Tenofovir drug-drug interactions

1 November 2003. Related: PK and drug interactions.

Paul E. Sax, M.D. TheBody.com

Tenofovir (TDF, Viread) is generally a well tolerated medication with a low pill burden and demonstrates potent antiretroviral activity. These characteristics have led to its widespread use in clinical practice. Unlike other NRTIs, however, tenofovir use is associated with several drug interactions, most notably the reduction in levels of atazanavir (ATV, Reyataz) and an increase in levels of ddI (didanosine, Videx).

The pharmacokinetic studies presented here explore further potential drug interactions related to tenofovir, specifically related to lopinavir/ritonavir (LPV/r, Kaletra), abacavir (ABC, Ziagen) and oral contraceptives.

In the lopinavir/ritonavir study, 27 HIV-negative controls received an initial seven days of tenofovir alone at standard doses; they were then randomized to receive lopinavir/ritonavir both with and without tenofovir. At the end of 14 additional days, they were crossed over to the other treatment arm. Careful pharmacokinetic analyses were performed, and showed no change in lopinavir or ritonavir levels regardless of whether tenofovir was co-administered. In contrast, tenofovir exposure was increased by 32% when administered with lopinavir/ritonavir compared with tenofovir alone.

To explore whether this increase in tenofovir levels was clinically significant, the investigators reviewed renal and other safety data on 271 patients in the tenofovir expanded access programme who also received lopinavir/ritonavir. Five (1.8%) patients experienced serum creatinine changes leading to tenofovir discontinuation, with one developing Fanconi’s syndrome with hypophosphatemia; this individual had a similar complication from high-dose adefovir (Hepsera) in the past.

While the data presented provide reassurance that tenofovir does not lead to a clinically significant reduction in lopinavir levels, the issue of lopinavir/ritonavir increasing tenofovir exposure (and possible toxicity) remains unsettled. This will require further analyses in larger populations of patients treated with this combination, controlling for other potential causes of renal dysfunction. In the meantime, patients receiving these two drugs in combination should have their renal function regularly monitored as part of their routine safety laboratories. Furthermore, the combination should be used with caution — and appropriate tenofovir dose reduction — in those with pre-existing renal disease.

The triple-NRTI combination of tenofovir, abacavir and 3TC (lamivudine, Epivir) has shown surprisingly poor antiviral activity in two prospective studies: a single-arm study presented previously at this year’s IAS meeting in Paris, and a comparative study presented at ICAAC. Potential (but still unproven) explanations for this include: 1) a tenofovir-abacavir pharmacokinetic drug interaction; 2) intracellular interaction, such as competition for a critical intracellular enzyme; or 3) low barrier to resistance via the K65R mutation. This pharmacokinetic study explored the first of these potential explanations.

Eight non-HIV-infected volunteers received a single 300-mg dose of abacavir while receiving either no other treatment or tenofovir 300-mg daily. Tenofovir and abacavir concentrations in plasma were measured, with calculated Cmax, Cmin, and area under the curve. The results showed that abacavir plasma levels were not affected by tenofovir, and that similarly, tenofovir levels did not differ from historical controls.

The results of this small pilot study suggest it is unlikely that a tenofovir-abacavir drug interaction is the cause of the suboptimal antiviral responses seen in abacavir-tenofovir-3TC treated patients, and that other explanations should be pursued. Furthermore, it enables clinicians to use abacavir and tenofovir together as part of a more comprehensive salvage regimen using other active drugs.

Hormonal contraception is an important and commonly-used medication in women with HIV infection. While tenofovir would not be expected to lead to suboptimal drug concentrations and lower contraceptive efficacy, this study explored this potential drug interaction.

Twenty-four HIV-negative women receiving norgestimate/ethinyl estradiol (Ortho Tri-Cyclen, OTC) were enrolled, with 20 ultimately eligible for pharmacokinetic analyses. OTC drug levels were assessed on study day one, with tenofovir 300 mg started on day 23. On day 29, both OTC and tenofovir pharmacokinetic measurements were repeated. The results showed that time curves for OTC levels with and without tenofovir were virtually superimposable, showing no significant drug interaction. Similarly, tenofovir levels were similar to those observed in prior studies.

The above three studies provide important data on use of tenofovir with three commonly used drugs. The precise mechanism of action accounting for the various tenofovir drug interactions remains under investigation, as does the explanation for the suboptimal response to the abacavir-tenofovir-3TC regimen.

Source: TheBody.com

References:

1. Kearney B et al. The pharmacokinetics of abacavir, a purine nucleoside analog, are not affected by tenofovir DF. 43rd ICAAC, September, 2003; Abstract A-1615.
2. Kearney B et al. Pharmacokinetic drug interaction and long term safety profile of tenofovir DF and lopinavir/ritonavir. 43rd ICAAC, September, 2003; Abstract A-1617.
3. Kearney B et al. Tenofovir DF and oral contraceptives: lack of a PK drug interaction. 43rd ICAAC, September, 2003; Abstract A-1618.