An evaluation of the drug interaction potential of netupitant with palonosetron, dexamethasone, and oral contraceptives.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19532-e19532
Author(s):  
Jan Vouis ◽  
Anders Henriksson ◽  
Wolfgang Timmer ◽  
Selma Calcagnile ◽  
Giorgia Rossi
Keyword(s):  
Drug Interaction ◽  
Oral Contraceptives ◽  
Systemic Exposure ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Dependent Manner ◽  
Dose Combination ◽  
Neurokinin 1 ◽  
Practice Methods ◽  
New Generation

e19532 Background: Netupitant (NETU) is a highly selective neurokinin 1 receptor antagonist (NK1 RA) developed to provide protection from nausea and vomiting in patients undergoing emetogenic chemotherapy. Three individual studies were aimed at determining NETU effect on the metabolism of the new generation 5-HT3 RA palonosetron (PALO), dexamethasone (DEX) and oral contraceptives which may be coadministered in clinical practice. Methods: Two 3-way crossover studies to determine the interaction between NETU (450 mg, day 1) and PALO (0.75 mg PO, day 1), and between NETU (100 mg, 300 mg or 450 mg PO, day 1) and DEX (20 mg PO, day 1; 8 mg BID PO, days 2-4), were performed in 18 and 25 healthy subjects, respectively. The study investigating the effect of NETU/PALO (300 mg/0.5 mg PO) as a fixed dose combination on the PK of oral contraceptives ethinylestradiol and levonorgestrel (60 μg/300 μg) was a 2-way crossover trial of 24 healthy women. Serial blood samples were collected over the course of the three studies and pharmacokinetic parameters were determined for all analytes. Results: There were no significant pharmacokinetic interactions between NETU and PALO. DEX mean AUC and Cmax increased respectively, by 1.7 and 1.1 fold on day 1 and by 2.4 and 1.7 fold on day 4 when coadministered with NETU. NETU was shown to increase exposure to DEX in a dose-dependent manner. The combination of NETU/PALO did not significantly affect exposure to ethinylestradiol; systemic exposure to levonorgestrel increased by 40%, a level that is not considered clinically relevant. Conclusions: A relevant drug interaction was seen between NETU and DEX and therefore dose reductions are recommended for DEX when administered with NETU. This drug interaction is likely due to inhibition of CYP3A4 by NETU. No interaction was clinically relevant between NETU and PALO, or between NETU/PALO and ethinylestradiol and levonorgestrel. Treatments were well-tolerated in all studies.

scholarly journals Pharmacokinetics of Single-Dose and Multi-Dose of Lovastatin/Niacin ER Tablet in Healthy Volunteers

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Yan-yan Jia ◽  
Song Ying ◽  
Chen-tao Lu ◽  
Jing Yang ◽  
Li-kun Ding ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Healthy Volunteers ◽  
Least Square ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Mixed Dyslipidemia ◽  
Dose Oral ◽  
Dose Combination ◽  
Healthy Chinese

An extended-release (ER) niacin and lovastatin fixed-dose combination has been developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The purpose of the present study was to examine the drug interaction between niacin and lovastatin after multi-dose oral administration of lovastatin/niacin ER combination in healthy Chinese volunteers. A single-center, randomized, open-label, 5-period crossover study was conducted in thirty healthy volunteers aged 18 to 45 years with a washout period of 8 days. Subjects were randomized to receive multiple doses of treatment A (1 500 mg niacin ER tablet), B (1 20 mg lovastatin tablet), C (1 20 mg lovastatin and 500 mg niacin-ER tablet), D (2 10 mg lovastatin and 350 mg niacin-ER tablets) or E (2 10 mg lovastatin and 500 mg niacin-ER tablets) in 1 of 5 sequences (ABCDE, BCDEA, CDEAB, DEABC, EABCD) per period. Lovastatin, niacin and its metabolites (nicotinuric acid and nicotinamide) were determined in plasma by LC/MS method. Pharmacokinetic parameters were calculated, and least square mean ratios and 90% confidence intervals for Cmax⁡ and AUC (0–24) were determined for lovastatin/niacin ER versus niacin ER or lovastatin. It revealed that the formulation had no potential drug interaction in healthy Chinese volunteers when the dosage was increased from 500 mg to 1000 mg.

An evaluation of the drug interaction potential of netupitant with substrates, inhibitor and inducer of CYP3A4.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19533-e19533
Author(s):  
Klaus Peter Kammerer ◽  
Giorgia Rossi ◽  
Selma Calcagnile ◽  
Wolfgang Timmer
Keyword(s):  
Drug Interaction ◽  
Competitive Inhibitor ◽  
Emetogenic Chemotherapy ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Pharmacokinetic Data ◽  
Relevant Effect ◽  
Dose Combination ◽  
Neurokinin 1 ◽  
Require Dose

e19533 Background: Neurokinin-1 receptor antagonist (NK1 RA) is commonly administered in combination with a 5-HT3 RA such as palonosetron (PALO) to prevent the stimulus of nausea and vomiting caused by emetogenic chemotherapy. Netupitant (NETU), a new NK1 RA under evaluation for its antiemetic efficacy and tolerability, is both a substrate for and a competitive inhibitor of CYP3A4. Two studies were designed to determine the potential risk for drug-drug interaction in clinical practice. In the first study, the effects of NETU on the metabolism of two representative CYP3A4 substrates, erythromycin (ERY) and midazolam (MID) were determined. In the second study, a CYP3A4 inhibitor, ketoconazole (KETO), or an inducer, rifampicin (RIF) was coadministered with a fixed dose combination of NETU/PALO to observe the potential effects on NETU and PALO metabolism. Methods: Serial blood samples were collected from healthy volunteers and pharmacokinetic (PK) parameters were determined in both studies. The first trial was a 3-period crossover performed in 20 subjects receiving NETU (300 mg), ERY (500 mg) or MID (7.5 mg). The second trial was a 2-way crossover in 36 subjects receiving a single dose of NETU/PALO (300 mg/0.5mg, Day 1) administered as a fixed dose combination and KETO (400 mg QD, from Day-2 to Day 10) or RIF (600 mg QD from Day -7 to Day 10). Results: NETU, by inhibiting the CYP3A4, increased Cmax and AUC parameters by 40% and 130%, respectively, when administered with MID and by 30% when administered with ERY. KETO increased NETU AUC by 140% and Cmax by 25%, while RIF decreased NETU AUC by 83% and Cmax by 62%. A decrease of 19% was observed in PALO AUC when administered with RIF, while KETO had no relevant effect on PALO PK. Conclusions: The results of these studies suggest that the coadministration of NETU with drugs that are substrates, inhibitors, or inducers of the CYP3A4 enzymes, may require dose adjustments. These results are in line with pharmacokinetic data of aprepitant, the only commercially available NK1 RA. The effect of RIF on PALO is not considered clinically relevant. Treatments were well tolerated in all studies.

scholarly journals Clinical and pharmacological approaches to the choice of a drug for a tension-type headache relief

2021 ◽  
Vol 93 (8) ◽  
pp. 862-868
Author(s):  
Evgeniya V. Shikh ◽  
Evgeniy D. Khaytovich ◽  
Aleksandr V. Perkov
Keyword(s):  
Comparative Analysis ◽  
Analgesic Effect ◽  
Dissolution Kinetics ◽  
Tension Type Headache ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Median Tmax ◽  
Dose Combination ◽  
Type Headache

The article goes to describe clinical and pharmacological approaches to choosing a drug with an optimal efficacy/safety profile, providing the necessary analgesic effect in tension-type headache. TRPV1 brain receptors are considered the main action point of the mediator. Aim. The purpose of this study is a comparative analysis of the pharmacodynamic and pharmacokinetic parameters of ibuprofen and paracetamol as a part of fixed dose combination and as monotherapy in tension type headaches. Materials and methods. Comparative dissolution kinetics test; Comparative analysis of pharmacokinetic parameters using the PubMed/MEDLINE database. Results. The median Tmax of ibuprofen as a part of a fixed-dose combination and as a monotherapy is 75 minutes. The median Tmax of paracetamol is 30 min when taken in a fixed dose combination and 40 min as a monotherapy. In patients who received the fixed dose combination, the concentration of ibuprofen in the blood plasma after 10 minutes 6.64 g/ml-1; after 20 minutes 16.81 g/ml-1, while when taken in the same dose in as a monotherapy, respectively, 0.58 and 9.00 g/ml-1. The mean plasma concentrations of paracetamol after 10 and 20 minutes in patients receiving the fixed combination were 5.43 and 14.54 g/ml-1, respectively, compared with 0.33 and 9.19 g/ml-1 for paracetamol as monotherapy. dissolution kinetics test of the Paracytolgin: after 5 minutes, 20% of paracetamol passed into the solution in a system with a pH of 1.2; in a system with a pH of 4.5 36.4%; in a system with a pH of 6.8 33.5%; after 10 minutes, respectively 68.5, 98.0 and 89.6%. After 15 minutes, almost complete dissolution was noted in all systems: 98.5, 98.8 and 100.5%, respectively. Discussion. The combination of ibuprofen and paracetamol makes it possible to enhance the analgesic effect as a result of additive action by the help of central mechanisms. The fixed dose combination of ibuprofen and paracetamol significantly increases the rate of absorption of paracetamol, which has potential therapeutic benefits in terms of a faster analgesias onset. Conclusion. The fixed dose combination of ibuprofen and paracetamol provides faster and long-term anaesthesia with a comparatively lower dosage of each analgesic.

Drug–Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir

2018 ◽  
Vol 57 (11) ◽  
pp. 1369-1383 ◽  
Author(s):  
Polina German ◽  
Anita Mathias ◽  
Diana M. Brainard ◽  
Brian P. Kearney
Keyword(s):  
Drug Interaction ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Combination Tablet ◽  
Dose Combination ◽  
Drug Drug Interaction

scholarly journals Herb-Drug Interaction Between Xiyanping Injection and Lopinavir/Ritonavir, Two Agents Used in COVID-19 Pharmacotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Linhu Ye ◽  
Lei Cheng ◽  
Yan Deng ◽  
Hong Liu ◽  
Xinyu Wu ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Liver Microsomes ◽  
Pharmacokinetic Parameters ◽  
Dependent Manner ◽  
Epidemic Outbreak ◽  
Global Epidemic ◽  
Incubation Study ◽  
Oral Pharmacokinetics

The global epidemic outbreak of the coronavirus disease 2019 (COVID-19), which exhibits high infectivity, resulted in thousands of deaths due to the lack of specific drugs. Certain traditional Chinese medicines (TCMs), such as Xiyanping injection (XYPI), have exhibited remarkable benefits against COVID-19. Although TCM combined with Western medicine is considered an effective approach for the treatment of COVID-19, the combination may result in potential herb-drug interactions in the clinical setting. The present study aims to verify the effect of XYPI on the oral pharmacokinetics of lopinavir (LPV)/ritonavir (RTV) using an in vivo rat model and in vitro incubation model of human liver microsomes. After being pretreated with an intravenous dose of XYPI (52.5 mg/kg) for one day and for seven consecutive days, the rats received an oral dose of LPV/RTV (42:10.5 mg/kg). Except for the t1/2 of LPV is significantly prolonged from 4.66 to 7.18 h (p < 0.05) after seven consecutive days pretreatment, the pretreatment resulted in only a slight change in the other pharmacokinetic parameters of LPV. However, the pharmacokinetic parameters of RTV were significantly changed after pretreatment with XYPI, particularly in treatment for seven consecutive days, the AUC0-∞ of RTV was significantly shifted from 0.69 to 2.72 h μg/mL (p < 0.05) and the CL exhibited a tendency to decrease from 2.71 L/h to 0.94 L/h (p < 0.05), and the t1/2 of RTV prolonged from 3.70 to 5.51 h (p < 0.05), in comparison with the corresponding parameters in untreated rats. After administration of XYPI, the expression of Cyp3a1 protein was no significant changed in rats. The in vitro incubation study showed XYPI noncompetitively inhibited human CYP3A4 with an apparent Ki value of 0.54 mg/ml in a time-dependent manner. Our study demonstrated that XYPI affects the pharmacokinetics of LPV/RTV by inhibiting CYP3A4 activity. On the basis of this data, patients and clinicians can take precautions to avoid potential drug-interaction risks in COVID-19 treatment.

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