Drug interaction studies with approved drugs
Marta Boffito, HIV-druginterations.org
The following summaries are selected from a longer report, available with hyperlinks to the conference abstracts, from www.hiv-druginteractions.org.
Lopinavir/r reduces gemfibrozil levels
The effect of lopinavir/ritonavir (400/100 mg twice daily) on a single dose of the lipid lowering drug gemfibrozil (600 mg) was studied in 15 HIV- subjects.
Coadministration decreased gemfibrozil AUC by 41% and Cmax by 33%. There was no effect on half-life and clearance increased by 69%. The mechanism for this interaction is unclear, but it would appear that lopinavir/ritonavir reduced absorption of gemfibrozil.
Ref: Busse K, et al. Lopinavir/ritonavir significantly decreases gemfibrozil plasma concentrations in healthy volunteers. 48th ICAAC, 25-28 October 2008. Washington. Abstract A-959.
Darunavir/r and raltegravir: rash seen in HIV-negative patients
Coadministration of raltegravir (400 mg twice daily) and darunavir/ritonavir (600/100 mg twice daily) was studied in 18 subjects.
Contrary to clinical experience in HIV+ patients, eight subjects presented with a clinical adverse experience of rash, which progressed from mild/moderate to serious in one subject. Only six subjects completed the study. Based on these limited pharmacokinetic data, raltegravir AUC decreased by 29%, Cmax decreased by 33% and Cmin increased by 38% (the latter parameter showing very marked variability). Darunavir pharmacokinetics were similar to historical data.
Ref: Anderson MS, et al. Pharmacokinetic evaluation of darunavir/ritonavir and raltegravir in healthy subjects. 48th ICAAC, 25-28 October 2008. Washington. Abstract A-962.
Raltegravir may reduce efficacy of omeprazole
The effect of omeprazole (20 mg single dose) on the pharmacokinetics of raltegravir (400 mg once daily) was studied in HIV- subjects.
Coadministration increased raltegravir AUC, Cmax and Cmin by 3.12-fold, 4.15-fold and 1.46-fold, respectively. There was no substantial effect on raltegravir Tmax or half-life. The mechanism for this interaction is likely a consequence of increased bioavailability secondary to increased gastric pH.
Due to the high prevalence of achlorhydria in HIV+ subjects, the effect of omeprazole on raltegravir in the target population may be diminished relative to healthy subjects.
Ref: Iwamoto M, et al. Omeprazole increases plasma levels of raltegravir in healthy subjects. 48th ICAAC, 25-28 October 2008. Washington. Abstract A-963.
Interaction between raltegravir and rifampicin requires caution
Coadministration of raltegravir and rifampicin has been shown to decrease raltegravir trough concentration by ~60%. This study looked at whether increasing raltegravir to 800 mg twice daily when given with rifampicin (600 mg once daily) could overcome this effect.
When compared to raltegravir alone (400 mg twice daily), coadministration of the higher dose with rifampicin decreased raltegravir trough concentrations by 53%, but increased AUC and Cmax by 27% and 62%, respectively. Therefore, doubling the dose of raltegravir does not overcome the effect of rifampicin on raltegravir trough concentrations.
Although trough concentrations have not been shown to correlate with efficacy, caution should be exercised when raltegravir is given with rifampicin.
Ref: Brainaird DM, et al. Doubling the dose of raltegravir does not increase trough levels in the presence of rifampin. 48th ICAAC, 25-28 October 2008. Washington. Abstract A-964.
Quinine requires dose adjustment when used with ritonavir
This study looked at the effect of ritonavir (200 mg twice daily) on pharmacokinetics of quinine (600 mg single dose) in 10 HIV- subjects. Ritonavir increased both the AUC and Cmax of quinine by ~4-fold and increased half-life by 20%. The metabolism of quinine to its major metabolite, 3-hydroxyquinine, was markedly inhibited. Quinine had no significant effect on ritonavir pharmacokinetics.
Dose adjustment of quinine is likely to be necessary when coadministered with ritonavir.
Ref: Soyinka JO, et al. Pharmacokinetic interaction between ritonavir and quinine. 48th ICAAC, 25-28 October 2008. Washington. Abstract A-965.
Tipranavir/r interactions with buprenorphine/naloxone
The effect of tipranavir/ritonavir (500/200 mg twice daily) on the pharmacokinetics of buprenorphine and naloxone was assessed in HIV- subjects stable on buprenorphine/naloxone therapy. Coadministration had no effect (<6%) on buprenorphine AUC or Cmin, but decreased Cmax by 14%. The AUC, Cmax and Cmin of norbuprenorphine (the major metabolite) decreased by ~80%. The AUC, Cmax and Cmin of naloxone decreased by 44%, 36% and 20%, respectively. Despite these changes, there was no evidence of opioid withdrawal and no need to modify the dose of buprenorphine.
When compared to historical data, there was no effect (<6%) on tipranavir Cmax, but AUC and Cmin decreased by 26% and 39%, respectively. Ritonavir Cmin was similar to historical data, but AUC decreased by 35% and Cmax decreased by 40-50%. The mechanism by which buprenorphine/naloxone affects tipranavir and ritonavir is unclear.
Caution should be used if coadministered as tipranavir may be less effective due to decreased concentrations.
Ref: Bruce R, et al. Pharmacokinetic interactions between buprenorphine/naloxone and tipranavir/ritonavir in HIV-negative subjects chronically receiving buprenorphine/naloxone. 48th ICAAC, 25-28 October 2008. Washington. Abstract A-967a.
Dose reduction and monitoring needed when rifabutin levels given with darunavir/r
Coadministration of darunavir/ritonavir (600/100 mg twice daily) and rifabutin (300 mg once daily alone or 150 mg every other day when coadministered) was studied in HIV- subjects. Rifabutin AUC was comparable when given at the standard dose alone or at the reduced dose in combination. The AUC of 25-O-desacetyl rifabutin increased by 881% when coadministered with darunavir/ritonavir. Coadministration increased the AUC of darunavir by 57% and increased ritonavir AUC by 66%.
A dose reduction of rifabutin by 75% (i.e., 150 mg every other day) and increased monitoring for rifabutin-related adverse events is warranted when coadministered with darunavir/ritonavir.
Ref: Sekar VJ, et al. Pharmacokinetic interaction between darunavir in combination with low-dose ritonavir and rifabutin. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-4053.
Maraviroc reduces raltegravir levels but no dose adjustment needed
The pharmacokinetics of raltegravir (400 mg twice daily) and maraviroc (300 mg twice daily) was assessed in 17 HIV- subjects. Coadministration decreased maraviroc AUC, Cmax and Cmin by 14%, 21% and 10%, respectively. Raltegravir AUC, Cmax and Cmin were decreased by 37%, 33% and 28%, respectively. In all subjects the maraviroc average concentration (AUC/12) was greater than 100 ng/ml, the apparent threshold for increased risk of virologic failure.
The 28% decrease in raltegravir Cmin was not considered clinically relevant (only decreases above 60% are considered clinically relevant) and so no dose adjustments are recommended.
Andrews E, et al. A pharmacokinetic study to evaluate an interaction between maraviroc and raltegravir in healthy adults. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-4055.