Dataset Information

Evaluation of drug interactions of saxagliptin with sildenafil in healthy volunteers.

ABSTRACT:

Purpose

The purpose of this study is to investigate the effect of sildenafil a CYP3A4 substrate and inhibitor on the pharmacokinetics and safety of saxagliptin.

Methods

Eighteen healthy volunteers were recruited in sequential; single-center study to determine pharmacokinetic parameters of saxagliptin and sildenafil, and (AUC_0-∞), (AUC_0-t); C_max; t_max; t_½, k_e; k_a were measured using validated LC-MS/MS method. Therapeutic doses were given as follows: Sildenafil 50 mg single dose on day one, then washout period from day two till day eight. Saxagliptin 5 mg once/day was given from day 9 till day 12; then on day 13, the two drugs were co-administered. Blood samples for pharmacokinetic analysis were collected on days 1 and 13 for sildenafil and on days 12 and 13 for saxagliptin.

Results

Saxagliptin ratios of T/R and 90% CI were 132.1% (122.7-142.3) for AUC_0-t, and 167.6% (154.6-181.8) for C_max. On the other hand, sildenafil pharmacokinetics were not affected. G_max changed from 93.7 mg/dl to 95.6 mg/dl (P > 0.001) and AUC_g0-t from 512.8 ng.h/ml to 532.75 ng.h/ml (P > 0.001) after co-administration of both drugs.

Conclusion

Sildenafil significantly affected the pharmacokinetic parameters of saxagliptin when co-administered.

Registration

This trial was registered at clinicaltrials.gov under identifier number: [NCT04170790] in November 2019.

SUBMITTER: Mansour RY

PROVIDER: S-EPMC9549831 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Evaluation of drug interactions of saxagliptin with sildenafil in healthy volunteers.

Mansour Rania Y RY ElBorolossy Radwa R Shaheen Sara M SM Sabri Nagwa A NA

European journal of clinical pharmacology 20221010 12

<h4>Purpose</h4>The purpose of this study is to investigate the effect of sildenafil a CYP3A4 substrate and inhibitor on the pharmacokinetics and safety of saxagliptin.<h4>Methods</h4>Eighteen healthy volunteers were recruited in sequential; single-center study to determine pharmacokinetic parameters of saxagliptin and sildenafil, and (AUC<sub>0-∞</sub>), (AUC<sub>0-t</sub>); C<sub>max</sub>; t<sub>max</sub>; t<sub>½</sub>, k<sub>e</sub>; k<sub>a</sub> were measured using validated LC-MS/MS meth ...[more]

PMID: 36214883

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Project description:Polypharmacy may be considered as the customary practice to provide optimum care services to patients but inter resulted in augmented probability of multiple drug interaction. Keeping in view the importance of drug interaction possibility, this study was designed to evaluate the effect of ranitidine on pharmacokinetics of amoxicillin in the local population of Karachi, Pakistan. Amoxicillin and ranitidine are the most commonly prescribed drugs to treat duodenal ulcer caused by Helicobacter pylori. The current investigation was carried out as a single center, open label, two phase, single dose, randomized way in cross over manner to evaluate the potential of pharmacokinetic interaction among amoxicillin formulation and ranitidine in adult healthy male volunteers. Post dosing blood samples were collected at multiple time points that are 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours after administering amoxicillin 250mg capsule with and without ranitidine. For estimation of amoxicillin concentration in plasma, an HPLC method was developed and validated. The solvent system consisted of 0.025M phosphate buffer: acetonitrile (94:6 v/v). C18 column was employed with a flow rate of 1.0 ml/minute and at 230nm. A linear pattern with a correlation coefficient of 0.999 in the concentration ranges of 25μg/mL to 0.097μg/mL for amoxicillin and 25μg/mL to 0.048μg/mL for ranitidine was observed. Amoxicillin retention time was about 8 minutes and ranitidine retention time was around 12 minutes. Amoxicillin levels were computed and the concentrations were applied to calculate the pharmacokinetic parameters. Pharmacokinetic parameters were estimated by Kinetica TM 4.4.1 (Thermo Electron Corp. USA). The analysis of variance (two way) and t test (two one sided) were applied on log transformed pharmacokinetic parameters of amoxicillin. The Tmax was determined between amoxicillin alone and amoxicillin with ranitidine by Friedman test. The 90% confidence interval values for Cmax(calc) (0.687-0.743) and Tmax(calc) (1.148-1.742) for amoxicillin with or without ranitidine were not found within the FDA acceptable limits of 0.8-1.25. Study demonstrated the significant reduction in peak plasma levels of amoxicillin in presence of ranitidine. It is advisable to administer both drugs with time interval to avoid such interactions and increases in the bactericidal efficacy of amoxicillin.

Project description:Background and objectiveTucatinib is approved for treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Understanding potential drug-drug interactions (DDIs) informs proper dosing when co-administering tucatinib with other therapies. The aim of this study was to evaluate DDIs between tucatinib and metabolizing enzymes and transporters in healthy volunteers.MethodsParts A-C assessed the impact of itraconazole (cytochrome P450 [CYP] 3A4 inhibitor), rifampin (CYP3A4/CYP2C8 inducer), or gemfibrozil (CYP2C8 inhibitor) on the pharmacokinetics of a single 300 mg dose of tucatinib administered orally and its primary metabolite, ONT-993. Parts D and E assessed the effect of steady-state tucatinib on the pharmacokinetics of repaglinide (CYP2C8 substrate), tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), and digoxin (P-glycoprotein substrate).ResultsTucatinib area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf) increased by ~ 1.3- and 3.0-fold with itraconazole and gemfibrozil, respectively, and decreased by 48% with rifampin, indicating that tucatinib is metabolized primarily by CYP2C8, and to a lesser extent via CYP3A. Tucatinib was a strong inhibitor of CYP3A (midazolam AUC0-inf increased 5.7-fold), a weak inhibitor of CYP2C8 and P-glycoprotein, and had no impact on CYP2C9-mediated metabolism in humans. Tucatinib was well tolerated, alone and with co-administered drugs.ConclusionThe potential DDIs identified here may be mitigated by avoiding concomitant use of tucatinib with strong CYP3A inducers, moderate CYP2C8 inducers, CYP3A substrates with a narrow therapeutic window (modifying substrate dose where concomitant use is unavoidable), and strong CYP2C8 inhibitors (decreasing tucatinib dose where concomitant use is unavoidable), or by reducing the dose of P-glycoprotein substrates with a narrow therapeutic window.Trial registrationThis trial (NCT03723395) was registered on October 29, 2018.

Dataset Information

Evaluation of drug interactions of saxagliptin with sildenafil in healthy volunteers.

Purpose

Methods

Results

Conclusion

Registration

Publications

Evaluation of drug interactions of saxagliptin with sildenafil in healthy volunteers.

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