Summary of drug-drug interaction studies

15 June 2005. Related: Conference reports, PK and drug interactions, PK Workshop 6th 2005.

Simon Collins, HIV i-Base

There were over two-dozen drug-drug interaction studies presented at the meeting. This included good news with many of these studies reporting no clinically significant reactions, as well as newly identified interactions with clinical significance. The most clinically important interactions requiring dose monitoring or modification are summarised below.

Famotidine reduces atazanavir: dose increase and separated dosing required

Last year BMS issued a safety letter warning of the interaction between atazanavir and proton pump inhibitors and H2 receptor agonists after a study showed that omeprazole reduced atazanavir uptake. Atazanavir absorption is reduced when gastric pH is increased.

Several proposed dosing strategies were investigated with famotidine (40mg BID), which reduced unboosted atazanavir AUC and Cmin by a significant 40%. [1]

Of these, 400mg atazanavir/100mg ritonavir, taken 10 hours after, and two hour before famotidine, in order to produced comparable drug levels to the 300/100mf ATZ/RTV levels when famotidine is not used.

The study also looked at whether cola could help maintain stomach acidity but no effect was seen. A caveat to this study is that is was in HIV-negative volunteers who stomach pH can differ from that of HIV-positive individuals.

COMMENT

Although TDM datasets have reported that some patients on ATV + PPIs have adequate levels, there definitely is an interaction (and dissolution/solubility studies confirm this is a problem).

Management recommendations include:

i) For patients already on ATV + PPI with VL<50 copies/mL: assess need for any acid-modifying drug. If necessary use TDM, and then if low levels are shown, consider switching to H2RA or increasing ATV dose to 400/100mg/day.

ii) For patients already on ATV + PPI who have detectable HIV viraemia: manage as per BHIVA guidelines recommendations for treatment failure.

iii) For patients on ATV who need acid-modifying drugs: avoid PPIs, it may be possible to use H2RA.

An additional area for debate is:

iv) For patients on ATV who need 1-2 weeks of helicobacter eradication therapy (these are based on PPI-containing regimens)- to switch to an alternative PI (‘acid-robust’ PIs are LPV/r or SQV/r) for at least 3 weeks. The pH modulation of PPIs lasts for some time after the drug has been discontinued.

Lopinavir/r reduces lamotrigine: dose increase required

Lamotrigine is an anti-epileptic drug that is also used to treat neuropathy. Van der Lee and colleagues reported that lamotrigine levels were significantly reduced in a group of 24 HIV-negative volunteers after lopinavir/r was added to lamotrigine at steady state. [2]

Progressive dose increments in the study found that a 50mg dose of lamotrigine had to be increased to 200mg in order to maintain pre-lopinavir/r levels.

Lamotrigine did not affect levels of lopinavir/r.

Fosamprenavir reduces SSRI inhibitor paroxetine: titration of paroxetine required

In a randomised cross-over study in 26 HIV-negative volunteers, half received 20mg paroxetine QD for 10 days, followed by a washout period of 16 days and then paroxetine + fosamprenavir/ritonavir 700/100 BID; and half received the two regimens in reversed order. [3]

Paroxetine levels were reduced by around 60%. These results were surprising as ritonavir was expected to inhibit metabolism of paroxetine, and it is unclear whether reduced levels were related to decreased absorption or increased metabolism. The dosing recommendation was to titrate paroxetine levels in patients using ritonavir-boosted fosamprenavir.

Ritonavir increases prednisolone levels

Use of corticosteroids are indicated in management of some HIV-related conditions, but use is minimised due to an increasing concern about bone-disease relating to HIV, and which is a side effects of corticosteroid use.

This study looked at the levels of prednisolone, the primary metabolite of prednisone, after taking single oral doses of 20mg prednisone at baseline, and again after 4 days and 14 days of ritonavir dosed at 200mg BID in nine HIV-negative individuals. [4]

Ritonavir was associated with increased prednisolone AUC and reduced clearance. Geometric mean ratios (90%CI) compared to baseline, at 4 and 14 days respectively, was 1.41 (1.08-1.74) and 1.30 (1.09-1.49) for AUC and 0.71 (0.57-0.93) and 0.77 (0.67-0.92) for oral clearance. All changes were highly statistically significant. Cmax levels were not altered and prednisolone PK didn’t differ further between day 4 and 14.

Tacrolimus clearance significant reduced in HIV-positive patients restarting HAART with nelfinavir- or lopinavir/r-based combinations: dose reduction essential

This study of ten HIV-positive French patients who had received liver transplant related to HCV-related end-stage liver disease, was designed to looked at interactions between immune suppressive medication and HAART. [5]

PK parameters of tacrolimus were calculated when liver function normalised (approximately 10 days post transplant) and ten days after reintroduction of HAART (two nucleosides, plus nelfinavir (n=2), lopinavir/r (n=3) or efavirenz (n=2); one patient used a triple nucleoside combination). Doses of tacrolimus were individually adjusted to maintain target range of 8-20 ng/mL from day 1 to week 6; and of 5-15 ng/mL from week 6 onwards.

Tacrolimus oral clearance ranged form 5.3-19.4 l/h during the first 6 weeks and then dropped dramatically in to 0.5-0.9 l/h with lopinavir/r and to 1.1-3.0 l/h with nelfinavir. Tacrolimus half-life increased up to 234 hours and dosing was reduced to once every 5-10 days depending on individual patient levels.

Comment

This is the first systemic study evaluating the important interaction between post-transplant immune suppressant therapy and HAART. Previous case reports have highlighted the interactions between PIs and tacrolimus. [6]

This is an important interaction for a number of reasons. Firstly, adequate levels of immune suppression need to be maintained in order to prevent acute graft rejection and failure. Additionally, tacrolimus toxicity is associated with complications that include hyperglycaemia and renal failure.

As this report highlights there may be a huge individual variation in the doses of tacrolimus required with PIs. Physicians need to adjust individual levels with frequent monitoring. Other potential interactions are possible between sarolimus and PIs and NNRTIs (CYP3A4 metabolism); and mycophenalate (MMF) and nucleoside analogues (MMF may increase intracellular levels of abacavir, ddI and tenofovir). As we gain in experience with solid-organ transplantation more data will emerge.

References:

Unless stated otherwise, all references are to the Final Programme and Abstracts from the 6th International Workshop on Clinical Pharmacology of HIV Therapy, 28-30 April 2005. Quebec.

Abstracts, posters and some presentations are available at:
http://www.hivpresentation.com

1. Agarwala S, Child M, Grasela D et al. Pharmacokinetic effect of famotidine on atazanavir with and without ritonavir in healthy subjects. Abstract 11.
2. Van der Lee MJ, Dawood L, Burger D et al. The effect of lopinavir/ritonavir on the pharmacokinetics of lamotrigine in healthy subjects. Abstract 12.
3. Blenke A, Van der Lee M, Burger D et al. Combined use of paroxetine and fosamprenavir/ritonavir: a [pharmacokinetic study in healthy volunteers. Abstract 13.
4. Penzak S, Fomentini E, Kovacs J et al. Low-dose ritonavir significantly increases prednisolone exposure in HIV-negative volunteers receiving prednisone. Abstract 14.
5. Faivre L, Teicher H, Taburet AM et al. Potent drug interactions between tacrolimus and lopinavir/ritonavir thereapy in HIV-infected liver transplant recipients. Abstract 26. Poster 2.24.
6. Jain A, et al. Liver transplantation 2003; 9: 954-960.