Co-administration of fosamprenavir 700 mg twice daily with ritonavir in doses greater than 100 mg twice daily has not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile of the combination and therefore is not recommended.
Telzir Summary of Product Characteristics, ViiV Healthcare UK Ltd, January 2021.

The recommended dose of fosamprenavir/ritonavir in therapy-naive patients is 1400/200 mg once daily 1400/100 mg once daily or 700/100 mg twice daily. In protease inhibitor-experienced patients, the recommended dose of fosamprenavir/ritonavir is 700/100 mg twice daily; once-daily administration of fosamprenavir/ritonavir is not recommended in protease inhibitor-experienced patients. Higher-than-approved dose combinations of fosamprenavir plus ritonavir are not recommended due to an increased risk of transaminase elevations.
Lexiva Prescribing Information, ViiV Healthcare, October 2020.

Amprenavir has been approved for use with ritonavir as a pharmacokinetic enhancer at the noted doses: amprenavir 600 mg twice daily with ritonavir 100 mg twice daily, fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily. Coadministration of amprenavir (600 mg twice daily) and ritonavir (100 mg twice daily) increased amprenavir AUC by 64% and Cmin by 5-fold, based on cross-study comparison to amprenavir alone (1200 mg twice daily). Ritonavir increases the serum levels of amprenavir as a result of CYP3A4 inhibition. Clinical trials confirmed the safety and efficacy of 600 mg amprenavir twice daily with ritonavir 100 mg twice daily. Ritonavir oral solution should not be co-administered with amprenavir oral solution to children due to the risk of toxicity from excipients in the two formulations. Coadministration of fosamprenavir (700 mg twice daily) and ritonavir (100 mg twice daily) increased amprenavir AUC by 2.4-fold and Cmin by 11-fold. Ritonavir increases the serum levels of amprenavir (from fosamprenavir) as a result of CYP3A4 inhibition. Fosamprenavir must be given with ritonavir to ensure its therapeutic effect. Clinical trials confirmed the safety and efficacy of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily. Co-administration of fosamprenavir with ritonavir in doses greater than 100 mg twice daily has not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile of the combination and therefore is not recommended.
Norvir Summary of Product Characteristics, AbbVie Ltd, September 2016.

Coadministration is expected to increase amprenavir concentrations. See the complete Prescribing Information for fosamprenavir for details on co-administration of fosamprenavir with ritonavir.
Norvir Prescribing Information, AbbVie Inc, December 2016.

A retrospective observational study looked at APV trough concentrations in HIV+ subjects receiving FPV (1400 mg once daily) with RTV (100 or 200 mg once daily). Median APV concentrations between the two groups were not statistically different (1340 vs 1520 ng/ml; 100 vs 200 mg RTV; n=25 vs n=24).
Assessment of amprenavir plasma levels in patients receiving once daily fosamprenavir in combination with either 100 or 200 mg ritonavir. Muret P, et al. 8th International Workshop on Clinical Pharmacology of HIV Therapy, Budapest, April 2007, abstract 26.

The effect of ritonavir (100 mg twice daily) on the pharmacokinetics of amprenavir (600 mg twice daily, n=11) or fosamprenavir (700 mg twice daily, n=15) was investigated in HIV-negative subjects. Ritonavir increased plasma amprenavir exposure to a similar extent when coadministered with either amprenavir or fosamprenavir. Geometric least square mean ratios for AUC, Cmax and Cmin (alone vs with ritonavir) for amprenavir were 3.16, 1.27 and 10.73 respectively, and for fosamprenavir were 3.40, 1.51 and 12.68 respectively, When given with ritonavir, amprenavir mean AUC increased from 8.21 to 26.2 µg.h/ml, Cmax from 3.66 to 4.69 µg/ml and Cmin from 0.12 to 1.32 µg/ml. Increases observed when fosamprenavir was coadministered with ritonavir were AUC increasing from 9.51 to 33.2 µg.h/ml, Cmax increasing from 3.19 to 4.92 µg/ml and Cmin increasing from 0.14 to 1.77 µg/ml.
Ritonavir increases plasma amprenavir (APV) exposure to a similar extent when coadministered with either fosamprenavir or APV. Wire MB, Baker KL, Jones LS, et al. Antimicrob Agents Chemother, 2006, 50(4): 1578-1580.

The pharmacokinetics of fosamprenavir (1400 mg once daily) with ritonavir (100 mg or 200 mg once daily) were investigated in 36 healthy subjects. Amprenavir Cmin was 38% lower when administered with 100 mg ritonavir than with 200 mg ritonavir (GM 0.86 vs 1.40 µg/ml); however, it remained ~6-fold higher than the protein-binding adjusted IC50 for WT HIV (0.146 µg/ml). Amprenavir Cmax and AUC were also lower with 100 mg ritonavir (Cmax 7.93 vs 8.17 µg/ml; AUC 66.4 vs 73.8 µg/ml.h). The lower dose of ritonavir provided tolerability advantages to the 200 mg dose and achieved equivalent amprenavir Cmax and AUC.
Plasma amprenavir pharmacokinetics and safety following coadministration of fosamprenavir with a reduced ritonavir dose once daily (COL 10053). Ruane P, Wire M, Shelton M, et al. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, October/November 2004, abstract A-449.

The pharmacokinetics of amprenavir following standard doses of fosamprenavir/ritonavir (700/100 mg twice daily) or high doses of fosamprenavir/ritonavir (1400/100 mg or 1400/200 mg) were investigated in healthy subjects (13 per group). When compared to the standard dose, fosamprenavir/ritonavir 1400/100 mg produced increases in amprenavir Cmin, Cmax and AUC of 26%, 81% and 54% respectively; ritonavir Cmin decreased by 11% and Cmax and AUC increased by 71% and 49% respectively. Fosamprenavir/ritonavir (1400/200 mg) resulted in increases in amprenavir Cmin, Cmax and AUC of 32%, 48% and 26%. The regimen where only fosamprenavir was increased (i.e. 1400/100 mg) achieved the highest plasma amprenavir exposure. In contrast, the regimen where both fosamprenavir and ritonavir were increased (i.e. 1400/200 mg) was associated with the highest incidence of ALT and AST elevations and is not recommended.
Pharmacokinetic and safety evaluation of high dose combinations of fosamprenavir and ritonavir (APV10028). Shelton MJ, Wire MB, Lou Y, et al. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, October/November 2004, abstract A-451.

The pharmacokinetics of amprenavir and ritonavir were assessed in healthy volunteers and it was found that amprenavir (450, 750 or 1200 mg twice daily) appeared to have no effect on the pharmacokinetics of ritonavir (200 or 400 mg twice daily). Ritonavir improved the pharmacokinetic profile of amprenavir with all three regimens (400R/450A, 400R/750A, 200R/1200A) yielding higher AUC and Cmin than amprenavir alone (1200 mg twice daily).
Pharmacokinetic interactions between ritonavir and amprenavir in healthy volunteers. Hsu A, Williams I, Chiu Y-L et al. 13th International AIDS Conference, Durban, July 2000, abstract WeOrB546.

The effect of ritonavir on the pharmacokinetics of amprenavir was studied in 14 HIV+ subjects receiving amprenavir (1200 mg twice daily) and 15 HIV+ subjects receiving amprenavir (600 mg twice daily) with ritonavir (100 mg twice daily). Cmin for amprenavir alone ranged from 20–3022 ng/ml and for amprenavir + ritonavir from 115–4848 ng/ml. The combination appeared to be potent, safe and useful for compliance.
Therapeutic drug monitoring of amprenavir combined with ritonavir as salvage therapy in HIV-1 infected patients. Taburet AM, Paci-Bonaventure S, Goujard C, et al. 13th International AIDS Conference, Durban, July 2000, abstract TuPeB3305.

The pharmacokinetics of amprenavir were investigated in two groups of patients receiving amprenavir alone or with ritonavir (both with NNRTIs). The mean amprenavir Cmin concentration was 58 ng/ml in the alone group and 1320 ng/ml when given with ritonavir.
Amprenavir inhibitory quotient and virological response in human immunodeficiency virus-infected patients on an amprenavir-containing salvage regimen without or with ritonavir. Duval X, Lamotte C, Race E, et al. Antimicrobial Agents Chemother, 2002, 46:570-574.

The safety and pharmacokinetic kinetic interaction between amprenavir and ritonavir was studied in healthy volunteers. Amprenavir was dosed twice daily at 450 or 900 mg alone and with 100 or 300 mg ritonavir. Relative to amprenavir alone, ritonavir coadministration resulted in 3.3-4 fold increase in amprenavir AUC and a 10.8-14.2 fold increase in amprenavir Cmin. The two ritonavir doses had similar effects on amprenavir, but adverse events were more frequent with the higher dose.
Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, coadministration to healthy volunteers. Sadler BM, Piliero PJ, Preston SL, et al. AIDS, 2001, 15:1009-1018.

The pharmacokinetic of amprenavir (1200 mg) and ritonavir (200) when given once daily) were studied in 8 HIV-infected subjects from 2 to 48 weeks of treatment. Plasma amprenavir concentrations were maintained over the 48 weeks with geometric mean values for AUC, Cmax and Cmin being 54.6 vs 56.1 µg/ml.h, 6.86 vs 7.21 µg/ml, 1.42 vs 1.21 µg/ml (week 2 vs week 48 respectively).
An assessment of plasma amprenavir pharmacokinetics following long term administration of Agenerase and low dose ritonavir QD in HIV-infected adult subjects (APV20001 and COL30500). Wood R, Wire MB, Lancaster T, et al. 3rd International Workshop on Clinical Pharmacology of HIV Therapy, Washington, 2002, abstract 2.6.

Amprenavir + Efavirenz + Ritonavir

This study, ACTG5043, was developed when the routine use of boosted protease inhibitors was not considered standard of care, and the optimal approach to combining PIs with efavirenz was under investigation. ACTG5043 had a relatively complex design and examined PK interactions between amprenavir and efavirenz, both by themselves and when nelfinavir, indinavir, ritonavir, or saquinavir was added. A PK study was conducted after the administration of single doses of amprenavir (600 mg, day 0). Subjects (n=56) received efavirenz (600 mg once daily) for 10 days and restarted amprenavir (600 mg twice daily) with efavirenz for days 11 to 13 with a PK study on day 14. A second PI (nelfinavir 1250 mg twice daily; indinavir 1200 mg twice daily; ritonavir 100 mg twice daily; or saquinavir 1600 mg twice daily) was added to amprenavir and efavirenz on day 15, and a PK study was conducted on day 21. Controls continued amprenavir and efavirenz without a second PI. Amprenavir AUC was 46-61% lower with efavirenz (day 14 vs day 0; P values of <0.05). In the nelfinavir, indinavir, and ritonavir groups, day 21 amprenavir AUCs with efavirenz were higher than AUCs for efavirenz alone. The authors conclude that efavirenz lowered amprenavir AUC, but NFV, IDV or RTV compensated for efavirenz induction.
Amprenavir and efavirenz pharmacokinetics before and after the addition of nelfinavir, indinavir, ritonavir, or saquinavir in seronegative individuals. Morse GD, Rosenkranz S, Para MF, et al. Antimicrob Agents Chemother, 2005, 49: 3373-3381.

The timing of the amprenavir-efavirenz interaction and the effect of adding ritonavir were evaluated in seven HIV+ individuals receiving amprenavir (1200 mg twice daily) and efavirenz (600 mg once daily). In one patient efavirenz had no effect on amprenavir. The remaining individuals showed a decrease in amprenavir concentrations as early as day 7. The addition of low dose ritonavir reversed the effect of efavirenz on amprenavir concentrations.
Efavirenz-induced decrease in plasma amprenavir levels in human immunodeficiency virus infected patients and correction by ritonavir. Duval X, Le Moing V, Longuet P et al. Antimicrob Agents Chemother 2000;44:259.