New drug interaction summary tables: maraviroc, integrase inhibitors, etravirine, hormonal contraceptives

1 December 2007. Related: PK and drug interactions.

HIV-druginteractions.org has compiled 3 new summary tables relating to interactions with the latest and most developed pipeline drugs and a similar chart for oral contraceptives.

Maraviroc

Maraviroc, the CCR5 antagonist that blocks the entry of HIV-1 into cells, is now licensed in Europe and the USA as Celsentri and Selzentry, respectively.

The Summary of Product Characteristics and the Prescribing Information contain details of drug interactions with maraviroc. Some of the dosing recommendations in these documents differ from those submitted to the FDA and on which the June 2007 chart was based.

Two key differences are that a dose increase of maraviroc to 600 mg is no longer recommended when coadministered with rifabutin or nevirapine; instead maraviroc is to be dosed at 300 mg twice daily with either of these drugs. Dosing recommendations are now given for coadministration of maraviroc and efavirenz with the boosted PIs atazanavir, darunavir and fosamprenavir (in addition to saquinavir and lopinavir which appeared previously). The combinations of St John’s wort and maraviroc and rifampicin + efavirenz and maraviroc are not recommended for coadministration.

A new chart (October 2007) of drug interactions has been prepared and is available in pdf format via the link below. Links to the Summary of Product Characteristics and Prescribing Information can be found in the Links/antiretrovirals section of this website.

http://www.hiv-druginteractions.org/new/Uploaded_Attachment/52_Maraviroc%20Oct07.pdf 340 Kb

Integrase inhibitors: raltegravir and elvitegravir

The first of the integrase inhibitors, raltegravir, has received accelerated approval by the U.S. Food and Drug Administration (FDA). Interaction Charts have been produced for raltegravir and a second integrase inhibitor, elvitegravir, which is currently in Phase III trials.

Raltegravir (Isentress®, MK-0518) has been approved for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes and does not inhibit (IC50 >100 µM) CYP3A or induce CYP3A4. Further in vitro studies have shown it not to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6. Similarly, raltegravir is not an inhibitor (IC50 >50 µM) of the UDP glucuronosyltransferases UGT1A1 or UGT2B7, and does not inhibit P-glycoprotein-mediated transport. Based on in vivo and in vitro data, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway. Caution should be used when coadministering raltegravir with strong inducers of UGT1A1, especially in patients with different UGT1A1 genotypes as plasma concentrations of raltegravir may be reduced.

Elvitegravir is being developed for once daily dosing with low dose ritonavir. Ritonavir doses as low as 20 mg have been shown to substantially increase elvitegravir concentrations, but the coadministered dose is likely to be higher. Interactions with elvitegravir are likely to be driven by the co-dosing with ritonavir.

When elvitegravir is added to a boosted protease inhibitor regimen, the ritonavir dose is that specified by the protease inhibitor (e.g., if given with tipranavir/ritonavir, the ritonavir dose would be 200 mg twice daily). Thus, plasma concentrations of elvitegravir may be affected by the “additional” ritonavir doses.

http://www.hiv-druginteractions.org/new/Uploaded_Attachment/55_Integrase_Oct07.pdf 500 Kb

Etravirine

A chart of interactions with etravirine (TMC125) is now available.

Etravirine is a next generation NNRTI that shows high intrinsic activity against both wild-type HIV-1 and strains with resistance-inducing mutations. Etravirine is metabolised by CYP3A4, CYP2C19 and UDP-glucuronyl transferase, and has been shown to induce CYP3A and inhibit CYP2C19 in vivo.

A substantial improvement in the oral bioavailability was achieved by means of reformulation, with the licensed phase III formulation (F060) showing a 9-fold increase in AUC when compared to a phase II formulation (TF035). As a result of the reformulation, several phase II formulations (TF002, TF034, TF035) and doses have been used in interaction studies as well as the phase III formulation (F060, 200 mg twice daily). However, interactions are expected to be independent of formulation (Kakuda T et al, 8th congress on HIV Therapy, November 2006, Glasgow. Abstract PL5.2).

An interaction chart has been produced to summarise all the studies performed to date – this is available in PDF format via the link below. Interactions between etravirine and the other anti-HIV drugs (i.e. as rows) have been added to the interactive charts. Interactions between etravirine and other drugs (i.e. a column) will be added once etravirine is licensed in Europe and/or the US.

http://www.hiv-druginteractions.org/new/Uploaded_Attachment/51_Etravirine_Chart.pdf (344 Kb)

Hormonal contraceptives

Information on hormonal contraceptives is listed on the charts in the steroid section under ethinylestradiol and progesterone/progestogens. The information available is predominantly for daily oral contraceptives, but other routes and frequencies of administration are now available.

The site has produced a chart which details the various forms of hormonal contraception and, for the newer forms, any interactions or contraceptive failures that have been reported. A link to this chart has been added to the relevant interaction descriptions in the interactive charts.

http://www.hiv-druginteractions.org/new/Uploaded_Attachment/57_Hormonal%20Contraceptives.pdf (304 Kb)