Chemical formula: C₂₅H₃₅N₃O₆S Molecular mass: 505.627 g/mol PubChem compound: 65016
Amprenavir is a competitive inhibitor of HIV-1 protease. Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral gag and gag-pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles. The in vitro antiviral activity observed with fosamprenavir is due to the presence of trace amounts of amprenavir.
The in vitro antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, H9) and in peripheral blood lymphocytes. The 50% inhibitory concentration (IC50) of amprenavir ranged from 0.012 to 0.08 µM in acutely infected cells and was 0.41 µM in chronically infected cells (1 µM = 0.50 µg/ml). The relationship between in vitro anti-HIV-1 activity of amprenavir and the inhibition of HIV-1 replication in humans has not been defined.
HIV-1 isolates with decreased susceptibility to amprenavir have been selected during in vitro serial passage experiments. Reduced susceptibility to amprenavir was associated with virus that had developed I50V or I84V or V32I+I47V or I54M mutations.
After oral administration, amprenavir is rapidly and well absorbed. The absolute bioavailability is unknown due to the lack of an acceptable intravenous formulation for use in man. Approximately 90% of an orally administered radiolabelled amprenavir dose was recovered in the urine and the faeces, primarily as amprenavir metabolites. Following oral administration, the mean time (tmax) to maximal serum concentrations of amprenavir is between 1-2 hours for the capsule and 0.5 to 1 hour for the oral solution. A second peak is observed after 10 to 12 hours and may represent either delayed absorption or enterohepatic recirculation.
At therapeutic dosages (1200 mg twice daily), the mean maximum steady state concentration (Cmax,ss) of amprenavir capsules is 5.36 μg/ml (0.92-9.81) and the minimum steady state concentration (Cmin,ss) is 0.28 μg/ml (0.12-0.51). The mean AUC over a dosing interval of 12 hours is 18.46 μg.h/ml (3.02- 32.95). The 50 mg and 150 mg capsules have been shown to be bioequivalent. The bioavailability of the oral solution at equivalent doses is lower than that of the capsules, with an AUC and Cmax approximately 14% and 19% lower, respectively.
The AUC and Cmin of amprenavir were increased by 64% and 508% respectively and the Cmax decreased by 30% when ritonavir (100 mg twice daily) was coadministered with amprenavir (600 mg twice daily) compared to values achieved after 1200 mg twice daily doses of amprenavir.
While administration of amprenavir with food results in a 25% reduction in AUC, it had no effect on the concentration of amprenavir 12 hours after dosing (C12). Therefore, although food affects the extent and rate of absorption, the steady-state trough concentration (Cmin,ss) was not affected by food intake.
The apparent volume of distribution is approximately 430 litres (6 l/kg assuming a 70 kg body weight), suggesting a large volume of distribution, with penetration of amprenavir freely into tissues beyond the systemic circulation. The concentration of amprenavir in the cerebrospinal fluid is less than 1% of plasma concentration.
In in vitro studies, the protein binding of amprenavir is approximately 90%. Amprenavir is primarily bound to the alpha-1-acid glycoprotein (AAG), but also to albumin. Concentrations of AAG have been shown to decrease during the course of antiretroviral therapy. This change will decrease the total active substance concentration in the plasma, however the amount of unbound amprenavir, which is the active moiety, is likely to be unchanged. While absolute free active substance concentrations remain constant, the percent of free active substance will fluctuate directly with total active substance concentrations at steady-state go from Cmax,ss to Cmin,ss over the course of the dosing interval. This will result in a fluctuation in the apparent volume of distribution of total active substance, but the volume of distribution of free active substance does not change.
Clinically significant binding displacement interactions involving medicinal products primarily bound to AAG are generally not observed. Therefore, interactions with amprenavir due to protein binding displacement are highly unlikely.
Amprenavir is primarily metabolised by the liver with less than 3% excreted unchanged in the urine. The primary route of metabolism is via the cytochrome P450 CYP3A4 enzyme. Amprenavir is a substrate of and inhibits CYP3A4. Therefore, medicinal products that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with amprenavir.
The plasma elimination half-life of amprenavir ranges from 7.1 to 10.6 hours. The plasma amprenavir half-life is increased when amprenavir capsules are co-administered with ritonavir. Following multiple oral doses of amprenavir (1200 mg twice a day), there is no significant active substance accumulation. The primary route of elimination of amprenavir is via hepatic metabolism with less than 3% excreted unchanged in the urine. The metabolites and unchanged amprenavir account for approximately 14% of the administered amprenavir dose in the urine, and approximately 75% in the faeces.
The pharmacokinetics of amprenavir in children (4 years of age and above) are similar to those in adults. Dosages of 20 mg/kg twice a day and 15 mg/kg three times a day with amprenavir capsules provided similar daily amprenavir exposure to 1200 mg twice a day in adults. Amprenavir is 14% less bioavailable from the oral solution than from the capsules; therefore, amprenavir capsules and amprenavir oral solution are not interchangeable on a milligram per milligram basis.
The pharmacokinetics of amprenavir have not been studied in patients over 65 years of age.
Patients with renal impairment have not been specifically studied. Less than 3% of the therapeutic dose of amprenavir is excreted unchanged in the urine. The impact of renal impairment on amprenavir elimination should be minimal therefore, no initial dose adjustment is considered necessary. Renal clearance of ritonavir is also negligible; therefore the impact of renal impairment on amprenavir and ritonavir elimination should be minimal.
The pharmacokinetics of amprenavir are significantly altered in patients with moderate to severe hepatic impairment. The AUC increased nearly three-fold in patients with moderate impairment and four fold in patients with severe hepatic impairment. Clearance also decreased in a corresponding manner to the AUC. The dosage should therefore be reduced in these patients. These dosing regimens will provide plasma amprenavir levels comparable to those achieved in healthy subjects given a 1200 mg dose twice daily without concomitant administration of ritonavir.
In long-term carcinogenicity studies with amprenavir in mice and rats, there were benign hepatocellular adenomas in males at exposure levels equivalent to 2.0-fold (mice) or 3.8-fold (rats) those in humans given 1200 mg twice daily of amprenavir alone. In male mice altered hepatocellular foci were seen at doses that were at least 2.0 times human therapeutic exposure.
A higher incidence of hepatocellular carcinoma was seen in all amprenavir male mouse treatment groups. However, this increase was not statistically significantly different from male control mice by appropriate tests. The mechanism for the hepatocellular adenomas and carcinomas found in these studies has not been elucidated and the significance of the observed effects for humans is uncertain. However, there is little evidence from the exposure data in humans, both in clinical trials and from marketed use, to suggest that these findings are of clinical significance.
Amprenavir was not mutagenic or genotoxic in a battery of in vivo and in vitro genetic toxicity assays, including bacterial reverse mutation (Ames Test), mouse lymphoma, rat micronucleus, and chromosome aberration in human peripheral lymphocytes.
In toxicological studies with mature animals, the clinically relevant findings were mostly confined to the liver and gastrointestinal disturbances. Liver toxicity consisted of increases in liver enzymes, liver weights and microscopic findings including hepatocyte necrosis. This liver toxicity can be monitored for and detected in clinical use, with measurements of AST, ALT and alkaline phosphatase activity. However, significant liver toxicity has not been observed in patients treated in clinical studies, either during administration of amprenavir or after discontinuation.
Amprenavir did not affect fertility.
Local toxicity and sensitising potential was absent in animal studies, but slight irritating properties to the rabbit eye were identified.
Toxicity studies in young animals, treated from four days of age, resulted in high mortality in both the control animals and those receiving amprenavir. These results imply that young animals lack fully developed metabolic pathways enabling them to excrete amprenavir or some critical components of the formulation (e.g. propylene glycol, PEG 400). However, the possibility of anaphylactic reaction related to PEG 400 cannot be excluded. In clinical studies, the safety and efficacy of amprenavir have not yet been established in children below four years of age.
In pregnant mice, rabbits and rats there were no major effects on embryo-foetal development. However, at systemic plasma exposures significantly below (rabbits) or not significantly higher (rat) than the expected human exposures during therapeutic dosing, a number of minor changes, including thymic elongation and minor skeletal variations were seen, indicating developmental delay. A dosedependent increase in placental weight was found in the rabbit and rat which may indicate effects on placental function. It is therefore recommended that women of child-bearing potential taking amprenavir should practice effective contraception (e.g. barrier methods).
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