Important new pharmacokinetic data for atazanavir sulfate (Reyataz) in combination with tenofovir disoproxil fumarate (Viread)

1 October 2003. Related: Treatment alerts.

The following is a Dear Doctor letter from BMS circulated to US doctors on 8 August. For comment see bottom of page.

Dear Health Care Provider,

Bristol-Myers Squibb Company would like to make clinicians caring for HIV-positive patients aware of important new pharmacokinetic (PK) data concerning the coadministration of atazanavir sulfate (Reyataz™) and tenofovir disoproxil fumarate (Viread®, Gilead Sciences Inc.). Two studies have been conducted to evaluate the potential PK interaction between atazanavir sulfate and tenofovir disoproxil fumarate (tenofovir DF), and an additional ongoing clinical study has provided preliminary data on the safety profile of this combination. Data from these trials are currently under review by the [US] Food and Drug Administration. For more details on these studies, please refer to the Study Information section below.

The following observations were made from these three trials:

Study AI454-181: In healthy volunteers atazanavir AUC and Cmin were decreased by approximately 25% and 40%, respectively, when unboosted atazanavir sulfate 400 mg was coadministered with tenofovir DF 300 mg once daily (QD) as compared to atazanavir sulfate alone. In addition, an increase of approximately 24% in tenofovir AUC was observed.

Study PUZZLE 2 (ANRS 107): Atazanavir AUC and Cmin were decreased by approximately 25% and 23%, respectively, when atazanavir sulfate 300 mg and ritonavir 100 mg (boosted atazanavir sulfate) were coadministered with tenofovir DF 300 mg QD, as compared to atazanavir sulfate 300 mg and ritonavir 100 mg administered without tenofovir DF to HIV-positive patients.

For the combination of boosted atazanavir sulfate with tenofovir DF, the atazanavir AUC and Cmin observed in the Puzzle 2 study were approximately 1.2 and 4 fold higher than the respective values observed for unboosted atazanavir sulfate, 400 mg given alone, to healthy volunteers in Study AI424-181.

Study AI424-045: Interim safety data from an ongoing clinical trial suggest that the treatment emergent adverse events of moderate or severe intensity are comparable for boosted atazanavir sulfate in treatment experienced patients and for unboosted atazanavir sulfate treated patients in other clinical trials.

Based on these results:

Clinicians should use caution when administering unboosted atazanavir sulfate with tenofovir DF. Unboosted atazanavir sulfate may be less effective due to decreased atazanavir concentrations in patients taking atazanavir sulfate and tenofovir DF. As a result, the coadministration of unboosted atazanavir sulfate with tenofovir DF may lead to loss or lack of virologic response and possible resistance to atazanavir sulfate.

If atazanavir sulfate is coadministered with tenofovir DF, consideration should be given to administering atazanavir sulfate 300 mg with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food), until additional data are obtained. Coadministration of atazanavir sulfate 300 mg and ritonavir 100 mg QD is currently under clinical investigation.

The increase in tenofovir AUC does not appear to be associated with increased toxicity over 24 weeks.

STUDY INFORMATION:

Study AI454-181 conducted by Bristol-Myers Squibb (BMS) Pharmaceutical Research Institute

Design: Phase I, open-label study in healthy subjects to evaluate whether the PK parameters of either unboosted Reyataz 400 mg QD or tenofovir DF 300 mg QD were affected by their coadministration. The PK parameters of atazanavir sulfate 400 mg QD administered with food were compared to those of atazanavir sulfate 400 mg QD when coadministered with tenofovir 300 mg QD and food.

Puzzle 2 (ANRS 107) Trial – PK sub-study conducted by Taburet et al.

Design: An ongoing efficacy study and PK sub-study in highly treatment-experienced HIV-positive subjects. HIV-positive subjects experiencing failure on a protease inhibitor (PI)-containing regimen were treated for the initial two weeks of the study with atazanavir sulfate 300 mg QD plus ritonavir 100 mg QD substituted for the failing PI. Current nucleoside reverse transcriptase inhibitors (NRTIs) were continued for the initial two-week period after which time they were replaced with tenofovir DF 300 mg QD and a second NRTI chosen by genotypic testing. Atazanavir pharmacokinetics were determined at Week 2 before the introduction of tenofovir DF and again at Week 6.

Study AI424-045 conducted by Bristol-Myers Squibb (BMS) Pharmaceutical Research Institute

Design: An ongoing 48-week, Phase III, randomised, multinational, open-label three-arm trial of 358 highly treatment-experienced HIV-positive subjects. One arm of this study is evaluating the efficacy, safety and tolerability of the combination of atazanavir sulfate 300 mg and ritonavir 100 mg QD coadministered with tenofovir DF 300 mg QD and one NRTI.

Sincerely,
Sally Hodder, MD
Vice President, Virology Medical Affairs, Bristol-Myers Squibb Company

Reyataz™ is a trademark of Bristol-Myers Squibb Company.

Viread® is a registered trademark of Gilead Sciences, Inc.

Comment

There are several important reasons why this issue of HTB carries a Dear Doctor letter circulated to US doctors, for a new drug, atazanavir, which is still not yet approved in Europe.

The first is that in practice it is already being used by UK patients – either in trials or on the expanded access programme. So this information is important, and although this data on the interaction was presented in February 2003, [1] we still receive calls to the i-Base phoneline over six months later from patients on routine doses of both drugs whose doctors are not aware of the interaction.

The second is that the interaction is with tenofovir and many of the people using one will be likely to want to use the other. Both drugs are taken once daily with food. Because they are both recent drugs, and tenofovir has activity against some levels of nucleoside resistant virus, they are both likely to be used in treatment-experienced patients.

The third is a safety issue not addressed in the BMS letter – that of the other side of the two-way interaction: tenofovir reduces atazanavir but atazanavir also increase levels of tenofovir. Un-boosted atazanavir, given at 400mg standard dose increases tenofovir AUC by 24%. This level is not clinically important. However, atazanavir AUC and Cmin increase by up to 10-fold when a lower 300mg dose of atazanavir is boosted by 100mg ritonavir. There is no data on what happens to tenofovir levels with boosted atazanavir, or published data on the mechanism. So, this 10-fold increase in atazanavir has at least the potential to have a knock-on effect on the levels of tenofovir, perhaps pushing the interaction to a clinically important level. We cannot understand how the ritonavir boosting can be recommend under these circumstances.

Data from patients using boosted atazanavir and tenofovir in the BMS045 treatment experienced study did not show any increase in reporting of tenofovir-related toxicity, but this involves small numbers of patients followed for a short time. [2] Until more data is available, clinicians should at least be aware of this potential interaction.

In addition to the issue of ritonavir boosting, this raises the issue of access to both 150mg and 200mg formulations of atazanavir in the UK and the expanded access programme. As we went to press, UK patients had only just received access to the 150mg dose that had previously been delayed by ethics committee approval. Until then, as capsules cannot be split in the same way as a pill can be cut in half, this had left people the option of either boosting 400mg atazanavir with 100mg ritonavir – presumably reaching even higher levels – or increasing the dose of unboosted atazanavir to 600mg.

Given that atazanavir was approved and available in the US since May 2003, it is unacceptable that UK patients have to take this uncertainty over dosing. Again, as we went to press the TDM lab in Liverpool University had still not been given the pure compound needed to develop a therapeutic drug monitoring (TDM) assay for atazanavir, which takes 6-8 weeks to develop and validate. So, patients currently can only guess, and continue to guess until this is available. In their favour, BMS is looking to support a programme for TDM for UK patients who need to confirm drug levels. We hope that this programme becomes available quickly.

Finally, on an issue of patient care, it is useful to point out specific timelines and understand why these interactions are dealt with poorly from an individual patient concern. For interaction data to be presented to the February Retrovirus meeting it had to be available several months earlier. The details of the two-way interactions presented at ICAAC were available in July. There should be a regulatory requirement for basic interaction data not to be withheld until a conference presentation but released early as an issue of public safety.

The initial atazanavir expanded access programme has now enrolled. Unlike every previous expanded access programme, the UK ethics committee responsible capped enrolment. A new named-patient programme is available for the period prior to licensing. Physicians should call Dr Ian Hitchcock at BMS on 0208 754 3684.

A similar interaction, between lopinavir/r (Kaletra) and tenofovir is reported in ICAAC poster A-1617 (see Conference reports for details of access). Lopinavir levels are slightly reduced and steady-state tenofovir levels increased by 31%. On the basis of short-term data, neither change is thought to be clinically significant.

References:

1. A. M. Taburet, C. Piketty, L. Gérard et al. Pharmacokinetic parameters of atazanavir/ritonavir when combined to tenofovir in HIV infected patients with multiple treatment failures: a sub-study of Puzzle2-ANRS 107 Trial. 10th Conference on Retroviruses and OIs, Boston 2003. Poster 537.
2. Badaro R, DeJesus E, Lazzarin A, et al. Efficacy and safety of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) versus lopinavir/ritonavir (LPV/RTV) in combination with tenofovir (TFV) and one NRTI in patients who have experienced virologic failure to multiple HAART regimens: 16-week results from BMS AI424-045. 2nd IAS Conference, Paris 2003. Abstract 118.