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Background

Comparison of the in vivo pharmacokinetics and in vitro dissolution of raltegravir in HIV patients receiving the drug by swallowing or by chewing ( abs.TUPDB0105 ).

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  1. Comparison of the in vivo pharmacokinetics and in vitro dissolution of raltegravir in HIV patients receiving the drug by swallowing or by chewing (abs.TUPDB0105) Cristina Gervasoni, Sara Baldelli, MatteoCerea, SimonaLandonio, Paola Meraviglia, EmanuelaSimioni, Andrea Gazzaniga, Emilio Clementi, Massimo Galli, GiulianoRizzardini and Dario Cattaneo Department of Infectious Diseases, Luigi Sacco University Hospital, Milan, Italy Unit of Clinical Pharmacology, Luigi Sacco University Hospital, Milan, Italy Department of Pharmaceutical Sciences, UniversitàdegliStudidi Milano, Milan, Italy

  2. Background • Studies on healthy volunteers and on HIV-infected patients have shown that raltegravir pharmacokinetics is characterised by high inter-and intra-patient variability. • Neither gender, race, age, body mass index, food intake, nor renal or hepatic insufficiency had clinically relevant effect on raltegravir pharmacokinetics. • The presence of allelic variants in the UGT1A1 gene only minimally affects plasma concentrations of raltegravir.

  3. Aim of the Study • To investigate whether the observed variability in the pharmacokinetics of raltegravir is eventually related to the way the drug is delivered by the pharmaceutical dosage form.

  4. In vivo Study 50 HIV patients given raltegravir by swallowing Blood sampling at 0, 1, 2, 3 and 4 hours after the morning raltegravir dose. versus 10 HIV patients given raltegravir by chewing due to swallowing difficulties • Raltegravir plasma concentrations were determined by LC-MS/MS • Raltegravir AUC0-4 was estimated using the trapezoidal rule • Raltegravir AUC0-12= 2.08C0 + 0.82C1 + 1.24C2 – 0.210C3 +4.280C4 + 783.1 [*] [*] Cattaneo D, Ripamonti D, Gervasoni C, Landonio S, Meraviglia P, Baldelli S, Cozzi V, Fucile S, Clementi E. Limitedsamplingstrategiesfor the estimationofraltegravirdailyexposure in HIV-infectedpatients. J ClinPharmacol. 2012;52:440-5

  5. Raltegravir time-concentration profiles in 60 HIV-patients given the drug by swallowing the whole tablet (n=50) or by chewing the tablet before swallowing (n=10) ** *

  6. Main raltegravir pharmacokinetic parameters measured in HIV patients given the drug by swallowing or by chewing

  7. In vitro Study • The dissolution of raltegravir tablets in water, in acidic solution (pH 1) and in pH 6.8 buffer was evaluated. (mimics swallowing) versus (mimics chewing) • Dissolution tests were conducted according to USP guidelines (paddle method, Model AT7, Sotax) with 900 mL dissolution medium maintained at 37 ± 0.5°C and agitated at 50 rpm (n = 6).

  8. Whole tablets Crushed tablets water pH 1 pH 6.8

  9. Working Hypothesis • The gastric residence time as the major source of drug variability, being affected by the interplay between: • fast/fed conditions • time of food intake • type of food • duration of digestive phase • pharmaceutical form • dimensions of particles • contraction of gastric muscular tissues Negligible drug release in the stomach (pH 1.0) Optimal drug release in the duodenum (pH 6.8)

  10. Conclusions • HIV-infected patients taking raltegravir by chewing the tablets have higher drug absorption and lower drug inter-subject pharmacokinetic variability compared with patients taking the drug by swallowing the whole tablets. • Whole tablets do not fully disintegrate in the stomach leading to a negligible drug release for the entire duration of the gastric residence. Crushed tablets were associated with higher drug dissolution at each pH condition. • The improvement of the drug pharmaceutical formulation could potentially increase the response of HIV-infected patients to raltegravir-based regimens.

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