|
|
| Line 1: |
Line 1: |
| __NOTOC__
| | #redirect [[Sofosbuvir#Clinical Pharmacology]] |
| {{Sofosbuvir}}
| |
| {{CMG}}
| |
| | |
| ==Clinical Pharmacology==
| |
| | |
| ===Pharmacodynamics===
| |
| | |
| Effect on Electrocardiogram
| |
| | |
| The effect of sofosbuvir 400 and 1200 mg on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, SOVALDI does not prolong QTc to any clinically relevant extent.
| |
| | |
| ===Pharmacokinetics===
| |
| | |
| ====Absorption====
| |
| | |
| The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of SOVALDI, sofosbuvir was absorbed with a peak plasma concentration observed at ~0.5–2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in subjects with genotype 1 to 6 [[HCV]] infection who were coadministered [[ribavirin]] (with or without pegylated interferon), geometric mean steady state sofosbuvir (N=838) and GS-331007 (N=1695) AUC0–24 were 828 ng∙hr/mL and 6790 ng∙hr/mL, respectively. Relative to healthy subjects administered sofosbuvir alone (N = 272), the sofosbuvir AUC0–24was 39% higher and GS-331007 AUC0–24 was 39% lower, respectively, in [[HCV]]-infected subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg.
| |
| | |
| ====Effect of Food====
| |
| | |
| Relative to fasting conditions, the administration of a single dose of SOVALDI with a standardized high fat meal did not substantially affect the sofosbuvir Cmax or AUC0–inf. The exposure of GS-331007 was not altered in the presence of a high-fat meal. Therefore, SOVALDI can be administered without regard to food.
| |
| | |
| ====Distribution====
| |
| | |
| Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.
| |
| | |
| ====Metabolism====
| |
| | |
| Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-[[HCV]] activity in vitro.
| |
| | |
| After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007 accounted for approximately 4% and >90% of drug related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure, respectively.
| |
| | |
| ====Elimination====
| |
| | |
| Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively.
| |
| | |
| ====Specific Populations====
| |
| | |
| =====Race=====
| |
| | |
| Population pharmacokinetics analysis in [[HCV]]-infected subjects indicated that race had no clinically relevant effect on the exposure of sofosbuvir and GS-331007.
| |
| | |
| =====Gender=====
| |
| | |
| No clinically relevant pharmacokinetic differences have been observed between men and women for sofosbuvir and GS-331007.
| |
| | |
| =====Pediatric Patients=====
| |
| | |
| The pharmacokinetics of sofosbuvir in pediatric patients have not been established [See Use in Specific Populations (8.4)].
| |
| | |
| =====Geriatric Patients=====
| |
| | |
| Population pharmacokinetic analysis in [[HCV]]-infected subjects showed that within the age range (19 to 75 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007 [See Use in Specific Populations (8.5)].
| |
| | |
| =====Patients with Renal Impairment=====
| |
| | |
| The pharmacokinetics of sofosbuvir were studied in [[HCV]] negative subjects with mild (eGFR ≥ 50 and < 80 mL/min/1.73m2), moderate (eGFR ≥30 and <50 mL/min/1.73m2), severe renal impairment (eGFR <30 mL/min/1.73m2) and subjects with end stage renal disease (ESRD) requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR >80 mL/min/1.73m2), the sofosbuvir AUC0–inf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC0–inf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0–inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18% of administered dose. No dose adjustment is required for patients with mild or moderate renal impairment. The safety and efficacy of SOVALDI have not been established in patients with severe renal impairment or ESRD. No dose recommendation can be given for patients with severe renal impairment or ESRD [See Dosage and Administration (2.4) and Use in Specific Populations (8.6)].
| |
| | |
| =====Patients with Hepatic Impairment=====
| |
| | |
| The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in [[HCV]]-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0–24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0–24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in [[HCV]]-infected subjects indicated that cirrhosis had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No dose adjustment of SOVALDI is recommended for patients with mild, moderate and severe hepatic impairment [See Use in Specific Populations (8.7)].
| |
| | |
| =====Assessment of Drug Interactions=====
| |
| | |
| The effects of coadministered drugs on the exposure of sofosbuvir and GS-331007 are shown in Table 6. The effects of sofosbuvir on the exposure of coadministered drugs are shown in Table 7 [See Drug Interactions (7.3)].
| |
| | |
| {|
| |
| |-
| |
| |[[File:Sofosbuvir 2.jpg|thumb|1600px|left]]
| |
| |-
| |
| |}
| |
| No effect on the pharmacokinetic parameters of sofosbuvir and GS-331007 was observed with raltegravir.
| |
| {|
| |
| |-
| |
| |[[File:Sofosbuvir 3.jpg|thumb|1600px|left]]
| |
| |-
| |
| |}
| |
| No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with sofosbuvir: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone or rilpivirine.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = SOVALDI (SOFOSBUVIR) TABLET, FILM COATED [GILEAD SCIENCES, INC.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=80beab2c-396e-4a37-a4dc-40fdb62859cf | publisher = | date = | accessdate = 7 January 2014 }}</ref>
| |
| | |
| ==References==
| |
| {{Reflist}}
| |
| | |
| {{FDA}}
| |
| | |
| [[Category:Antiviral]]
| |
| [[Category:Wikinfect]]
| |