Chemical formula: C₂₅H₃₆N₃O₉PS Molecular mass: 585.607 g/mol PubChem compound: 131536
The in vitro antiviral activity observed with fosamprenavir is due to the presence of trace amounts of amprenavir. Amprenavir is a competitive inhibitor of the 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.
Administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily results in plasma amprenavir concentrations (data from study APV30003 in antiretroviral experienced patients) which results in protein adjusted median ratios of Cmin/IC50 and Cmin/IC95 of 21.7 (range 1.19-240) and 3.21 (range 0.26-30.0), respectively.
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.
a) ART-naïve or PI-naïve patients:
Various regimens have been assessed in the amprenavir/fosamprenavir development programs with and without co-administration of ritonavir. Analysis of the virological failure samples across these regimens defined four main resistance pathways: V32I+I47V, I50V, I54L/M and I84V. Additional mutations observed which may contribute to resistance were: L10V/F/R, I13V, K20R/T, L33F/V, M36I, M46I/L, I47V/L Q58E, I62V, L63P, V77I, I85V, and I93L.
When ART naïve adult patients were treated with the currently approved doses of fosamprenavir/ritonavir, as for other ritonavir boosted PI regimens, the mutations described were infrequently observed. Sixteen of 434 ART-naïve patients who received fosamprenavir 700 mg/ritonavir 100 mg twice daily in ESS100732 experienced virological failure by Week 48 with 14 isolates genotyped. Three of 14 isolates had protease resistance mutations. One resistance mutation was observed in each of 3 isolates: K20K/R, I54I/L and I93I/L respectively
Among the 81 PI-naïve paediatric patients treated with fosamprenavir/ritonavir, 15 patients met protocol-defined virological failure through 48 weeks in APV29005 and up to 108 weeks in APV20003. Treatment-emergent major or APV-associated protease mutations were observed in virus isolated from 2 patients. Resistance patterns were similar to those observed in adults.
b) PI-experienced patients:
Amprenavir: In the studies of PI-experienced adult patients, PRO30017 (amprenavir 600 mg/ritonavir 100 mg twice daily in sub-study A and B with 80 and 37 patients respectively), the following mutations emerged in patients with virological failure: L10F/I/V, V11I, I13V, K20R, V32I, L33F, E34Q, M36I, M46I/L, I47V, G48V, I50V, I54L/M/T/V, Q58E, D60E, I62V, A71V, V77I, V82A/I, I84V, I85V, L90M and I93L/M.
Fosamprenavir: In the studies of PI-experienced adult patients, APV30003 and its extension, APV30005 (fosamprenavir 700 mg/ritonavir 100 mg twice daily: n=107), the following mutations emerged in patients experiencing virological failure through 96 weeks: L10F/I, L24I, V32I, L33F, M36I, M46I/L, I47V, I50V, I54L/M/S, A71I/T/V, G73S, V82A, I84V, and L90M.
In the paediatric studies APV20003 and APV29005, 77 PI-experienced patients were treated with fosamprenavir/ritonavir-based regimens and 43 patients met study-defined virologic failure criteria through 48 weeks in APV29005 and up to 108 weeks in APV20003. Treatment-emergent major protease or APV-associated mutations were observed in virus isolated from 1 patient in APV29005 and 6 patients from APV20003. The mutational profiles were similar to those described for PIexperienced adults treated with fosamprenavir/ritonavir.
Genotypic interpretation systems may be used to estimate the activity of amprenavir/ritonavir or fosamprenavir/ritonavir in subjects with PI-resistant isolates. The current (July 2006) ANRS AC-11 algorithm for fosamprenavir/ritonavir defines resistance as the presence of the mutations V32I+I47A/V, or I50V, or at least four mutations among: L10F/I/V, L33F, M36I, I54A/L/M/S/T/V, I62V, V82A/C/F/G, I84V and L90M and is associated with increased phenotypic resistance to fosamprenavir with ritonavir as well as reduced likelihood of virological response (resistance). Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.
Clinically validated phenotypic interpretation systems may be used in association with the genotypic data to estimate the activity of amprenavir/ritonavir or fosamprenavir/ritonavir in patients with PI resistant isolates. Resistance testing diagnostic companies have developed clinical phenotypic cut-offs for FPV/RTV that can be used to interpret resistance test results.
After oral administration, fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. The conversion of fosamprenavir to amprenavir appears to primarily occur in the gut epithelium.
The pharmacokinetic properties of amprenavir following co-administration of fosamprenavir with ritonavir have been evaluated in healthy adult subjects and HIV-infected patients and no substantial differences were observed between these two groups.
Fosamprenavir tablet and oral suspension formulations, both given fasted, delivered equivalent plasma amprenavir AUC∞ values and the fosamprenavir oral suspension formulation delivered a 14% higher plasma amprenavir Cmax as compared to the oral tablet formulation.
After single dose administration of fosamprenavir, amprenavir peak plasma concentrations are observed approximately 2 hours after administration. Fosamprenavir AUC values are, in general, less than 1% of those observed for amprenavir. The absolute bioavailability of fosamprenavir in humans has not been established.
After multiple dose oral administration of equivalent fosamprenavir and amprenavir doses, comparable amprenavir AUC values were observed; however, Cmax values were approximately 30% lower and Cmin values were approximately 28% higher with fosamprenavir.
Co-administration of ritonavir with fosamprenavir increase plasma amprenavir AUC by approximately 2-fold and plasma Cτ,ss by 4- to 6-fold, compared to values obtained when fosamprenavir is administered alone.
After multiple dose oral administration of fosamprenavir 700 mg with ritonavir 100 mg twice daily, amprenavir was rapidly absorbed with a geometric mean (95% CI) steady state peak plasma amprenavir concentration (Cmax) of 6.08 (5.38-6.86) µg/ml occurring approximately 1.5 (0.75-5.0) hours after dosing (tmax). The mean steady state plasma amprenavir trough concentration (Cmin) was 2.12 (1.77-2.54) µg/ml and AUC0-tau was 39.6 (34.5–45.3) h*µg/ml.
Administration of the fosamprenavir tablet formulation in the fed state (standardised high fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) did not alter plasma amprenavir pharmacokinetics (Cmax, tmax or AUC0-∞) compared to the administration of this formulation in the fasted state. Fosamprenavir tablets may be taken without regard to food intake.
Co-administration of amprenavir with grapefruit juice was not associated with clinically significant changes in plasma amprenavir pharmacokinetics.
The apparent volume of distribution of amprenavir following administration of fosamprenavir is approximately 430 l (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. This value is decreased by approximately 40% when fosamprenavir is co-administered with ritonavir, most likely due to an increase in amprenavir bioavailability.
In in vitro studies, the protein binding of amprenavir is approximately 90%. It is bound to the alpha-1- acid glycoprotein (AAG) and albumin,but has a higher affinity for AAG. 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.
CSF penetration of amprenavir is negligible in humans. Amprenavir appears to penetrate into semen, though semen concentrations are lower than plasma concentrations.
Fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate as it is absorbed through the gut epithelium, following oral administration. Amprenavir is primarily metabolised by the liver with less than 1% excreted unchanged in the urine. The primary route of metabolism is via the cytochrome P450 3A4 enzyme. Amprenavir metabolism is inhibited by ritonavir, via inhibition of CYP3A4, resulting in increased plasma concentrations of amprenavir. Amprenavir in addition is also an inhibitor of the CYP3A4 enzyme, although to a lesser extent than ritonavir. Therefore medicinal products that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with fosamprenavir with ritonavir.
Following administration of fosamprenavir, the half-life of amprenavir is 7.7 hours. When fosamprenavir is co-administered with ritonavir, the half-life of amprenavir is increased to 15-23 hours. The primary route of elimination of amprenavir is via hepatic metabolism with less than 1% excreted unchanged in the urine and no detectable amprenavir in faeces. Metabolites account for approximately 14% of the administered amprenavir dose in the urine, and approximately 75% in the faeces.
In a clinical study on pharmacokinetics of fosamprenavir in paediatric patients, eight subjects 12 to 18 years of age received the standard fosamprenavir adult tablet dose of 700 mg twice daily (with ritonavir 100 mg twice daily). Compared to the historical adult population receiving fosamprenavir/ritonavir 700/100 mg twice daily, 12 to 18 year old subjects had 20% lower plasma APV AUC(0-24), 23% lower Cmax, and 20% lower Cmin values. Children 6 to 11 years of age (n=9) receiving fosamprenavir/ritonavir 18/3 mg/kg twice daily had 26% higher AUC(0-24) and similar Cmax and Cmin values when compared to the historical adult population receiving fosamprenavir/ritonavir 700/100 mg twice daily.
APV20002 is a 48 week, Phase II, open label study designed to evaluate the pharmacokinetics, safety, tolerability and antiviral activity of fosamprenavir with and without ritonavir in paediatric subjects 4 weeks to <2 years of age. Compared to the historical adult population receiving fosamprenavir with ritonavir 700 mg/100 mg twice daily, a subset of five pediatric subjects ages 6 to <24-months receiving fosamprenavir/ritonavir 45/7 mg/kg twice daily demonstrated that despite an approximate 5-fold increase in fosamprenavir and ritonavir doses on a mg/kg basis, plasma amprenavir AUC(0-τ) was approximately 48% lower, Cmax 26% lower, and Cτ 29% lower in the paediatric subjects. No dosing recommendations can be made for the very young (children <2 years of age) and fosamprenavir with ritonavir is not recommended for this patient population.
The pharmacokinetics of fosamprenavir in combination with ritonavir has not been studied in patients over 65 years of age.
Patients with renal impairment have not been specifically studied. Less than 1% of the therapeutic dose of amprenavir is excreted unchanged in the urine. Renal clearance of ritonavir is also negligible, therefore the impact of renal impairment on amprenavir and ritonavir elimination should be minimal
Fosamprenavir is converted in man to amprenavir. The principal route of amprenavir and ritonavir elimination is hepatic metabolism.
The plasma amprenavir pharmacokinetics were evaluated in a 14 day repeat-dose study in HIV-1 infected adult subjects with mild, moderate, or severe hepatic impairment receiving fosamprenavir with ritonavir compared to matched control subjects with normal hepatic function.
In subjects with mild hepatic impairment (Child-Pugh score of 5-6), the dosage regimen of fosamprenavir 700 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily provided slightly higher plasma amprenavir Cmax (17%), slightly higher plasma amprenavir AUC(0-12) (22%), similar plasma total amprenavir C12 values and approximately 117% higher plasma unbound amprenavir C12 values compared to subjects with normal hepatic function receiving the standard fosamprenavir/ritonavir 700 mg/100 mg twice daily regimen.
In subjects with moderate hepatic impairment (Child-Pugh score of 7-9), a reduced dose of fosamprenavir 450 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily is predicted to deliver similar plasma amprenavir Cmax and AUC(0-12), but approximately 35% lower plasma total amprenavir C12 values and approximately 88% higher plasma unbound amprenavir C12 values than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg/100 mg twice daily regimen. Predicted exposures are based on extrapolation from data observed following administration of fosamprenavir 300 mg twice daily with ritonavir 100 mg once daily in subjects with moderate hepatic impairment.
In subjects with severe hepatic impairment (Child-Pugh score of 10-13), a reduced dose of fosamprenavir 300 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily delivered 19% lower plasma amprenavir Cmax, 23% lower AUC(0-12), and 38% lower C12 values, but similar unbound plasma amprenavir C12 values than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg/100 mg twice dailyregimen. Despite reducing the dosing frequency of ritonavir, subjects with severe hepatic impairment had 64% higher ritonavir Cmax, 40% higher ritonavir AUC(0-24), and 38% higher ritonavir C12 than achievedin subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg/100 mg twice daily regimen.
Fosamprenavir with ritonavir was generally well-tolerated in subjects with mild, moderate, or severe hepatic impairment, and these regimens had similar adverse event and clinical laboratory profiles as previous studies of HIV-1 infected subjects with normal hepatic function.
Amprenavir (APV) pharmacokinetics were studied in pregnant women receiving FPV/RTV 700/100 mg twice daily during the second trimester (n=6) or third trimester (n=9) and postpartum. APV exposure was 25-35% lower during pregnancy. APV geometric mean (95% CI) and Ctau values were 1.31 (0.97, 1.77), 1.34 (0.95, 1.89), and 2.03 (1.46, 2.83) µg/mL for the second trimester, third trimester, and postpartum, respectively and within the range of values in non-pregnant patients on the same FPV/RTV containing regimens.
Toxicity was similar to that of amprenavir and occurred at amprenavir plasma exposure levels below human exposure after treatment with fosamprenavir in combination with ritonavir at the recommended dose.
In repeated dose toxicity studies in adult rats and dogs, fosamprenavir produced evidence of gastrointestinal disturbances (salivation, vomiting and soft to liquid faeces), and hepatic changes (increased liver weights, raised serum liver enzyme activities and microscopic changes, including hepatocyte necrosis). Toxicity was not aggravated when juvenile animals were treated as compared with adult animals, but the data did indicate a steeper dose response.
In reproductive toxicity studies with fosamprenavir in rats, male fertility was not affected. In females, at the high dose, there was a reduction in the weight of gravid uterus (0 to 16%) probably due to a reduction of the number of ovarian corporea lutea and implantations. In pregnant rats and rabbits there were no major effects on embryo-foetal development. However, the number of abortions increased. In rabbits, systemic exposure at the high dose level was only 0.3 times human exposure at the maximum clinical dose and thus the developmental toxicity of fosamprenavir has not been fully determined. In rats exposed pre- and post-natally to fosamprenavir, pups showed impaired physical and functional development and reduced growth. Pup survival was decreased. In addition, decreased number of implantation sites per litter and a prolongation of gestation were seen when pups were mated after reaching maturity.
Fosamprenavir was not mutagenic or genotoxic in a standard battery of in vitro and in vivo assays. In long-term carcinogenicity studies with fosamprenavir in mice and rats, there were increases in hepatocellular adenomas and hepatocellular carcinomas in mice at exposure levels equivalent to 0.1 to 0.3-fold those in humans given 700 mg of fosamprenavir plus 100 mg ritonavir twice daily, and increases in hepatocellular adenomas and thyroid follicular cell adenomas in rats at exposure levels equivalent to 0.3 to 0.6-fold those in humans given 700 mg of fosamprenavir plus 100 mg ritonavir twice daily. The relevance of the hepatocellular findings in the rodents for humans is uncertain; however, there is no evidence from clinical trials or marketed use to suggest that these findings are of clinical significance. Repeat dose studies with fosamprenavir in rats produced effects consistent with hepatic enzyme induction, which predisposes rats to thyroid neoplasms. The thyroid tumorigenic potential is regarded to be species-specific. The clinical relevance of these findings is unknown. In rats only there was an increase in interstitial cell hyperplasia in males at exposure levels equivalent to 0.5-fold those in humans, and an increase in uterine endometrial adenocarcinoma in females at an exposure level equivalent to 1.1-fold those in humans. The incidence of endometrial findings was slightly increased over concurrent controls, but within background range for female rats. The relevance of the uterine endometrial adenocarcinomas for humans is uncertain; however there is no evidence from clinical trials or marketed use to suggest that these findings are of clinical significance.
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