July 30, 2016
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Lexiva

"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended 150 mg lamivudine/300 mg raltegravir (Dutrebis, Merck Sharp & Dohme Limited) for the treatment of HIV 1 infection in adults, adolesce"...

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Lexiva




CLINICAL PHARMACOLOGY

Mechanism Of Action

Fosamprenavir is an antiviral agent [see Microbiology].

Pharmacokinetics

The pharmacokinetic properties of amprenavir after administration of LEXIVA, with or without ritonavir, have been evaluated in both healthy adult volunteers and in HIV-1-infected subjects; no substantial differences in steady-state amprenavir concentrations were observed between the 2 populations.

The pharmacokinetic parameters of amprenavir after administration of LEXIVA (with and without concomitant ritonavir) are shown in Table 8.

Table 8: Geometric Mean (95% CI) Steady-state Plasma Amprenavir Pharmacokinetic Parameters in Adults

Regimen Cmax
(mcg/mL)
Tmax
(hours)a
AUC24
(mcg•h/mL)
Cmin
(mcg/mL)
LEXIVA 1,400 mg b.i.d. 4.82
(4.06-5.72)
1.3
(0.8-4.0)
33.0
(27.6-39.2)
0.35
(0.27-0.46)
LEXIVA 1,400 mg q.d. plus Ritonavir 200 mg q.d. 7.24
(6.32-8.28)
2.1
(0.8-5.0)
69.4
(59.7-80.8)
1.45
(1.16-1.81)
LEXIVA 1,400 mg q.d. plus Ritonavir 100 mg q.d. 7.93
(7.25-8.68)
1.5
(0.75-5.0)
66.4
(61.1-72.1)
0.86
(0.74-1.01)
LEXIVA 700 mg b.i.d. plus Ritonavir 100 mg b.i.d. 6.08
(5.38-6.86)
1.5
(0.75-5.0)
79.2
(69.0-90.6)
2.12
(1.77-2.54)
a Data shown are median
(range).

The mean plasma amprenavir concentrations of the dosing regimens over the dosing intervals are displayed in Figure 1.

Figure 1: Mean (±SD) Steady-state Plasma Amprenavir Concentrations and Mean EC50 Values against HIV from Protease Inhibitor-na´ve Subjects (in the Absence of Human Serum)

Mean (±SD) Steady-state Plasma Amprenavir Concentrations and Mean EC50 Values - Illustration

Absorption And Bioavailability

After administration of a single dose of LEXIVA to HIV-1-infected subjects, the time to peak amprenavir concentration (Tmax) occurred between 1.5 and 4 hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of LEXIVA in humans has not been established.

After administration of a single 1,400-mg dose in the fasted state, LEXIVA oral suspension (50 mg per mL) and LEXIVA tablets (700 mg) provided similar amprenavir exposures (AUC); however, the Cmax of amprenavir after administration of the suspension formulation was 14.5% higher compared with the tablet.

Amprenavir is both a substrate for and inducer of P-glycoprotein.

Effects Of Food On Oral Absorption

Administration of a single 1,400-mg dose of LEXIVA tablets in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared with the fasted state was associated with no significant changes in amprenavir Cmax, Tmax, or AUC0-∞. [see DOSAGE AND ADMINISTRATION].

Administration of a single 1,400-mg dose of LEXIVA oral suspension in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared with the fasted state was associated with a 46% reduction in Cmax, a 0.72-hour delay in Tmax, and a 28% reduction in amprenavir AUC0-∞.

Distribution

In vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha1-acid glycoprotein. In vitro, concentration-dependent binding was observed over the concentration range of 1 to 10 mcg per mL, with decreased binding at higher concentrations. The partitioning of amprenavir into erythrocytes is low, but increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher concentrations.

Metabolism

After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. This occurs in the gut epithelium during absorption. Amprenavir is metabolized in the liver by the CYP3A4 enzyme system. The 2 major metabolites result from oxidation of the tetrahydrofuran and aniline moieties. Glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces.

Elimination

Excretion of unchanged amprenavir in urine and feces is minimal. Unchanged amprenavir in urine accounts for approximately 1% of the dose; unchanged amprenavir was not detectable in feces. Approximately 14% and 75% of an administered single dose of 14C-amprenavir can be accounted for as metabolites in urine and feces, respectively. Two metabolites accounted for greater than 90% of the radiocarbon in fecal samples. The plasma elimination half-life of amprenavir is approximately 7.7 hours.

Special Populations

Hepatic Impairment: The pharmacokinetics of amprenavir have been studied after the administration of LEXIVA in combination with ritonavir to adult HIV-1-infected subjects with mild, moderate, and severe hepatic impairment. Following 2 weeks of dosing with LEXIVA plus ritonavir, the AUC of amprenavir was increased by approximately 22% in subjects with mild hepatic impairment, by approximately 70% in subjects with moderate hepatic impairment, and by approximately 80% in subjects with severe hepatic impairment compared with HIV-1- infected subjects with normal hepatic function. Protein binding of amprenavir was decreased in subjects with hepatic impairment. The unbound fraction at 2 hours (approximate Cmax) ranged between a decrease of -7% to an increase of 57% while the unbound fraction at the end of the dosing interval (Cmin) increased from 50% to 102% [see DOSAGE AND ADMINISTRATION].

The pharmacokinetics of amprenavir have been studied after administration of amprenavir given as AGENERASE® capsules to adult subjects with hepatic impairment. Following administration of a single 600-mg oral dose, the AUC of amprenavir was increased by approximately 2.5-fold in subjects with moderate cirrhosis and by approximately 4.5-fold in subjects with severe cirrhosis compared with healthy volunteers [see DOSAGE AND ADMINISTRATION].

Renal Impairment: The impact of renal impairment on amprenavir elimination in adults has not been studied. The renal elimination of unchanged amprenavir represents approximately 1% of the administered dose; therefore, renal impairment is not expected to significantly impact the elimination of amprenavir.

Pediatric Patients: The pharmacokinetics of amprenavir following administration of LEXIVA oral suspension and LEXIVA tablets, with or without ritonavir, have been studied in a total of 212 HIV-1-infected pediatric subjects enrolled in 3 trials. LEXIVA without ritonavir was administered as 30 or 40 mg per kg twice daily to children aged 2 to 5 years. LEXIVA with ritonavir was administered as LEXIVA 30 mg per kg plus ritonavir 6 mg per kg once daily to children aged 2 to 18 years and as LEXIVA 18 to 60 mg per kg plus ritonavir 3 to 10 mg per kg twice daily to children aged at least 4 weeks to 18 years; body weights ranged from 3 to 103 kg.

Amprenavir apparent clearance decreased with increasing weight. Weight-adjusted apparent clearance was higher in children younger than 4 years, suggesting that younger children require higher mg-per-kg dosing of LEXIVA.

The pharmacokinetics of LEXIVA oral suspension in protease inhibitor-naive infants younger than 6 months (n = 9) receiving LEXIVA 45 mg per kg plus ritonavir 10 mg per kg twice daily generally demonstrated lower AUC12 and Cmin than adults receiving twice-daily LEXIVA 700 mg plus ritonavir 100 mg, the dose recommended for protease-experienced adults. The mean steady-state amprenavir AUC12, Cmax, and Cmin were 26.6 mcg·hour per mL, 6.25 mcg per mL, and 0.86 mcg per mL, respectively. Because of expected low amprenavir exposure and a requirement for large volume of drug, twice-daily dosing of LEXIVA alone (without ritonavir) in pediatric subjects younger than 2 years was not studied.

Pharmacokinetic parameters for LEXIVA administered with food and with ritonavir in this patient population at the recommended weight-band-based dosage regimens are provided in Table 9.

Table 9: Geometric Mean (95% CI) Steady-state Plasma Amprenavir Pharmacokinetic Parameters by Weight in Pediatric and Adolescent Subjects Aged at Least 4 Weeks to 18 Years Receiving LEXIVA with Ritonavir

Weight Recommended Dosage Regimen Cmax AUC24 Cmin
n (mcg/mL) n (mcg•h/mL) n (mcg/mL)
< 11 kg LEXIVA 45 mg/kg plus Ritonavir 7 mg/kg b.i.d. 12 6.00
(3.88, 9.29)
12 57.3
(34.1, 96.2)
27 1.65
(1.22, 2.24)
11 kg - < 15 kg LEXIVA 30 mg/kg plus Ritonavir 3 mg/kg b.i.d. Not studieda
15 kg - < 20 kg LEXIVA 23 mg/kg plus Ritonavir 3 mg/kg b.i.d. 5 9.54
(4.63, 19.7)
5 121
(54.2, 269)
9 3.56
(2.33, 5.43)
20 kg - < 39 kg LEXIVA 18 mg/kg plus Ritonavir 3 mg/kg b.i.d. 13 6.24
(5.01, 7.77)
12 97.9
(77.0, 124)
23 2.54
(2.11, 3.06)
≥ 39 kg LEXIVA 700 mg plus Ritonavir 100 mg b.i.d. 15 5.03
(4.04, 6.26)
15 72.3
(59.6, 87.6)
42 1.98
(1.72, 2.29)
a Recommended dose for pediatric patients weighing 11 kg to less than 15 kg is based on population pharmacokinetic analysis.

Subjects aged 2 to younger than 6 years receiving LEXIVA 30 mg per kg twice daily without ritonavir achieved geometric mean (95% CI) amprenavir Cmax (n = 9), AUC12 (n = 9), and Cmin (n = 19) of 7.15 (5.05, 10.1), 22.3 (15.3, 32.6), and 0.513 (0.384, 0.686), respectively.

Geriatric Patients: The pharmacokinetics of amprenavir after administration of LEXIVA to patients older than 65 years have not been studied [see Use in Specific Populations].

Gender: The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between males and females.

Race: The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between blacks and non-blacks.

Drug Interactions

[See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]

Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Data also suggest that amprenavir induces CYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1, or uridine glucuronosyltransferase (UDPGT). Amprenavir is both a substrate for and inducer of P-glycoprotein.

Drug interaction trials were performed with LEXIVA and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, Cmax, and Cmin values are summarized in Table 10 (effect of other drugs on amprenavir) and Table 12 (effect of LEXIVA on other drugs). In addition, since LEXIVA delivers comparable amprenavir plasma concentrations as AGENERASE, drug interaction data derived from trials with AGENERASE are provided in Tables 11 and 13. For information regarding clinical recommendations, [see DRUG INTERACTIONS].

Table 10: Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of LEXIVA in the Presence of the Coadministered Drug(s)

Coadministered Drug(s) and Dose(s) Dose of LEXIVAa n % Change in Amprenavir Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmm
Antacid (MAALOX TC®) 30 mL single dose 1,400 mg single dose 30 ↓35
(↓24 to ↓42)
↓18
(↓9 to ↓26)
↑14
(↓7 to ↑39)
Atazanavir 300 mg q.d. for 10 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days 22
Atorvastatin 10 mg q.d. for 4 days 1,400 mg b.i.d. for 2 weeks 16 ↓18
(↓34 to ↑1)
↓27
(↓41 to ↓12)
↓12
(↓27 to ↓6)
Atorvastatin 10 mg q.d. for 4 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 16
Efavirenz 600 mg q.d. for 2 weeks 1,400 mg q.d. plus ritonavir 200 mg q.d. for 2 weeks 16 ↓13
(↓30 to ↑7)
↓36
(↓8 to ↓56)
Efavirenz 600 mg q.d. plus additional ritonavir 100 mg q.d. for 2 weeks 1,400 mg q.d. plus ritonavir 200 mg q.d. for 2 weeks 16 ↑18
(↑1 to ↑38)
↑11
(0 to ↑24)
Efavirenz 600 mg q.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 16 ↓17
(↓4 to ↓29)
Esomeprazole 20 mg q.d. for 2 weeks 1,400 mg b.i.d. for 2 weeks 25
Esomeprazole 20 mg q.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 23
Ethinyl estradiol/ norethindrone 0.035 mg/0.5 mg q.d. for 21 days 700 mg b.i.d. plus ritonavirb 100 mg b.i.d. for 21 days 25 c c c
Ketoconazoled 200 mg q.d. for 4 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 4 days 15
Lopinavir/ritonavir 533 mg/133 mg b.i.d. 1,400 mg b.i.d. for 2 weeks 18 ↓13e ↓26e ↓42e
Lopinavir/ritonavir 400 mg/100 mg b.i.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 18 ↓58
(↓42 to ↓70)
↓63
(↓51 to ↓72)
↓65
(↓54 to ↓73)
Maraviroc 300 mg b.i.d. for 10 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 20 days 14 ↓34
(↓25 to ↓41)
↓35
(↓29 to ↓41)
↓36
(↓27 to ↓43)
Maraviroc 300 mg q.d. for 10 days 1,400 mg q.d. plus ritonavir 100 mg q.d. for 20 days 14 ↓29
(↓20 to ↓38)
↓30
(↓23 to ↓36)
↓15
(↓3 to ↓25)
Methadone 70 to 120 mg q.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 19 c c c
Nevirapine 200 mg b.i.d. for 2 weeksf 1,400 mg b.i.d. for 2 weeks 17 ↓25
(↓37 to ↓10)
↓33
(↓45 to ↓20)
↓35
(↓50 to ↓15)
Nevirapine 200 mg b.i.d. for 2 weeksf 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 17 ↓11
(↓23 to ↑3)
↓19
(↓32 to ↓4)
Phenytoin 300 mg q.d. for 10 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days 13 ↑20
(↑8 to ↑34)
↑19
(↑6 to ↑33)
Raltegravir 400 mg b.i.d. for 14 days 1,400 mg b.i.d. for 14 days
(fasted)
14 ↓27
(↓46 to ↔)
↓36
(↓53 to ↓13)
↓43g
(↓59 to ↓21)
1,400 mg b.i.d. for 14 daysh 14 ↓15
(↓27 to ↓1)
↓17
(↓27 to ↓6)
↓32g
(↓53 to ↓1)
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 14 days
(fasted)
14 ↓14
(↓39 to ↑20)
↓17
(↓38 to ↑12)
↓20g
(↓45 to ↑17)
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 14 daysh 12 ↓25
(↓42 to ↓2)
↓25
(↓44 to ↔)
↓33g
(↓52 to ↓7)
Raltegravir 400 mg b.i.d. for 14 days 1,400 mg q.d. plus ritonavir 100 mg q.d. for 14 days
(fasted)
13 ↓18
(↓34 to ↔)
↓24
(↓41 to ↔)
↓50g
(↓64 to ↓31)
1,400 mg q.d. plus ritonavir 100 mg q.d. for 14 daysh 14 ↑27
(↓1 to ↑62)
↑13
(↓7 to ↑38)
↓17g
(↓45 to ↑26)
Ranitidine 300 mg single dose
(administered 1 hour before fosamprenavir)
1,400 mg single dose 30 ↓51
(↓43 to ↓58)
↓30
(↓22 to ↓37)

(↓19 to ↑21)
Rifabutin 150 mg q.o.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 15 ↑36c
(↑18 to ↑55)
↑35c (↑17 to ↑56) ↑17c
(↓1 to ↑39)
Tenofovir 300 mg q.d. for 4 to 48 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 4 to 48 weeks 45 NA NA i
Tenofovir 300 mg q.d. for 4 to 48 weeks 1,400 mg q.d. plus ritonavir 200 mg q.d. for 4 to 48 weeks 60 NA NA i
a Concomitant medication is also shown in this column where appropriate.
b Ritonavir Cmax, AUC, and Cmin increased by 63%, 45%, and 13%, respectively, compared with historical control.
c Compared with historical control.
d Subjects were receiving LEXIVA/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and LEXIVA/ritonavir.
e Compared with LEXIVA 700 mg/ritonavir 100 mg b.i.d. for 2 weeks.
fSubjects were receiving nevirapine for at least 12 weeks prior to trial.
g Clast (C12 h or C24 h).
h Doses of LEXIVA and raltegravir were given with food on pharmacokinetic sampling days and without regard to food all other days.
i Compared with parallel control group.
↑= Increase; ↓= Decrease; ↔ = No change (↑or ↓ less than or equal to 10%), NA = Notapplicable.

Table 11: Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of AGENERASE in the Presence of the Coadministered Drug(s)

Coadministered Drug(s) and Dose(s) Dose of AGENERASEa n % Change in Amprenavir Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmin
Abacavir 300 mg b.i.d. for 2 to 3 weeks 900 mg b.i.d. for 2 to 3 weeks 4 a a a
Clarithromycin 500 mg b.i.d. for 4 days 1,200 mg b.i.d. for 4 days 12 ↑15
(↑1 to ↑31)
↑18
(↑8 to ↑29)
↑39
(↑31 to ↑47)
Delavirdine 600 mg b.i.d. for 10 days 600 mg b.i.d. for 10 days 9 ↑40b ↑130b ↑125b
Ethinyl estradiol/norethindrone 0.035 mg/1 mg for 1 cycle 1,200 mg b.i.d. for 28 days 10 ↓22
(↓35 to ↓8)
↓20
(↓41 to ↑8)
Indinavir 800 mg t.i.d. for 2 weeks (fasted) 750 or 800 mg t.i.d. for 2 weeks
(fasted)
9 ↑18
(↑13 to ↑58)
↑33
(↑2 to ↑73)
↑25
(↓27 to ↑116)
Ketoconazole 400 mg single dose 1,200 mg single dose 12 ↓16
(↓25 to ↓6)
↑31
(↑20 to ↑42)
NA
Lamivudine 150 mg single dose 600 mg single dose 11 NA
Methadone 44 to 100 mg q.d. for > 30 days 1,200 mg b.i.d. for 10 days 16 ↓27c ↓30c ↓25c
Nelfinavir 750 mg t.i.d. for 2 weeks (fed) 750 or 800 mg t.i.d. for 2 weeks
(fed)
6 ↓14
(↓38 to ↑20)
↑189
(↑52 to ↑448)
Rifabutin 300 mg q.d. for 10 days 1,200 mg b.i.d. for 10 days 5 ↓15
(↓28 to 0)
↓15
(↓38 to ↑17)
Rifampin 300 mg q.d. for 4 days 1,200 mg b.i.d. for 4 days 11 ↓70
(↓76 to ↓62)
↓82
(↓84 to ↓78)
↓92
(↓95 to ↓89)
Saquinavir 800 mg t.i.d. for 2 weeks (fed) 750 or 800 mg t.i.d. for 2 weeks
(fed)
7 ↓37
(↓54 to ↓14)
↓32
(↓49 to ↓9)
↓14
(↓52 to ↑54)
Zidovudine 300 mg single dose 600 mg single dose 12 ↑13
(↓2 to ↑31)
NA
a Compared with parallel control group.
bMedian percent change; confidence interval not reported.
c Compared with historical data.
↑ = Increase; ↓ = Decrease; ↔ = No change
(↑or ↓ less than 10%); NA = Cmin not calculated for single-dose trial.

Table 12: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of LEXIVA

Coadministered Drug(s) and Dose(s) Dose of LEXIVAa n % Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)
Cmax AUC Cmin
Atazanavir 300 mg q.d. for 10 daysb 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days 21 ↓24
(↓39 to ↓6)
↓22
(↓34 to ↓9)
Atorvastatin 10 mg q.d. for 4 days 1,400 mg b.i.d. for 2 weeks 16 ↑304
(↑205 to ↑437)
↑130
(↑100 to ↑164)
↓10
(↓27 to ↑12)
Atorvastatin 10 mg q.d. for 4 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 16 ↑184
(↑126 to ↑257)
↑153
(↑115 to ↑199)
↑73
(↑45 to ↑108)
Esomeprazole 20 mg q.d. for 2 weeks 1,400 mg b.i.d. for 2 weeks 25 ↑55
(↑39 to ↑73)
ND
Esomeprazole 20 mg q.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 23 ND
Ethinyl estradiolc 0.035 mg q.d. for 21 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 21 days 25 ↓28
(↓21 to ↓35)
↓37
(↓30 to ↓42)
ND
Dolutegravir 50 mg q.d. 700 mg b.i.d. plus ritonavir 100 mg b.i.d. 12 ↓24
(↓8 to ↓37)
↓35
(↓22 to ↓46)
↓49
(↓37 to ↓59)
Ketoconazoled 200 mg q.d. for 4 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 4 days 15 ↑25
(↑0 to ↑56)
↑169
(↑108 to ↑248)
ND
Lopinavir/ritonavire 533 mg/133 mg b.i.d. for 2 weeks 1,400 mg b.i.d. for 2 weeks 18 f f f
Lopinavir/ritonavire 400 mg/100 mg b.i.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 18 ↑30
(↓15 to ↑47)
↑37
(↓20 to ↑55)
↑52
(↓28 to ↑82)
Maraviroc 300 mg b.i.d. for 10 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 20 days 14 ↑52
(↑27 to ↑82)
↑149
(↑119 to ↑182)
↑374
(↑303 to ↑457)
Maraviroc 300 mg q.d. for 10 days 1,400 mg q.d. plus ritonavir 100 mg q.d. for 20 days 14 ↑45
(↑20 to ↑74)
↑126
(↑99 to ↑158)
↑80
(↑53 to ↑113)
Methadone 70 to 120 mg q.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 19 R-Methadone
(active)
↓21g
(↓30 to ↓12)
↓18g
(↓27 to ↓8)
↓11g
(↓21 to ↑1)
S-Methadone
(inactive)
↓43g (↓49 to ↓37) ↓43g (↓50 to ↓36) ↓41g
(↓49 to ↓31)
Nevirapine 200 mg b.i.d. for 2 weeksh 1,400 mg b.i.d. for 2 weeks 17 ↑25
(↑14 to ↑37)
↑29
(↑19 to ↑40)
↑34
(↑20 to ↑49)
Nevirapine 200 mg b.i.d. for 2 weeksh 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 17 ↑13
(↑3 to ↑24)
↑14
(↑5 to ↑24)
↑22
(↑9 to ↑35)
Norethindronec 0.5 mg q.d. for 21 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 21 days 25 ↓38
(↓32 to ↓44)
↓34
(↓30 to ↓37)
↓26
(↓20 to ↓32)
Phenytoin 300 mg q.d. for 10 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days 14 ↓20
(↓12 to ↓27)
↓22
(↓17 to ↓27)
↓29
(↓23 to ↓34)
Rifabutin 150 mg every other day for 2 weeks i
(25-O-desacetylrifabutin metabolite) Rifabutin + 25-O-desacetylrifabutin metabolite
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 15 ↓14
(↓28 to ↑4)
↑28
(↑12 to ↑46)
↑579
(↑479 to ↑698)
↑1,120
(↑965 to ↑1,300)
↑2,510
(↑1,910 to ↑3,300)
NA ↑64
(↑46 to ↑84)
NA
Rosuvastatin 10 mg single dose 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 7 days (↑45) (↑8) NA
a Concomitant medication is also shown in this column where appropriate.
b Comparison arm of atazanavir 300 mg q.d. plus ritonavir 100 mg q.d. for 10 days.
c Administered as a combination oral contraceptive tablet: ethinyl estradiol 0.035 mg/norethindrone 0.5 mg.
d Subjects were receiving LEXIVA/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and LEXIVA/ritonavir.
e Data represent lopinavir concentrations.
fCompared with lopinavir 400 mg/ritonavir 100 mg b.i.d. for 2 weeks.
g Dose normalized to methadone 100 mg. The unbound concentration of the active moiety, R-methadone, was unchanged.
hSubjects were receiving nevirapine for at least 12 weeks prior to trial.
i Comparison arm of rifabutin 300 mg q.d. for 2 weeks. AUC is AUC(0-48 h).
↑ = Increase; ↓= Decrease; ↔ = No change (↑or ↓less than 10%); ND = Interaction cannot be determined as Cmin was below the lower limit of quantitation.

Table 13: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of AGENERASE

Coadministered Drug(s) and Dose(s) Dose of AGENERASE n % Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)
Cmax AUC Cmm
Abacavir 300 mg b.i.d. for 2 to 3 weeks 900 mg b.i.d. for 2 to 3 weeks 4 a a a
Clarithromycin 500 mg b.i.d. for 4 days 1,200 mg b.i.d. for 4 days 12 ↓10
(↓24 to ↑7)
Delavirdine 600 mg b.i.d. for 10 days 600 mg b.i.d. for 10 days 9 ↓47b ↓61b ↓88b
Ethinyl estradiol 0.035 mg for 1 cycle 1,200 mg b.i.d. for 28 days 10 ↑32
(↓3 to ↑79)
Indinavir 800 mg t.i.d. for 2 weeks (fasted) 750 mg or 800 mg t.i.d. for 2 weeks
(fasted)
9 ↓22a ↓38a ↓27a
Ketoconazole 400 mg single dose 1,200 mg single dose 12 ↑19
(↑8 to ↑33)
↑44
(↑31 to ↑59)
NA
Lamivudine 150 mg single dose 600 mg single dose 11 NA
Methadone 44 to 100 mg q.d. for > 30 days 1,200 mg b.i.d. for 10 days 16 R-Methadone (active)
↓25
(↓32 to ↓18)
↓13
(↓21 to ↓5)
↓21
(↓32 to ↓9)
S-Methadone (inactive)
↓48
(↓55 to ↓40)
↓40
(↓46 to ↓32)
↓53
(↓60 to ↓43)
Nelfinavir 750 mg t.i.d. for 2 weeks (fed) 750 mg or 800 mg t.i.d. for 2 weeks
(fed)
6 ↑12a ↑15a ↑14a
Norethindrone 1 mg for 1 cycle 1,200 mg b.i.d. for 28 days 10 ↑18
(↑1 to ↑38)
↑45
(↑13 to ↑88)
Rifabutin 300 mg q.d. for 10 days 1,200 mg b.i.d. for 10 days 5 ↑119
(↑82 to ↑164)
↑193
(↑156 to ↑235)
↑271
(↑171 to ↑409)
Rifampin 300 mg q.d. for 4 days 1,200 mg b.i.d. for 4 days 11 ND
Saquinavir 800 mg t.i.d. for 2 weeks (fed) 750 mg or 800 mg t.i.d. for 2 weeks
(fed)
7 ↑21a ↓19a ↓48a
Zidovudine 300 mg single dose 600 mg single dose 12 ↑40
(↑14 to ↑71)
↑31
(↑19 to ↑45)
NA
a Compared with historical data.
b Median percent change; confidence interval not reported.
↑ = Increase; ↓ = Decrease; ↔= No change
(↑or ↓ less than 10%); NA = Cmin not calculated forsingle-dose trial; ND = Interaction cannot be determined as Cmin was below the lower limit of quantitation.

Microbiology

Mechanism Of Action

Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by cellular phosphatases in the gut epithelium as it is absorbed. Amprenavir is an 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.

Antiviral Activity

Fosamprenavir has little or no antiviral activity in cell culture. The 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 in cell culture. The 50% effective concentration (EC50) of amprenavir ranged from 0.012 to 0.08 microM in acutely infected cells and was 0.41 microM in chronically infected cells (1 microM = 0.50 mcg per mL). The median EC50 value of amprenavir against HIV-1 isolates from clades A to G was 0.00095 microM in peripheral blood mononuclear cells (PBMCs). Similarly, the EC50 values for amprenavir against monocytes/macrophage tropic HIV-1 isolates (clade B) ranged from 0.003 to 0.075 microM in monocyte/macrophage cultures. The EC50 values of amprenavir against HIV-2 isolates grown in PBMCs were higher than those for HIV-1 isolates, and ranged from 0.003 to 0.11 microM. Amprenavir exhibited synergistic anti-HIV-1 activity in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, stavudine, tenofovir, and zidovudine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and efavirenz; and the protease inhibitors atazanavir and saquinavir. Amprenavir exhibited additive anti-HIV-1 activity in combination with the NNRTI nevirapine, the protease inhibitors indinavir, lopinavir, nelfinavir, and ritonavir; and the fusion inhibitor enfuvirtide. These drug combinations have not been adequately studied in humans.

Resistance

HIV-1 isolates with decreased susceptibility to amprenavir have been selected in cell culture and obtained from subjects treated with fosamprenavir. Genotypic analysis of isolates from treatment-naive subjects failing amprenavir-containing regimens showed substitutions in the HIV-1 protease gene resulting in amino acid substitutions primarily at positions V32I, M46I/L, I47V, I50V, I54L/M, and I84V, as well as substitutions in the p7/p1 and p1/p6 Gag and Gag-Pol polyprotein precursor cleavage sites. Some of these amprenavir resistance-associated substitutions have also been detected in HIV-1 isolates from antiretroviral-naive subjects treated with LEXIVA. Of the 488 antiretroviral-naive subjects treated with LEXIVA 1,400 mg twice daily or LEXIVA 1,400 mg plus ritonavir 200 mg once daily in Trials APV30001 and APV30002, respectively, 61 subjects (29 receiving LEXIVA and 32 receiving LEXIVA/ritonavir) with virologic failure (plasma HIV-1 RNA greater than 1,000 copies per mL on 2 occasions on or after Week 12) were genotyped. Five of the 29 antiretroviral-naive subjects (17%) receiving LEXIVA without ritonavir in Trial APV30001 had evidence of genotypic resistance to amprenavir: I54L/M (n = 2), I54L + L33F (n = 1), V32I + I47V (n = 1), and M46I + I47V (n = 1). No amprenavir resistance-associated substitutions were detected in antiretroviral-naive subjects treated with LEXIVA/ritonavir for 48 weeks in Trial APV30002. However, the M46I and I50V substitutions were detected in isolates from 1 virologic failure subject receiving LEXIVA/ritonavir once daily at Week 160 (HIV-1 RNA greater than 500 copies per mL). Upon retrospective analysis of stored samples using an ultrasensitive assay, these resistant substitutions were traced back to Week 84 (76 weeks prior to clinical virologic failure).

Cross-resistance

Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. An association between virologic response at 48 weeks (HIV-1 RNA level less than 400 copies per mL) and protease inhibitor-resistance substitutions detected in baseline HIV-1 isolates from protease inhibitor-experienced subjects receiving LEXIVA/ritonavir twice daily (n = 88), or lopinavir/ritonavir twice daily (n = 85) in Trial APV30003 is shown in Table 14. The majority of subjects had previously received either one (47%) or 2 protease inhibitors (36%), most commonly nelfinavir (57%) and indinavir (53%). Out of 102 subjects with baseline phenotypes receiving twice-daily LEXIVA/ritonavir, 54% (n = 55) had resistance to at least one protease inhibitor, with 98% (n = 54) of those having resistance to nelfinavir. Out of 97 subjects with baseline phenotypes in the lopinavir/ritonavir arm, 60% (n = 58) had resistance to at least one protease inhibitor, with 97% (n = 56) of those having resistance to nelfinavir.

Table 14: Responders at Trial Week 48 by Presence of Baseline Protease Inhibitor Resistance-associated Substitutionsa

Protease Inhibitor Resistance-associated Substitutionsb LEXIVA/Ritonavir b.i.d.
(n = 88)
Lopinavir/Ritonavir b.i.d.
(n = 85)
D30N 21/22 95% 17/19 89%
N88D/S 20/22 91% 12/12 100%
L90M 16/31 52% 17/29 59%
M46I/L 11/22 50% 12/24 50%
V82A/F/T/S 2/9 22% 6/17 35%
I54V 2/11 18% 6/11 55%
I84V 1/6 17% 2/5 40%
a Results should be interpreted with caution because the subgroups were small.
bMost subjects had greater than 1 protease inhibitor resistance-associated substitution at baseline.

The virologic response based upon baseline phenotype was assessed. Baseline isolates from protease inhibitor-experienced subjects responding to LEXIVA/ritonavir twice daily had a median shift in susceptibility to amprenavir relative to a standard wild-type reference strain of 0.7 (range: 0.1 to 5.4, n = 62), and baseline isolates from individuals failing therapy had a median shift in susceptibility of 1.9 (range: 0.2 to 14, n = 29). Because this was a select patient population, these data do not constitute definitive clinical susceptibility break points. Additional data are needed to determine clinically relevant break points for LEXIVA.

Isolates from 15 of the 20 subjects receiving twice-daily LEXIVA/ritonavir up to Week 48 and experiencing virologic failure/ongoing replication were subjected to genotypic analysis. The following amprenavir resistance-associated substitutions were found either alone or in combination: V32I, M46I/L, I47V, I50V, I54L/M, and I84V. Isolates from 4 of the 16 subjects continuing to receive twice-daily LEXIVA/ritonavir up to Week 96 who experienced virologic failure underwent genotypic analysis. Isolates from 2 subjects contained amprenavir resistance-associated substitutions: V32I, M46I, and I47V in 1 isolate and I84V in the other.

Clinical Studies

Therapy-naive Adult Trials

APV30001

A randomized, open-label trial evaluated treatment with LEXIVA tablets (1,400 mg twice daily) versus nelfinavir (1,250 mg twice daily) in 249 antiretroviral treatment-naive subjects. Both groups of subjects also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily).

The mean age of the subjects in this trial was 37 years (range: 17 to 70 years); 69% of the subjects were male, 20% were CDC Class C (AIDS), 24% were white, 32% were black, and 44% were Hispanic. At baseline, the median CD4+ cell count was 212 cells per mm³ (range: 2 to 1,136 cells per mm³ ; 18% of subjects had a CD4+ cell count of less than 50 cells per mm³ and 30% were in the range of 50 to less than 200 cells per mm³). Baseline median HIV-1 RNA was 4.83 log10 copies per mL (range: 1.69 to 7.41 log10 copies per mL; 45% of subjects had greater than 100,000 copies per mL).

The outcomes of randomized treatment are provided in Table 15.

Table 15: Outcomes of Randomized Treatment through Week 48 (APV30001)

Outcome (Rebound or discontinuation = failure) LEXIVA 1,400 mg b.i.d.
(n = 166)
Nelfinavir 1,250 mg b.i.d.
(n = 83)
Respondera 66% (57%) 52% (42%)
Virologic failure 19% 32%
  Rebound 16% 19%
  Never suppressed through Week 48 3% 13%
Clinical progression 1% 1%
Death 0% 1%
Discontinued due to adverse reactions 4% 2%
Discontinued due to other reasonsb 10% 10%
a Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL (less than 50 copies per mL) through Week 48 (Roche AMPLICOR HIV-1 MONITOR Assay Version 1.5).
b Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons.

Treatment response by viral load strata is shown in Table 16.

Table 16: Proportions of Responders through Week 48 by Screening Viral Load (APV30001)

Screening Viral Load HIV-1 RNA (copies/mL) LEXIVA 1,400 mg b.i.d. Nelfinavir 1,250 mg b.i.d.
< 400 copies/mL n < 400 copies/mL n
≤ 100,000 65% 93 65% 46
> 100,000 67% 73 36% 37

Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 201 cells per mm³ in the group receiving LEXIVA and 216 cells per mm³ in the nelfinavir group.

APV30002

A randomized, open-label trial evaluated treatment with LEXIVA tablets (1,400 mg once daily) plus ritonavir (200 mg once daily) versus nelfinavir (1,250 mg twice daily) in 649 treatment-naive subjects. Both treatment groups also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily).

The mean age of the subjects in this trial was 37 years (range: 18 to 69 years); 73% of the subjects were male, 22% were CDC Class C, 53% were white, 36% were black, and 8% were 3 Hispanic. At baseline, the median CD4+ cell count was 170 cells per mm (range: 1 to 1,055 cells per mm³ ; 20% of subjects had a CD4+ cell 3count of less than 50 cells per mm and 3 35% were in the range of 50 to less than 200 cells per mm ). Baseline median HIV-1 RNA was 4.81 log10 copies per mL (range: 2.65 to 7.29 log10 copies per mL; 43% of subjects had greater than 100,000 copies per mL).

The outcomes of randomized treatment are provided in Table 17.

Table 17: Outcomes of Randomized Treatment through Week 48 (APV30002)

Outcome (Rebound or discontinuation = failure) LEXIVA 1,400 mg q.d./ Ritonavir 200 mg q.d.
(n = 322)
Nelfinavir 1,250 mg b.i.d.
(n = 327)
Respondera 69% (58%) 68% (55%)
Virologic failure 6% 16%
  Rebound 5% 8%
  Never suppressed through Week 48 1% 8%
Death 1% 0%
Discontinued due to adverse reactions 9% 6%
Discontinued due to other reasonsb 15% 10%
a Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL (less than 50 copies per mL) through Week 48 (Roche AMPLICOR HIV-1 MONITOR Assay Version 1.5).
b Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons.

Treatment response by viral load strata is shown in Table 18.

Table 18: Proportions of Responders through Week 48 by Screening Viral Load (APV30002)

Screening Viral Load HIV-1 RNA (copies/mL) LEXIVA 1,400 mg q.d./ Ritonavir 200 mg q.d. Nelfinavir 1,250 mg b.i.d.
< 400 copies/mL n < 400 copies/mL n
&e;100,000 72% 197 73% 194
> 100,000 66% 125 64% 133

Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 203 cells per mm³ in the group receiving LEXIVA and 207 cells per mm³ in the nelfinavir group.

Protease Inhibitor-experienced Adult Trials

APV30003

A randomized, open-label, multicenter trial evaluated 2 different regimens of LEXIVA plus ritonavir (LEXIVA tablets 700 mg twice daily plus ritonavir 100 mg twice daily or LEXIVA tablets 1,400 mg once daily plus ritonavir 200 mg once daily) versus lopinavir/ritonavir (400 mg/100 mg twice daily) in 315 subjects who had experienced virologic failure to 1 or 2 prior protease inhibitor-containing regimens.

The mean age of the subjects in this trial was 42 years (range: 24 to 72 years); 85% were male, 33% were CDC Class C, 67% were white, 24% were black, and 9% were Hispanic. The median CD4+ cell count at baseline was 263 cells per mm³ (range: 2 to 1,171 cells per mm³ ). Baseline median plasma HIV-1 RNA level was 4.14 log10 copies per mL (range: 1.69 to 6.41 log10 copies per mL).

The median durations of prior exposure to NRTIs were 257 weeks for subjects receiving LEXIVA/ritonavir twice daily (79% had greater than or equal to 3 prior NRTIs) and 210 weeks for subjects receiving lopinavir/ritonavir (64% had greater than or equal to 3 prior NRTIs). The median durations of prior exposure to protease inhibitors were 149 weeks for subjects receiving LEXIVA/ritonavir twice daily (49% received greater than or equal to 2 prior protease inhibitors) and 130 weeks for subjects receiving lopinavir/ritonavir (40% received greater than or equal to 2 prior protease inhibitors).

The time-averaged changes in plasma HIV-1 RNA from baseline (AAUCMB) at 48 weeks (the endpoint on which the trial was powered) were -1.4 log10 copies per mL for twice-daily LEXIVA/ritonavir and -1.67 log10 copies per mL for the lopinavir/ritonavir group. The proportions of subjects who achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL (secondary efficacy endpoint) were 58% with twice-daily LEXIVA/ritonavir and 61% with lopinavir/ritonavir (95% CI for the difference: -16.6, 10.1). The proportions of subjects with HIV-1 RNA less than 50 copies per mL with twice-daily LEXIVA/ritonavir and with lopinavir/ritonavir were 46% and 50%, respectively (95% CI for the difference: -18.3, 8.9).

The proportions of subjects who were virologic failures were 29% with twice-daily LEXIVA/ritonavir and 27% with lopinavir/ritonavir.

The frequency of discontinuations due to adverse events and other reasons, and deaths were similar between treatment arms.

Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 81 cells per mm³ with twice-daily LEXIVA/ritonavir and 91 cells per mm³ with lopinavir/ritonavir.

This trial was not large enough to reach a definitive conclusion that LEXIVA/ritonavir and lopinavir/ritonavir are clinically equivalent.

Once-daily administration of LEXIVA plus ritonavir is not recommended for protease inhibitor-experienced patients. Through Week 48, 50% and 37% of subjects receiving LEXIVA 1,400 mg plus ritonavir 200 mg once daily had plasma HIV-1 RNA less than 400 copies per mL and less than 50 copies per mL, respectively.

Pediatric Trials

Three open-label trials in pediatric subjects aged at least 4 weeks to 18 years were conducted. In one trial (APV29005), twice-daily dosing regimens (LEXIVA with or without ritonavir) were evaluated in combination with other antiretroviral agents in pediatric subjects aged 2 to 18 years. In a second trial (APV20002), twice-daily dosing regimens (LEXIVA with ritonavir) were evaluated in combination with other antiretroviral agents in pediatric subjects aged at least 4 weeks to younger than 2 years. A third trial (APV20003) evaluated once-daily dosing of LEXIVA with ritonavir; the pharmacokinetic data from this trial did not support a once-daily dosing regimen in any pediatric patient population.

APV29005

LEXIVA: Twenty (18 therapy-naive and 2 therapy-experienced) pediatric subjects received LEXIVA oral suspension without ritonavir twice daily. At Week 24, 65% (13 of 20) achieved HIV-1 RNA less than 400 copies per mL, and the median increase from baseline in CD4+ cell count was 350 cells per mm³.

LEXIVA plus Ritonavir: Forty-nine protease inhibitor-naive and 40 protease inhibitor-experienced pediatric subjects received LEXIVA oral suspension or tablets with ritonavir twice daily. At Week 24, 71% of protease inhibitor-naive (35 of 49) and 55% of protease inhibitor-experienced (22 of 40) subjects achieved HIV-1 RNA less than 400 copies per mL; median increases from baseline in CD4+ cell counts were 184 cells per mm³ and 150 cells per mm³ in protease inhibitor-naive and experienced subjects, respectively.

APV20002

Fifty-four pediatric subjects (49 protease inhibitor-naive and 5 protease inhibitor-experienced) received LEXIVA oral suspension with ritonavir twice daily. At Week 24, 72% of subjects achieved HIV-1 RNA less than 400 copies per mL. The median increases from baseline in CD4+ 3 cell counts were 400 cells per mm³ in subjects aged at least 4 weeks to ounger than 6 months 3 and 278 cells per mm³ in subjects aged 6 months to 2 years.

Last reviewed on RxList: 6/21/2016
This monograph has been modified to include the generic and brand name in many instances.

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