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Elbasvir / Grazoprevir can inhibit the CYP 3A4 and potentially BCRP and increase the plasma concentration of Atorvastatin.
Elbasvir : 3A4; P-gp (minor) / Grazoprevir : OATP1B1 and 3A4; P-gp (minor)
Elbasvir : BCRP; P-gp (weak at intestinal leveel) / Grazoprévir : BCRP; 3A4 (weak not clinically significant)
3A4 (major), 2C8 (minor): metabolised in acid derivatives 2-hydroxy-atorvastatin and 4-hydroxy-atorvastatin. These active metabolites are responsable of about 70% of the inhibitory activity of HMG-CoA reductase circulating. OATP1B1 and P-gp.
3A4 (weak), OATP1B1 and P-gp.
Possible increased risk of HMG CoA inhibitor toxicity.
Start with a small dosage. Monitor closely for signs and symptoms of toxicity and adjust dosage as a function of efficacy and tolerance.
Maximum dose: 20 mg once daily.
Symptoms of toxicity associated with hypolipidemic agents : gastrointestinal effects, fatigue and muscular weaknesses, myalgias, muscular cramps, myopathies, rhabdomyolysis and myoglobinuria leading to renal insufficiency.
|200 mg *||50/200* mg|
|20 mg||10 mg|
|x 1||x 1|
|+ 200% (3x)||+ 94%|
|+ 466% (5.6x)||+ 334% (4.3x)|
* Since grazoprevir in HCV-infected patients demonstrates ~2-fold higher exposure compared to healthy subjects, a 200 mg dose was used in this study to match the exposure of a 100 mg dose (intended clinical dose).
Ref #3029 : † This study was conducted with grazoprevir alone.
Active atorvastatin metabolites (ortho- and para-hydroxyatorvastatin) had similar trends in PK to atorvastatin parent when coadministered with grazoprevir.