Effect of Milk on the Pharmacokinetics of Oseltamivir in Healthy Volunteers

doi:10.1002/jps.22627

Journal of Pharmaceutical Sciences

Volume 100, Issue 9, September 2011, Pages 3854-3861

https://doi.org/10.1002/jps.22627 Get rights and content

Abstract

We previously showed that oseltamivir, a prodrug of the influenza virus neuraminidase inhibitor Ro 64-0802, is a substrate of proton-coupled oligopeptide transporter (PEPT1), and its intestinal absorption in rats is markedly inhibited by administration with milk. To investigate the importance of PEPT1 for oseltamivir absorption in humans, and the characteristics of the drug–milk interaction, a crossover clinical study was conducted in healthy volunteers, who received 75 mg of oseltamivir with 400 mL of water or milk. Milk significantly reduced the maximum plasma concentration (C_max) and the area under the plasma concentration–time curve from 0 to 2 h (AUC_0–2) of both oseltamivir and Ro 64-0802 (oseltamivir, 68.9% and 34.5%; Ro 64-0802, 69.5% and 14.2%, respectively, vs. water), but had no significant effect on the apparent terminal half-life (t_1/2) or AUC_0–∞. Urinary recovery of oseltamivir and Ro 64-0802 was significantly reduced to 77.5% of the control by milk. The early reduction of oseltamivir absorption might be through the PEPT1 inhibition by milk peptides. However, the extent of interaction in humans was limited as compared with that in rats, possibly because of species difference in the PEPT1 expression and its contribution. This might be the first report suggesting the clinical drug–food interaction via PEPT1. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3854–3861, 2011

Section snippets

INTRODUCTION

Dietary constituents may influence drug response in various ways, ranging from loss of efficacy to toxicity. In particular, interactions that modify drug absorption may be of clinical importance because drug effects are dependent on the concentration of the active species at the site of action. The absorption process itself may be influenced by drug-metabolizing enzymes as well as by influx and efflux transporters expressed in the small intestine. For example, it is well known that dietary

Study Design

A randomized, open-label, two-period, crossover clinical pharmacokinetic study was conducted. Six healthy male Japanese volunteers aged 21–25 were enrolled. An evaluation before the study showed that the subjects had unremarkable medical history, and normal findings on physical examination and standard clinical laboratory tests (general hematology, blood chemistry). The study was conducted in compliance with the Declaration of Helsinki. All individuals gave written informed consent for the

Plasma Concentration

Figure 1 shows the plasma concentration–time profiles of oseltamivir and Ro 64-0802 after a single oral dose of 75 mg oseltamivir (as 98 mg phosphate salt) with either 400 mL of water or 400 mL of milk. The pharmacokinetic parameters of oseltamivir and Ro 64-0802 are summarized in Table 1. In the case of coadministration with water, C_max was 38.2 ng/mL at 1.4 h after administration, whereas AUC_0–2, AUC_2–4, AUC_0–24, and AUC_0–∞ were 47.6, 32.8, 109, and 114 ng·h/mL, respectively. In the case of

DISCUSSION

Our clinical study showed that milk reduced the total absorption of oseltamivir, estimated by adding the urinary recovery of oseltamivir and Ro 64-0802, to 77.5% of the control. However, the plasma concentration of Ro 64-0802 at 12 h after administration (C₁₂), an index of anti-influenza virus effect,¹³ was not significantly different between the two treatments. This suggests that no dose adjustment is required when oseltamivir is administered with milk.

Although the effects of milk in humans

CONCLUSION

Our results indicate that milk inhibited the intestinal absorption of oseltamivir in humans. However, the extent of interaction in humans was limited as compared with that in rats, possibly because of species difference in the regional expression of PEPT1 in the small intestine and/or differences in the contribution of other absorption mechanisms. Among PEPT1 substrates, it seems likely that compounds whose absorption would be largely completed within the transit time of the duodenum may show

Acknowledgements

This study was supported by a grant from the Research Foundation for Pharmaceutical Sciences, and by government grants-in-aid for scientific research.

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Pharmacokinetics, Pharmacodynamics and Drug MetabolismEffect of Milk on the Pharmacokinetics of Oseltamivir in Healthy Volunteers

Abstract

Section snippets

INTRODUCTION

Study Design

Plasma Concentration

DISCUSSION

CONCLUSION

Acknowledgements

J Pharm Sci

Biochem Pharmacol

Gastroenterology

J Pharm Sci

Drug Metab Pharmacokinet

J Mol Biol

Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine

Clin Pharmacol Ther

Pharmacokinetic–pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition

Clin Pharmacokinet

Peptide transporters: Structure, function, regulation, and application for drug delivery

Curr Drug Metab

The digestion and absorption of protein in man. 2. The form in which digested protein is absorbed

Br J Nutr