Background

Washington D.C., USA, 22-27 July 2012www.aids2012.org

Cristina Gervasoni, Sara Baldelli, Matteo Cerea, Simona Landonio, Paola Meraviglia, Emanuela Simioni, Andrea Gazzaniga,

Emilio Clementi, Massimo Galli, Giuliano Rizzardini 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, Università degli Studi di Milano, Milan, Italy

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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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Washington D.C., USA, 22-27 July 2012www.aids2012.org

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.

Background Logo University of Milan Logo L. Sacco HospitalLogo University of Milan Logo L. Sacco Hospital

Washington D.C., USA, 22-27 July 2012www.aids2012.org

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.

Aim of the Study Logo University of Milan Logo L. Sacco HospitalLogo University of Milan Logo L. Sacco Hospital

Washington D.C., USA, 22-27 July 2012www.aids2012.org

In vivo StudyLogo University of Milan Logo L. Sacco HospitalLogo University of Milan Logo L. Sacco Hospital

50 HIV patients given raltegravir by swallowing

10 HIV patients given raltegravir by chewing due to

swallowing difficulties

versusBlood sampling at 0, 1, 2, 3 and 4 hours after the morning raltegravir dose.

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. Limited sampling strategies for the estimation of raltegravir daily exposure in HIV-infected patients. J Clin Pharmacol. 2012;52:440-5

Washington D.C., USA, 22-27 July 2012www.aids2012.org

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2000

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10000 raltegravir tablet swallowedraltegravir tablet chewed

Time, h post-dosing

Ral

tegr

avir,

ng/

mL

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)

**

*

Washington D.C., USA, 22-27 July 2012www.aids2012.org

Main Pk parameters

RaltegravirChewed CV% Raltegravir

Swallowed CV% p-value

Ctrough, ng/mL 350 ± 414 118 544 ± 655 120

C1h, ng/mL 5397 ± 3043 56 2110 ± 2132 101 <0.0001

C2h, ng/mL 3480 ± 2415 69 2256 ± 2342 104 0.044

C3h, ng/mL 1975 ± 1490 75 1872 ± 1858 99

C4h, ng/mL 1212 ± 1004 82 1360 ± 1537 113

Cmax, ng/mL 5404 ± 3032 56 3128 ± 2588 83 0.004

Tmax, min* 60 (60 – 120) 25 180 (0 – 240) 63 0.028

AUC0-4, ng*h/mL 11634 ± 7288 62 7007 ± 5803 83 0.011

AUC0-12, ng*h/mL 15024 ± 9639 64 11803 ± 9544 83 0.084*median (interquartile range): CV: coefficient of variation

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

Washington D.C., USA, 22-27 July 2012www.aids2012.org

In vitro StudyLogo University of Milan Logo L. Sacco HospitalLogo University of Milan Logo L. Sacco Hospital

The dissolution of raltegravir tablets in water, in acidic solution (pH 1) and in pH 6.8 buffer was evaluated.

versus

(mimics swallowing)

(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).

Washington D.C., USA, 22-27 July 2012www.aids2012.org

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drug

dis

solv

ed, %

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drug

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dis

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pH 1

water

pH 6.8

Whole tablets

Crushed tablets

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Working HypothesisLogo University of Milan Logo L. Sacco HospitalLogo University of Milan Logo L. Sacco Hospital

Negligible drug release in the stomach

(pH 1.0)

Optimal drug release in the duodenum

(pH 6.8)

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

Washington D.C., USA, 22-27 July 2012www.aids2012.org

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.

ConclusionsLogo University of Milan Logo L. Sacco HospitalLogo University of Milan Logo L. Sacco Hospital