2007 - København - Denmark

PAGE 2007: Applications- Anti-infectives
Rocio Lledo

Population Pharmacokinetics of Saquinavir in rats after IV and IP administration. An approach to Saquinavir/Ritonavir Pharmacokinetic interaction.

R. Lledó-García (1), M. Merino Sanjuán (1), L. Prats (1), A. Nácher (1), V.G. Casabó (1)

(1) Department of Pharmacy and Pharmaceutical Technology, University of Valencia, Valencia, Spain.

Objectives: The protease inhibitor (PI) saquinavir (SQV) is characterized by a low and variable oral bioavailiability [1], which can be increased by the addition of ritonavir (RTV). This combination is currently used in the management of AIDS. Although the interaction between these two drugs has already been reported in previous studies [2], so far the roles of liver and intestine in SQV first pass metabolism have not been clarify. This study aimed to assess SQV pharmacokinetic disposition profile when IV administered and assess the hepatic first pass metabolism when IP administered.

Methods: 48, 24 and 12 mg doses of SQV were IV and IP administered to rats subjected to jugular vein cannulation. In addition, 24 and 6 mg dose of SQV/RTV were IV administered. Plasma samples were analysed for drugs content by HPLC/UV.
As a first approach to data, a non compartmental analysis (WinNonLin) was performed. Subsequently, a stepwise population pharmacokinetic approach was performed using NONMEM. Throughout the development of the model the interaction between drugs was assessed.

Results: The non-compartmental analysis shows an insignificant hepatic first pass metabolism where an important one was expected, being likely located at the gastrointestinal tract. In the population approach, a two-compartment model considering a plasma protein dynamic binding and an elimination process from central compartment following Michaelis-Menten kinetics, were used to describe SQV disposition processes. Moreover, the IP incorporation process was described by a precipitation of the drug in the IP cavity, being dissolution limitative factor for absorption. The main PK parameters are shown: Vc (0.244L), plasma proteins binding and unbinding constants resulted in Kb (2.71x10-06 L/mg.h) and Ku (0.137h-1), respectively; Vm (56.7 mg/h), Km (57.7 mg/L), being the last multiplied by 4.88 when RTV is coadministered. IP Ka (1 h-1), limited by the drug dissolution.

Conclusions: Data analysis showed non linear disposition processes for SQV and located drugs interaction at the elimination process, so that RTV inhibits SQV metabolism. Opposite to the expected result, IP data showed that SQV low bioavailability was not mainly due to its hepatic first pass metabolism, escaping most part of the drug from liver. However, further studies are being conducted, involving an oral administration required to properly describe the processes involved in SQV presystemic losses.

[1]. Guiard-Schmid, J.B., J.M. Poirier, J.L. Meynard, P. Bonnard, A.H. Gbadoe, C. Amiel, F. Calligaris, B. Abraham, G. Pialoux, P.M. Girard, P. Jaillon and W. Rozenbaum, High variability of plasma drug concentrations in dual protease inhibitor regimens. Antimicrob Agents Chemother, 2003. 47(3): p. 986-90.
[2]. Shibata, N., W. Gao, H. Okamoto, T. Kishida, K. Iwasaki, Y. Yoshikawa and K. Takada, Drug interactions between HIV protease inhibitors based on physiologically-based pharmacokinetic model. J Pharm Sci, 2002. 91(3): p. 680-9.

Reference: PAGE 16 (2007) Abstr 1097 [www.page-meeting.org/?abstract=1097]
Poster: Applications- Anti-infectives
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