Pharmacokinetic interactions between the protease inhibitors (PI) atazanavir, lopinavir, saquinavir and the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir-monophosphate, are complex and poorly understood. Atazanavir (alone or ritonavir boosted) and ritonavir-boosted lopinavir have been shown to increase tenofovir concentrations [1–4]. Higher tenofovir concentrations could potentiate TDF-associated adverse events, including renal disorders .
Fosamprenavir is a prodrug of amprenavir used in combination with low-dose ritonavir. Three fosamprenavir regimens are approved by the United States Food and Drug Administration  for HIV-1 PI-naive patients. Fosamprenavir/ritonavir 700/100 mg twice a day is the only approved regimen for HIV-1 PI-experienced patients and the only regimen approved in the European Union . No relevant pharmacokinetic interactions have been demonstrated for the combination of fosamprenavir or amprenavir with the nucleoside-analogue reverse transcriptase inhibitors abacavir, lamivudine, zidovudine and didanosine . There are no data, however, from prospective randomized studies available on the potential pharmacokinetic interactions when combining fosamprenavir/ritonavir with TDF.
This prospective, randomized, open-label, phase I crossover study (COL20081) was designed to assess the effect of the co-administration of TDF on the pharmacokinetics of amprenavir in combination with two fosamprenavir/ritonavir regimens (primary endpoint amprenavir area under the curve; AUC). Secondary objectives included the assessment of ritonavir and tenofovir-monophosphate pharmacokinetic parameters. The study was not designed to allow a direct assessment of the effect of fosamprenavir/ritonavir on tenofovir-monophosphate pharmacokinetic parameters, or the comparison of amprenavir pharmacokinetic parameters between the strata.
Thirty healthy male HIV-negative subjects received fosamprenavir/ritonavir 1400/100 mg with or without TDF 300 mg (treatments A and B; n = 8 and n = 7), and 1400/200 mg with or without TDF 300 mg (treatments C and D; n = 8 and n = 7), all given fasting for 14 days every day. TDF was added (A and C) or discontinued (B and D) for another 14 days. A 24 h pharmacokinetic profile was assessed on days 14 and 28. Patients reported to the unit every day. Serum samples were analysed by a validated liquid chromatography–mass spectrometry–mass spectrometry method for amprenavir, ritonavir and tenofovir-monophosphate. AUC, cmax and cτ,ss for amprenavir, ritonavir and tenofovir-monophosphate were compared by calculating the geometric mean ratios (GMR).
All study subjects gave written informed consent before enrolment into the study. The study was reviewed and approved by the local ethics committee.
Thirty out of 35 enrolled subjects completed the study. Three subjects discontinued because of adverse events and two subjects discontinued at their own request.
In combination with fosamprenavir/ritonavir 1400/100 mg, TDF had no effect on the overall amprenavir exposition (GMR for AUC 0.99; 0.86–1.15) or cmax for amprenavir (GMR 1.04; 0.91–1.20) and on ritonavir pharmacokinetic parameters. The co-administration of TDF with fosamprenavir/ritonavir 1400/200 mg did not alter the overall amprenavir exposition (GMR for AUC 1.06; 0.96–1.17; see Fig. 1).
TDF led to significant increases in ritonavir AUC (GMR 1.32; 0.93–1.88) and cmax (GMR 1.71; 1.05–2.80) when given with fosamprenavir/ritonavir 1400/200 mg. A descriptive comparison of tenofovir-monophosphate plasma levels resulted in comparable cτ,ss with both fosamprenavir/ritonavir regimens.
TDF was well tolerated with both fosamprenavir/ritonavir regimens, with no grade 3 or 4 adverse events or laboratory abnormalities. As expected, there was a significant increase from baseline in median triglyceride levels (+68 versus +39 mg/dl; fosamprenavir/ritonavir 1400/100 mg and 1400/200 mg, respectively) and low-density lipoprotein cholesterol (+13 versus +19 mg/dl) at day 29. Median values for aspartate aminotransferase, alanine aminotransferase and total bilirubin decreased slightly from baseline to day 29 in all groups, median gammaglutamyl transferase values were unchanged. Analyses of serum creatinine, phosphate and creatinine clearance revealed no relevant changes. The most common reported clinical adverse events (grade 1–2) were gastrointestinal disorders, including diarrhoea (16 versus 9%; fosamprenavir/ritonavir 1400/100 mg and 1400/200 mg, respectively), nausea (5 versus 12%) and vomiting (10 versus 0%).
The co-administration of TDF with fosamprenavir/ritonavir every day does not alter the overall plasma exposure or cmax of amprenavir in HIV-negative subjects. When combining TDF with fosamprenavir/ritonavir 1400/100 mg, a slight increase in amprenavir ct,ss is observed compared with TDF with fosamprenavir/ritonavir 1400/200 mg. TDF plus fosamprenavir/ritonavir 1400/100 mg has no effect on the ritonavir pharmacokinetic profile, but fosamprenavir/ritonavir 1400/200 mg results in a non-significant increase in ritonavir AUC. This increase in plasma ritonavir exposure when co-administering TDF with fosamprenavir/ritonavir 1400/200 mg does not affect the plasma exposure of amprenavir. One possible explanation is that the increase in ritonavir was not sufficient to result in an additional inhibition of CYP3A4-dependent amprenavir metabolism and consecutive increase in plasma levels.
To date, there are only limited clinical or pharmacokinetic data available for fosamprenavir/ritonavir plus TDF from prospective studies. In a clinical study with HIV-infected patients, a retrospective analysis showed no significant differences in amprenavir ct,ss in patients receiving fosamprenavir/ritonavir (1400/200 mg per day or 700/100 mg twice a day) alone or in combination with TDF 300 mg per day , which is consistent with the findings from our study.
Overall, these findings suggest that TDF plus fosamprenavir/ritonavir should not influence the antiviral efficacy or safety profile of an fosamprenavir/ritonavir-containing combination. A longer follow-up is needed, however, to exclude definitely the potential increase in long-term ritonavir-related adverse events when combining TDF with fosamprenavir/ritonavir 1400/200 mg.
In contrast, relevant pharmacokinetic interactions have been demonstrated for the combination of TDF with other boosted PI, resulting in an increase in saquinavir pharmacokinetic parameters , a reduction in atazanavir and lopinavir pharmacokinetic parameters [1–3,10], and an increase in tenofovir pharmacokinetic parameters [4,10].
Increases in TDF exposure could potentially increase the risk of TDF-related side effects such as renal toxicity when combining TDF with lopinavir/ritonavir . The co-administration of TDF with lopinavir/ritonavir resulted in a 30% decrease in urinary TDF excretion . On the other hand, decreased exposure of atazanavir or lopinavir could reduce the antiviral efficacy and result in the emergence of drug-resistant virus.
In summary, the co-administration of TDF 300 mg a day with fosamprenavir/ritonavir 1400/200 mg or 1400/100 mg a day appears to be generally well tolerated, has no effect on the pharmacokinetics of amprenavir, and results in non-significant increases in ritonavir pharmacokinetic parameters. The absence of relevant pharmacokinetic interactions suggests that no dose modification is necessary when combining fosamprenavir/ritonavir with TDF.
The authors would like to thank all volunteers who participated in this study, and Mary Beth Wire from the department for Clinical Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina, USA, for critical discussions.
Sponsorship: This study was sponsored by GlaxoSmithKline.
Parts of the data contained in this manuscript have been presented at the 6th International Workshop on Clinical Pharmacology of HIV Therapy, 28–30 April 2005, Quebec City, Quebec, Canada.
1. Kaul S, Bassi K, Damle BD, Xie J, Gale J, Kearney BP, et al
. Pharmacokinetic evaluation of the combination of atazanavir (ATV), enteric coated didanosine (ddI-EC), and tenofovir disoproxil fumarate (TDF) for a once-daily antiretroviral regime
. In: 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy
. Chicago, IL, USA, 14–17 September 2003 [Abstract A-1616].
2. Taburet AM, Piketty C, Chazallon C, Vincent I, Gérard L, Calvez V, et al
. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2004; 48:2091–2096.
3. Flaherty J, Kearney B, Wolf J, Sayre J, Coakley D. A multiple-dose, randomized, crossover, drug interaction study between tenofovir DF and efavirenz, indinavir or lopinavir/ritonavir
. In: 1st International AIDS Society Conference on HIV Treatment on Pathogenesis
. Buenos Aires, Argentina, 8–11 July 2001 [Abstract 336].
4. Chittick GE, Zong J, Blum MR, Sobel JJ, Begley JA, Adda N, et al
. Pharmacokinetics of tenofovir disoproxil fumarate and ritonavir-boosted saquinavir mesylate administered alone or in combination at steady state. Antimicrob Agents Chemother 2006; 50:1304–1310.
8. Wire MB, Shelton MJ, Studenberg S. Fosamprenavir: clinical pharmacokinetics and drug interactions of the amprenavir prodrug. Clin Pharmacokinet 2006; 45:137–168.
9. GlaxoSmithKline, CONTEXT, Amprenavir 30003 Study. A phase III, randomized, multicenter, parallel group, open-label, three arm study to compare the efficacy and safety of two dosing regimens of GW433908/ritonavir (700 mg/100 mg twice daily or 1400 mg/200 mg once daily) versus lopinavir/ritonavir (400 mg/100 mg twice daily) for 48 weeks in protease inhibitor experienced HIV-infected adults experiencing virological failure
. Uxbridge, Middx., UK: GlaxoSmithKline; 2003.
10. Agarwala S, Eley T, Villegas C, Wang Y, Hughes E, Grasela D. Pharmacokinetic interaction between tenofovir and atazanavir coadministered with ritonavir in healthy subjects.
In: 6th International Workshop on Clinical Pharmacology of HIV Therapy
. Quebec, Canada, 28–30 April 2005 [Abstract 10].
11. Kearney B, Mittan A, Sayre J, Flaherty J, Zhong L, Toole JJ, et al
. Pharmacokinetic drug interaction and long term safety profile of tenofovir DF and lopinavir/ritonavir.
In: 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy.
Chicago, IL, USA, 14–17 September 2003 [Abstract A–1617].
12. Kiser J, Carten M, Wolfe P, King T, Delahunty T, Bushman L, et al
. Effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients.
In: 13th Conference on Retroviruses and Opportunistic Infections
. Denver, CO, USA, 5–8 February 2006 [Abstract 570].