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Parallel Monitoring of Plasma and Intraluminal Drug Concentrations in Man After Oral Administration of Fosamprenavir in the Fasted and Fed State

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Abstract

Purpose

The purpose of this study was to explore the feasibility of linking the pharmacokinetic profile of a drug with its gastrointestinal behavior by simultaneously monitoring plasma and intraluminal drug concentrations. Fosamprenavir, a phosphate ester prodrug of the poorly water-soluble HIV-inhibitor amprenavir, was selected as model compound.

Methods

A single tablet of fosamprenavir (Telzir®) was administered to 5 volunteers in the fasted and fed state (simulated by intake of a nutritional drink). Gastric and duodenal fluids were aspirated in function of time and characterized with respect to the concentration of (fos)amprenavir, inorganic phosphate and pH. In parallel, blood samples were collected and analyzed for amprenavir.

Results

The observed plasma concentration-time profiles suggested a food-induced delay in the absorption of amprenavir: in the fed state, mean t max increased by more than 150 min compared to the fasted state. A similar delay was seen in the duodenal appearance of fosamprenavir (concentrations in mM-range) and, after dephosphorylation, amprenavir (concentrations below 160 μM). This observation could be related to the behavior of fosamprenavir in the stomach. In the fasted state, gastric dissolution of fosamprenavir started immediately, resulting in a C max of 4 ± 2 mM after 43 ± 15 min; however, in the fed state, the fosamprenavir concentration remained below 20 μM for the first 90 min after drug intake. The postponed gastric dissolution may be attributed to a food-induced delay in tablet disintegration.

Conclusion

For the first time, the pharmacokinetic profile of a drug was monitored in parallel with its gastrointestinal concentrations. The observed food effect in the plasma concentration-time profile of amprenavir after intake of its phosphate ester prodrug could be related to a food-induced delay in gastric dissolution of fosamprenavir.

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Acknowledgements

This study was supported by grants from: (1) ‘Fonds voor Wetenschappelijk Onderzoek’, Flanders, (2) ‘Onderzoeksfonds’ of the K.U.Leuven, Belgium, (3) Eli Lilly and Company and (4) Organon NV. We also wish to thank Rita Vos (Center for Gastroenterologic Research, University Hospitals Leuven, Belgium) for her assistance during the in vivo studies.

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Authors and Affiliations

  1. Laboratory for Pharmacotechnology and Biopharmacy, Katholieke Universiteit Leuven, Gasthuisberg O&N 2–Herestraat 49, box 921, Leuven, Belgium

    Joachim Brouwers & Patrick Augustijns

  2. Center for Gastroenterologic Research, University Hospitals Leuven, Gasthuisberg–Herestraat 49, Leuven, Belgium

    Jan Tack

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  1. Joachim Brouwers
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  2. Jan Tack
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  3. Patrick Augustijns
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Correspondence to Patrick Augustijns.

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Brouwers, J., Tack, J. & Augustijns, P. Parallel Monitoring of Plasma and Intraluminal Drug Concentrations in Man After Oral Administration of Fosamprenavir in the Fasted and Fed State. Pharm Res 24, 1862–1869 (2007). https://doi.org/10.1007/s11095-007-9307-3

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  • DOI: https://doi.org/10.1007/s11095-007-9307-3

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