routes to rainbow trout (Oncorhynchus mykiss) broodstock at temperatures of 10 ± 1.5 °C. In this study, thirty-six healthy rainbow trout broodstock (body weight, 1.45 ± 0.30 kg) were used. The plasma concentrations of carprofen were determined using high-performance liquid chromatography and pharmacokinetic parameters were calculated using non-compartmental analysis. Carprofen was measured up to 192 h for IV route and 240 h for IM, and oral routes in plasma. The elimination half-life (t1/2λz) was 30.66, 46.11, and 41.08 h for IV, IM and oral routes, respectively. Carprofen for the IV route showed the total clearance of 0.02 L/h/kg and volume of distribution at steady state of 0.60 L/kg. For IM and oral routes, the peak plasma concentration (Cmax) was 3.96 and 2.52 μg/mL with the time to reach Cmax of 2 and 4 h, respectively. The bioavailability was 121.89% for IM route and 78.66% for oral route. The favorable pharmacokinetic properties such as the good bioavailability and long t1/2λz for IM and oral route of carprofen suggest the possibility of its effective use for the treatment of various conditions in broodstock.

Influence of Pyrexia on Pharmacokinetics of Azithromycin and Its Interaction With Tolfenamic Acid in Goats

Azithromycin is a macrolide antimicrobial agent of the azalide group with a broad spectrum of activity against gram-negative and gram-positive bacterial organisms. Tolfenamic acid is a non-steroidal anti-inflammatory drug of the fenamate group, which is used extensively in humans and animals due to its anti-inflammatory, analgesic, and antipyretic properties. There is dearth of literature on any type of drug interaction between azithromycin and tolfenamic acid in any species, including human beings and alteration of its pharmacokinetics by fever. Therefore, the objective of this study was to investigate the alteration of disposition kinetics of azithromycin alone and in the presence of tolfenamic acid in Malabari goats by fever, following an intravenous administration at a dose rate of 20 mg/kg body weight. Blood samples collected from both afebrile and febrile goats at predetermined time intervals after the administration of azithromycin alone and then in combination with tolfenamic acid (2 mg/kg, intravenously), respectively, were analyzed using high-performance liquid chromatography. Non-compartmental analysis was used to determine the peak blood concentration (Cmax), time-to-peak plasma concentration (Tmax), half-life (t1/2λz), area under the curve (AUC 0−t, AUC 0−inf), area under the first moment curve (AUMC 0−inf), mean residence time (MRT0−inf), apparent volume of distribution at steady state (Vss), and the total body clearance of drug from the blood (Cl). In febrile animals, significant differences were noted in the values of Cmax, Cl, and Vss. Thus, azithromycin disappears into an additional compartment in febrile goats, which may be due to its extended cellular penetration into the inflammatory cells, resulting in anti-inflammatory activity. Tolfenamic acid significantly altered the pharmacokinetics of azithromycin in both normal and febrile animals. Tolfenamic acid, being a better anti-inflammatory agent, suppresses the inflammatory mediators, reducing the possibility of increased utilization of azithromycin in febrile condition.

Emulsification by TPGS or Quillaja Extract Increased Absorption and Affected Metabolism of Berberine in Humans

Objectives Berberine is a botanical alkaloid used widely for the prevention of several diseases. However, the absorption rate of berberine is less than 1% in human. The objectives of this study were to determine whether emulsification by TPGS or Quillaja extract affect the absorption and metabolism of orally ingested berberine in human volunteers. Methods Twelve healthy subjects (7 male and 5 females, 21–50-year-old) participated this study. Each subject received 800 mg berberine in a powder form or emulsified with TPGS or Quillaja extract using a randomized crossover design with one-week washout period. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after dose. Plasma was hydrolyzed with glucuronidase and sulfatase before total content of berberine and its metabolites were analyzed on LC/MS/MS. Free forms of metabolites were determined in plasma without hydrolysis. Pharmacokinetic parameters were calculated using a non-compartment model before they were compared by analysis of covariance. Results The area under the curve (AUC) and peak plasma concentration (Cmax) of berberine was 6.6 μM.hr and 0.9 μM in participants received berberine powder. They were increased to 18.3 μM.hr and 4.5 μM by TPGS emulsification and 28 μM.hr and 5.1 μM by Quillaja extract emulsification, respectively. Berberrubine and demethylberberine were major metabolites of berberine. The AUC of free Berberrubine and demethylberberine was increased by 1.9 fold and 1.6 fold by TPGS and 5.9 folds and 2.7 folds by Quillaja extract, respectively, compared to berberine powder. Participants received berberine powder had AUC of 254 μM.hr and Cmax of 33 μM for total berberrubine. TPGS emulsification increased these values to 425 μM.hr and 54 μM, while Quillaja extract increased them to 341 μM.hr and 44 μM, respectively. Significant increases of AUC and Cmax were also observed for total demethylberberine by TPGS or Quillaja extract emulsification. Conclusions Emulsification of berberine with TPGS or Quillaja extract significantly increased the absorption of berberine and its metabolites in human compared to berberine supplement without emulsifiers. Funding Sources Florida High Tech Corridor Council and Designs for Health.

Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC50 of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0–18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53–5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a Ki of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and Cmax) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

Pharmacokinetic evaluation of Chalcone derivatives with antimalarial activity in New Zealand White Rabbits

Objective: Malaria is a major global health concern with the urgent need for new treatment alternatives due to the alarming increase of drug-resistant Plasmodium strains. Chalcones and its derivatives are important pharmacophores showing antimalarial activity. Substandard pharmacokinetic variables are often responsible for insufficient therapeutic effect. Determination of the pharmacokinetic variables at the preliminary step of drug development for any drug candidates is an essential component of in vivo antimalarial efficacy tests. Therefore, three chalcone derivatives, 1, 2, and 3, having antimalarial potency were studied further for potential therapeutic efficacy. Results: In vivo pharmacokinetic studies of these three derivatives were performed on New Zealand White rabbits. The three derivatives were administered intra-peritoneally or orally at effective dose concentration and blood samples at different time points were collected. The determination of drug concentration was done through reverse phase-high performance liquid chromatography. The peak plasma concentration of derivative 1, 2, and 3 were 1.96 ± 0.46 µg/mL, 69.89 ± 5.49 µg/mL, and 3.74 ± 1.64 µg/mL. The results indicate a very low bioavailability of these derivatives. The present study gives a benchmark to advance the investigation of more derivatives in order to revamp the pharmacokinetic variables while maintaining both potency and metabolic constancy.