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Effect of food and tablet-dissolution characteristics on the bioavailability of linagliptin fixed-dose combination with metformin: evidence from two randomized trials.
Int J Clin Pharmacol Ther. 2014 Jul; 52(7):549-63.IJ

Abstract

OBJECTIVE

The objectives of the studies reported here were to determine the relative bioavailability of linagliptin and metformin when administered in a fixed-dose combination (FDC) tablet with and without food, and to investigate the relative bioavailability of linagliptin and metformin FDC tablets from two treatment batches with different dissolution behavior.

METHODS

These studies were open-label, single-dose, randomized, two-way crossover trials. After an overnight fast, healthy volunteers received an FDC tablet once (with/without food in the food-effect study; or from one of two batches with differing dissolution behavior in the tablet-dissolution study). On a separate visit, following a washout period of 35 days, participants received the alternative treatment. In the food-effect study the primary endpoints were maximum measured concentration in plasma (C(max)) for linagliptin and metformin, area under the plasma concentration-time curve from 0 to 72 hours (AUC(0-72)) for linagliptin and from 0 to infinity (AUC(0-inf)) for metformin. In the tablet-dissolution study the primary endpoints were Cmax for both analytes, AUC(0-72) for linagliptin, and from 0 to the time of the last quantifiable data point (AUC(0-t)) for metformin.

RESULTS

The administration of the FDC tablet with food had no influence on the relative bioavailability of linagliptin and metformin with regard to the extent of exposure as determined by AUC(0-72) (linagliptin) and AUC(0-inf) (metformin) compared with FDC tablet administration while fasting. After food intake, peak plasma concentrations of linagliptin were slightly lowered (from 4.99 to 4.56 nmol L⁻¹), but the 90% confidence interval (CI) of the geometric mean test/reference ratio was still located within the generally applied bioequivalence acceptance limits of 80 - 125%. The median time from dosing to the maximum concentration of linagliptin in plasma (t(max)) was similar under both conditions. Administration with food reduced the rate of absorption of metformin indicated by a prolongation in median tmax (from 2 to 4 hours) and a decrease in Cmax by ~ 18%. There were no notable differences between the two treatment groups with respect to safety and tolerability. In the tablet-dissolution study, bioequivalence was demonstrated between linagliptin/metformin FDC tablets with normal and slower dissolution characteristics. For both linagliptin and metformin, the 90% CI of all pharmacokinetic (PK) parameters were well within the bioequivalence acceptance limits of 80 - 125%. Tablets from both batches were well tolerated with no unexpected adverse events.

CONCLUSIONS

Food did not have a relevant impact on the bioavailability of linagliptin from the FDC tablet. The effect of food on the metformin component was comparable to that previously demonstrated. Furthermore, differences in tablet-dissolution characteristics did not have an impact on the bioavailability of linagliptin or metformin from the FDC tablet.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24755124

Citation

Metzmann, Katrin, et al. "Effect of Food and Tablet-dissolution Characteristics On the Bioavailability of Linagliptin Fixed-dose Combination With Metformin: Evidence From Two Randomized Trials." International Journal of Clinical Pharmacology and Therapeutics, vol. 52, no. 7, 2014, pp. 549-63.
Metzmann K, Schnell D, Jungnik A, et al. Effect of food and tablet-dissolution characteristics on the bioavailability of linagliptin fixed-dose combination with metformin: evidence from two randomized trials. Int J Clin Pharmacol Ther. 2014;52(7):549-63.
Metzmann, K., Schnell, D., Jungnik, A., Ring, A., Theodor, R., Hohl, K., Meinicke, T., & Friedrich, C. (2014). Effect of food and tablet-dissolution characteristics on the bioavailability of linagliptin fixed-dose combination with metformin: evidence from two randomized trials. International Journal of Clinical Pharmacology and Therapeutics, 52(7), 549-63. https://doi.org/10.5414/CP201961
Metzmann K, et al. Effect of Food and Tablet-dissolution Characteristics On the Bioavailability of Linagliptin Fixed-dose Combination With Metformin: Evidence From Two Randomized Trials. Int J Clin Pharmacol Ther. 2014;52(7):549-63. PubMed PMID: 24755124.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of food and tablet-dissolution characteristics on the bioavailability of linagliptin fixed-dose combination with metformin: evidence from two randomized trials. AU - Metzmann,Katrin, AU - Schnell,David, AU - Jungnik,Arvid, AU - Ring,Arne, AU - Theodor,Rudolf, AU - Hohl,Kathrin, AU - Meinicke,Thomas, AU - Friedrich,Christian, PY - 2014/06/30/accepted PY - 2014/4/24/entrez PY - 2014/4/24/pubmed PY - 2014/9/19/medline SP - 549 EP - 63 JF - International journal of clinical pharmacology and therapeutics JO - Int J Clin Pharmacol Ther VL - 52 IS - 7 N2 - OBJECTIVE: The objectives of the studies reported here were to determine the relative bioavailability of linagliptin and metformin when administered in a fixed-dose combination (FDC) tablet with and without food, and to investigate the relative bioavailability of linagliptin and metformin FDC tablets from two treatment batches with different dissolution behavior. METHODS: These studies were open-label, single-dose, randomized, two-way crossover trials. After an overnight fast, healthy volunteers received an FDC tablet once (with/without food in the food-effect study; or from one of two batches with differing dissolution behavior in the tablet-dissolution study). On a separate visit, following a washout period of 35 days, participants received the alternative treatment. In the food-effect study the primary endpoints were maximum measured concentration in plasma (C(max)) for linagliptin and metformin, area under the plasma concentration-time curve from 0 to 72 hours (AUC(0-72)) for linagliptin and from 0 to infinity (AUC(0-inf)) for metformin. In the tablet-dissolution study the primary endpoints were Cmax for both analytes, AUC(0-72) for linagliptin, and from 0 to the time of the last quantifiable data point (AUC(0-t)) for metformin. RESULTS: The administration of the FDC tablet with food had no influence on the relative bioavailability of linagliptin and metformin with regard to the extent of exposure as determined by AUC(0-72) (linagliptin) and AUC(0-inf) (metformin) compared with FDC tablet administration while fasting. After food intake, peak plasma concentrations of linagliptin were slightly lowered (from 4.99 to 4.56 nmol L⁻¹), but the 90% confidence interval (CI) of the geometric mean test/reference ratio was still located within the generally applied bioequivalence acceptance limits of 80 - 125%. The median time from dosing to the maximum concentration of linagliptin in plasma (t(max)) was similar under both conditions. Administration with food reduced the rate of absorption of metformin indicated by a prolongation in median tmax (from 2 to 4 hours) and a decrease in Cmax by ~ 18%. There were no notable differences between the two treatment groups with respect to safety and tolerability. In the tablet-dissolution study, bioequivalence was demonstrated between linagliptin/metformin FDC tablets with normal and slower dissolution characteristics. For both linagliptin and metformin, the 90% CI of all pharmacokinetic (PK) parameters were well within the bioequivalence acceptance limits of 80 - 125%. Tablets from both batches were well tolerated with no unexpected adverse events. CONCLUSIONS: Food did not have a relevant impact on the bioavailability of linagliptin from the FDC tablet. The effect of food on the metformin component was comparable to that previously demonstrated. Furthermore, differences in tablet-dissolution characteristics did not have an impact on the bioavailability of linagliptin or metformin from the FDC tablet. SN - 0946-1965 UR - https://www.unboundmedicine.com/medline/citation/24755124/Effect_of_food_and_tablet_dissolution_characteristics_on_the_bioavailability_of_linagliptin_fixed_dose_combination_with_metformin:_evidence_from_two_randomized_trials_ L2 - http://www.dustri.com/nc/journals-in-english?artId=11415 DB - PRIME DP - Unbound Medicine ER -