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Combination formulation of two antiviral compounds

A compound and composition technology, applied in the field of compound preparations of two antiviral compounds, can solve the problems of unknown treatment benefit of sofosbuvir

Active Publication Date: 2016-04-20
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the therapeutic benefit of administering compound I and crystalline sofosbuvir was previously unknown

Method used

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  • Combination formulation of two antiviral compounds
  • Combination formulation of two antiviral compounds
  • Combination formulation of two antiviral compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0216] Example 1: Tablet Preparation and Formulation

[0217] A. Dose Selection of Tablets

[0218] i. Sofosbuvir

[0219] The dose of sofosbuvir chosen for the tablet is 400 mg once daily. Support for the 400 mg sofosbuvir dose can be derived from early virological and human exposure data E max PK / PD modeling, which also supported selection of 400 mg sofosbuvir higher than other tested doses.

[0220] Mean sofosbuvir major metabolite AUC for 400 mg sofosbuvir dose tau Associated with approximately 77% of the maximum obtainable HCV RNA change from baseline (the value at the apex of the plateau of the exposure-response sigmoid curve) as determined by this model. In Recurve E max In the model, there is a relatively linear exposure-response relationship in the range of 20-80% of the maximum effect. Therefore, given that sofosbuvir exposure from the 200 mg tablet appears to be dose proportional to single doses up to 1200 mg, doses below 400 mg are expected to produce a sizab...

Embodiment 2

[0255] Example 2: Drug-Drug Interaction Between SOF and Compound 1

[0256] The PK drug-drug interaction between SOF and Compound I was assessed. Compound I plasma exposure (AUC tau 、C max and C tau ) was not affected by SOF co-administration and therefore no dose adjustment was required for Compound I. Sofosbuvir plasma exposure increased approximately 1.8-fold when co-administered with Compound I (C max ) and 2.4-fold (AUC). When SOF was co-administered with compound I (solid dispersion, compound I: copovidone 1:1), the C max and AUC increased by about 1.6-fold and 1.8-fold, respectively, when co-administered with Compound I was approximately 1.8-fold (C max ) and 2.4-fold (AUC). The Cmax of SOF metabolite II (the major circulating nucleoside metabolite of SOF) decreased by about 36%, but the AUC was not affected by co-administration of SOF and Compound I. See Table 6.

[0257] Table 6

[0258]

[0259]

[0260] Note: Data reported as GLSM. Contemporaneous g...

Embodiment 3

[0262] Example 3: Food Effects

[0263] Exposure of Compound I solid dispersion (Compound I:copovidone 1:1) administered as a single agent with a high-fat / high-calorie diet (HFM) was modestly reduced (14% of AUC) compared to fasted administration and a 25% reduction in Cmax) (Table 7). The relative increase in exposure of Compound I (solid dispersion) when administered as part of Sofosbuvir / Compound I (solid dispersion) FDC with HFM resulted in a modest increase in exposure compared to fasted administration (AUC ~20% improvement and ~5% improvement in Cmax, Table 8). This increase in exposure indicates an increase in the bioavailability of Compound I administered as part of a sofosbuvir / Compound IFDC relative to Compound I administered as a single agent tablet. Table 8 below shows the Compound I exposure and GMR of the fixed dose combination under different fed states.

[0264] Table 7

[0265]

[0266]

[0267] Table 8

[0268]

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Abstract

Disclosed are pharmaceutical compositions comprising Compound I, having the formula (I): and an effective amount of sofosbuvir wherein the sofosbuvir is substantially crystalline. Also disclosed are methods of use for the pharmaceutical composition.

Description

[0001] Cross References to Related Applications [0002] This application is required under 35 U.S.C. § 119(e) of U.S. Provisional Application Nos. 61 / 870,712, filed August 27, 2013, U.S. Provisional Application Nos. 61 / 898,690, filed November 1, 2013, and November 21, 2013 Benefit of U.S. Provisional Application No. 61 / 907,308 filed, the entire contents of which are hereby incorporated by reference. Background technique [0003] Hepatitis C is considered a chronic viral disease of the liver, characterized by liver disease. Although drugs targeting the liver are widely used and have shown effectiveness, toxicity and other side effects limit their use. Inhibitors of hepatitis C virus (HCV) are useful in limiting the establishment and progression of HCV infection and in diagnostic assays for HCV. [0004] Compound {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)]-2- Phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisobenzopyrano[4',...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/16A61K9/20A61K31/4188A61K31/513
CPCA61K9/1623A61K9/1635A61K9/2054A61K31/4188A61K31/7072A61P1/16A61P31/12A61P31/14A61P43/00A61K2300/00A61K9/284A61K31/7056
Inventor E·格曼E·莫加利安R·奥利亚D·斯蒂芬尼迪斯L·怀泽V·兹亚
Owner GILEAD SCI INC
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