scholarly journals Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2172
Author(s):  
Agnieszka Karbownik ◽  
Danuta Szkutnik-Fiedler ◽  
Tomasz Grabowski ◽  
Anna Wolc ◽  
Joanna Stanisławiak-Rudowicz ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Kinase Inhibitor ◽  
Opioid Analgesic ◽  
Plasma Concentrations ◽  
Response To Therapy ◽  
Maximum Plasma ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Pharmacokinetic Drug Interaction ◽  
Pharmacokinetic Drug

A combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic—morphine—can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug–drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curves (AUC0–t, and AUC0–∞) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0–t of its active metabolite—sorafenib N-oxide—was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0–t, and AUC0–∞ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects.

scholarly journals Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 778
Author(s):  
Bettina Gerner ◽  
Oliver Scherf-Clavel
Keyword(s):  
Hepatic Impairment ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Enterohepatic Recirculation ◽  
Maximum Plasma ◽  
Good Precision ◽  
Physiologically Based Pharmacokinetic ◽  
Starting Point ◽  
Physiologically Based

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

scholarly journals Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Roberto Sánchez-Sánchez ◽  
Ignacio Ferre ◽  
Michela Re ◽  
Juan José Ramos ◽  
Javier Regidor-Cerrillo ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Vertical Transmission ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Fetal Mortality ◽  
Maximum Plasma ◽  
Content Type ◽  
Pregnant Sheep

ABSTRACT Previous studies on drug efficacy showed low protection against abortion and vertical transmission of Toxoplasma gondii in pregnant sheep. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium-dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. Here, we present the safety and efficacy of BKI-1294 treatment (dosed orally at 100 mg/kg of body weight 5 times every 48 h) initiated 48 h after oral infection of sheep at midpregnancy with 1,000 TgShSp1 oocysts. BKI-1294 demonstrated systemic exposure in pregnant ewes, with maximum plasma concentrations of 2 to 3 μM and trough concentrations of 0.4 μM at 48 h after each dose. Oral administration of BKI-1294 in uninfected sheep at midpregnancy was deemed safe, since there were no changes in behavior, fecal consistency, rectal temperatures, hematological and biochemical parameters, or fetal mortality/morbidity. In ewes infected with a T. gondii oocyst dose lethal for fetuses, BKI-1294 treatment led to a minor rectal temperature increase after infection and a decrease in fetal/lamb mortality of 71%. None of the lambs born alive in the treated group exhibited congenital encephalitis lesions, and vertical transmission was prevented in 53% of them. BKI-1294 treatment during infection led to strong interferon gamma production after cell stimulation in vitro and a low humoral immune response to soluble tachyzoite antigens but high levels of anti-SAG1 antibodies. The results demonstrate a proof of concept for the therapeutic use of BKI-1294 to protect ovine fetuses from T. gondii infection during pregnancy.

Effects of Ginkgo biloba Extract Ingestion on the Pharmacokinetics of Talinolol in Healthy Chinese Volunteers

2009 ◽  
Vol 43 (5) ◽  
pp. 944-949 ◽  
Author(s):  
Lan Fan ◽  
Gong-You Tao ◽  
Guo Wang ◽  
Yao Chen ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Ginkgo Biloba ◽  
High Performance ◽  
Plasma Concentrations ◽  
Ginkgo Biloba Extract ◽  
Maximum Plasma ◽  
Time Curve ◽  
P Glycoprotein

Background Ginkgo biloba extract (GBE), the best selling herbal medicine in the world, has been reported to inhibit P-glycoprotein in vitro. However, the effects of GBE on P-glycoprotein activity in humans have not been clarified. Objective To investigate the effects of single and repeated GBE ingestion on the oral pharmacokinetics of talinolol, a substrate drug for P-glycoprotein in humans. Methods Ten unrelated healthy male volunteers were selected to participate in a 3-stage sequential study. Plasma concentrations of talinolol from 0 to 24 hours were measured by high-performance liquid chromatography after talinolol 100 mg was administrated alone, with a single oral dose of GBE (120 mg), and after 14 days of repeated GBE ingestion (360 mg/day). Results A single oral dose of GBE did not affect the pharmacokinetics of talinolol. Repeated ingestion of GBE increased the talinolol maximum plasma concentration (Cmax) by 36% (90% CI 10 to 68; p = 0.025), the area under the concentration-time curve (AUC)0-24 by 26% (90% CI 11 to 43; p = 0.008) and AUC0-∞ by 22% (90% CI 8 to 37; p = 0.014), respectively, without significant changes in elimination half-life and the time to Cmax. Conclusions Our results suggest that long-term use of GBE significantly influenced talinolol disposition in humans, likely by affecting the activity of P-glycoprotein and/or other drug transporters.

scholarly journals P-Glycoprotein Expression on Patients with Acute Lymphoblastic Leukemia

2017 ◽  
Vol 1 (1) ◽  
pp. 39
Author(s):  
R. Niiruri ◽  
I. Narayani ◽  
K. Ariawati ◽  
S. Herawati
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Cancer Patients ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Drug Efficacy ◽  
Expression Level ◽  
Newly Diagnosed ◽  
Glycoprotein P ◽  
P Glycoprotein

Abstract Objective: P-glycoprotein (P-gp) overexpression on neoplastic cells can deteriorate the therapeutic outcome on cancer patients. P-gp plays important role on drug efficacy and toxicity. This research aimed to measure P-gp expression on children with Acute Lymphoblastic Leukemia (ALL) on Sanglah Hospital, Denpasar. Method: Flowcytometry method was used to measure P-gp expression level on Bone Marrow samples from pediatric patients (0-12 years old) who were newly diagnosed with ALL in Sanglah Hospital. P-gp overexpression were based on the percentage of cell stained. Ten percent of P-gp expression were considered as the cut-off value of P-gp overexpression. Result: On this study, 11 samples were obtained with the range value of 56-97% on P-gp expression. Conclusion: All 11 patients had P-gp overexpression.

Assessment of Pharmacokinetic Drug–Drug Interactions in Humans: In Vivo Probe Substrates for Drug Metabolism and Drug Transport Revisited

2019 ◽  
Vol 59 (1) ◽  
pp. 507-536 ◽  
Author(s):  
Uwe Fuhr ◽  
Chih-hsuan Hsin ◽  
Xia Li ◽  
Wafaâ Jabrane ◽  
Fritz Sörgel
Keyword(s):  
Drug Transport ◽  
Quantitative Prediction ◽  
Pharmacokinetic Parameters ◽  
Glycoprotein P ◽  
Therapeutic Drugs ◽  
P Glycoprotein ◽  
Clinical Drug ◽  
Pharmacokinetic Drug

Pharmacokinetic parameters of selective probe substrates are used to quantify the activity of an individual pharmacokinetic process (PKP) and the effect of perpetrator drugs thereon in clinical drug–drug interaction (DDI) studies. For instance, oral caffeine is used to quantify hepatic CYP1A2 activity, and oral dagibatran etexilate for intestinal P-glycoprotein (P-gp) activity. However, no probe substrate depends exclusively on the PKP it is meant to quantify. Lack of selectivity for a given enzyme/transporter and expression of the respective enzyme/transporter at several sites in the human body are the main challenges. Thus, a detailed understanding of the role of individual PKPs for the pharmacokinetics of any probe substrate is essential to allocate the effect of a perpetrator drug to a specific PKP; this is a prerequisite for reliably informed pharmacokinetic models that will allow for the quantitative prediction of perpetrator effects on therapeutic drugs, also in respective patient populations not included in DDI studies.

Absorption profile, safety, and tolerability of a 200 μg dose of fentanyl buccal tablet (FBT) in opioid-tolerant cancer patients with or without oral mucositis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9053-9053
Author(s):  
L. Shaiova ◽  
J. G. Jiang ◽  
M. Darwish
Keyword(s):  
Cancer Patients ◽  
Oral Mucositis ◽  
Plasma Concentrations ◽  
Application Site ◽  
Maximum Plasma ◽  
Absorption Profile ◽  
Open Label ◽  
Fentanyl Buccal Tablet ◽  
Buccal Tablet ◽  
Study Results

9053 Background: Fentanyl buccal tablet (FBT) is an effervescent formulation of fentanyl indicated for the management of breakthough pain in opioid-tolerant cancer patients. This open-label study investigated the absorption profile, safety, and tolerability of FBT in cancer patients with or without oral mucositis. Methods: Patients self-administered a single 200 μg dose of FBT. Pharmacokinetic assessments, oral mucosal examinations, and measurements of vital signs were performed at intervals of up to 8 hours following FBT placement. Adverse events (AEs) were monitored throughout the study. Results: 16 patients (8 with, 8 without mucositis) received FBT and completed the study. Mucositis was mild (functional/symptomatic grade 1 for 7 patients, grade 2 for 1 patient; clinical grade 1 for all patients). The absorption profile of FBT was similar in patients with and without mucositis. Mean±SD Cmax values were 1.25±0.78 ng/mL and 1.24±0.77 ng/mL in patients with or without mucositis, respectively. Maximum plasma concentrations of fentanyl were achieved rapidly, and were not significantly different in the two groups: median (range) tmax 25.0 (15.0–45.0) min in patients with mucositis, 22.5 (10.0–121.0) min in patients without (p=0.79). FBT was well tolerated; 4 patients experienced =1 treatment-emergent AE. Dizziness (mild) was reported by 1 patient in each group, and resolved. One patient in each group experienced a treatment-related AE (dizziness). There were no deaths, serious AEs, or withdrawals due to AEs. No application site AEs or changes in oral mucosal assessments were reported. Conclusions: The absorption profile of FBT was similar in patients with or without oral mucositis, which suggests that dose adjustment of FBT is not required when mild oral mucositis is present. FBT was generally safe and well tolerated, and not associated with adverse changes in the oral mucosa. Further studies in patients with grade 3–4 mucositis are warranted. No significant financial relationships to disclose.

scholarly journals Pharmacokinetic Drug Interaction between Tofacitinib and Voriconazole in Rats

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 740
Author(s):  
Ji-Sang Lee ◽  
Hyo-Sung Kim ◽  
Yong-Seob Jung ◽  
Hyeon-Gyeom Choi ◽  
So-Hee Kim
Keyword(s):  
Kinase Inhibitor ◽  
Competitive Inhibition ◽  
Fungal Infections ◽  
Janus Kinase ◽  
Time Curve ◽  
Janus Kinase Inhibitor ◽  
Pharmacokinetic Drug Interaction ◽  
Intravenous And Oral Administration ◽  
Pharmacokinetic Drug

Fungal infections are prevalent in patients with immune diseases. Voriconazole, a triazole antifungal drug, inhibits the cytochromes CYP3A4 and CYP2C, and tofacitinib, a Janus kinase inhibitor for the treatment of rheumatoid arthritis, is metabolized by CYP3A4 and CYP2C19 in humans. Here, we investigated their interaction during simultaneous administration of both drugs to rats, either intravenously or orally. The area under the plasma concentration–time curve from time zero to time infinity (AUC) of tofacitinib was significantly greater, by 166% and 171%, respectively, and the time-averaged non-renal clearance (CLNR) of tofacitinib was significantly slower (59.5%) than that for tofacitinib alone. An in vitro metabolism study showed non-competitive inhibition of tofacitinib metabolism in the liver and intestine by voriconazole. The concentration/apparent inhibition constant (Ki) ratios of voriconazole were greater than two, indicating that the inhibition of tofacitinib metabolism could be due to the inhibition of the CYP3A1/2 and CYP2C11 enzymes by voriconazole. The pharmacokinetics of voriconazole were not affected by the co-administration of tofacitinib. In conclusion, the significantly greater AUC and slower CLNR of tofacitinib after intravenous and oral administration of both drugs were attributable to the non-competitive inhibition of tofacitinib metabolism via CYP3A1/2 and CYP2C11 by voriconazole in rats.

scholarly journals Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Parag Kumar ◽  
Lori A. Gordon ◽  
Kristina M. Brooks ◽  
Jomy M. George ◽  
Anela Kellogg ◽  
...  
Keyword(s):  
Dabigatran Etexilate ◽  
Maximum Plasma ◽  
Thrombin Time ◽  
Time Curve ◽  
Glycoprotein P ◽  
Time Zero ◽  
P Glycoprotein ◽  
Elimination Half ◽  
Effect Curve ◽  
Glycoprotein Transport

ABSTRACT Dabigatran etexilate (DE) is a P-glycoprotein (P-gp) probe substrate, and its active anticoagulant moiety, dabigatran, is a substrate of the multidrug and toxin extrusion protein-1 (MATE-1) transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE at 150 mg alone, followed by ritonavir at 100 mg or cobicistat at 150 mg daily for 2 weeks. DE was then given 2 h before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran pharmacokinetic (PK) exposure or thrombin time (TT) measures were observed with the simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean decrease in dabigatran PK exposure of 29% (90% confidence interval [CI], 18 to 40%) but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (area under the concentration-versus-time curve from time zero to infinity and maximum plasma concentration) by 127% each (90% CI, 81 to 173% and 59 to 196%, respectively) and increased TT measures (33% for the area-under-the-effect curve from time zero to 24 h [90% CI, 22 to 44%] and 51% for TT at 24 h [90% CI, 22 to 78%]) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by 2 h from the administration of dabigatran. In all comparisons, no significant increase in the dabigatran elimination half-life was observed. Therefore, it is likely safe to coadminister ritonavir with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with the coadministration of cobicistat due to the greater net inhibition of intestinal P-gp transport and increased bioavailability. (This study has been registered at ClinicalTrials.gov under identifier NCT01896622.)

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